bluuebunny/crossref_metadata_2025 huggingface dataset:
Restoring Adenine Nucleotides in a Brain Slice Model of Cerebral Reperfusion
Authors: Newman George C. , Hospod Frank E. , Trowbridge Sean D. , Motwani Shilpa , Liu Yan
Published: November 2003

Tissue adenine nucleotides are depleted during cerebral ischemia, impeding recovery after reperfusion. Although prior studies have attempted to prevent the initial loss of adenylates, the present study tests the hypothesis that stimulating synthesis of adenine nucleotides, through either adenosine kinase or adenine phosphoribosyltransferase, would result in significant cerebroprotection. To study the effects on neurons and glia directly while avoiding the influence of the cerebral vasculature, hippocampal brain slices were used for the model of transient ischemia with reperfusion. The standard brain slice insult of brief exposure to anoxia with aglycemia was modified based on studies which showed that a 30-minute exposure to air with 1 mmol/L glucose produced a stable, moderate reduction in ATP during the insult and that, 2 hours after return to normal conditions, there was moderate depletion of tissue adenine nucleotides and histologic injury. Treatments with 1 mmol/L adenosine, AMP, or adenine were equivalent in partially re-storing adenine nucleotides. Despite this, only adenosine af-forded histologic protection, suggesting a protective role for adenosine receptors. There also was evidence for metabolic cycling among adenine nucleotides, nucleosides, and purines. Adenosine may exert direct cerebroprotective effects on neural tissue as well as indirect effects through the cerebral vasculature.
Diffusion-, T2-, and Perfusion-Weighted Nuclear Magnetic Resonance Imaging of Middle Cerebral Artery Embolic Stroke and Recombinant Tissue Plasminogen Activator Intervention in the Rat
Authors: Jiang Quan , Zhang Rui Lan , Zhang Zheng Gang , Ewing James R. , Divine George W. , Chopp Michael
Published: November 2003

Thrombolysis of embolic stroke in the rat was measured using diffusion (DWI)-, T2 (T2WI)-, and perfusion (PWI)-weighted magnetic resonance imaging (MRI). An embolus was placed at the origin of the middle cerebral artery (MCA) by injection of an autologous single blood clot via an intraluminal catheter placed in the intracranial segment of internal carotid artery. Rats were treated with a recombinant tissue plasminogen activator (rt-PA) 1 hour after embolization (n = 9) or were not treated (n = 15). Diffusion-weighted imaging, T2WI, and PWI were performed before, during, and after embolization from 1 hour to 7 days. After embolization in both rt-PA-treated and control animals, the apparent diffusion coefficient of water (ADCw) and cerebral blood flow (CBF) in the ischemic region significantly declined from the preischemic control values ( P < 0.001). However, mean CBF and ADCw in the rt-PA—treated group was elevated early after administration of rt-PA compared with the untreated control group, and significant differences between the two groups were detected in CBF (24 hours after embolization, P < 0.05) and ADCw (3, 4, and 24 hours after embolization, P < 0.05). T2 values maximized at 24 (control group, P < 0.001) or 48 hours (treated group, P < 0.01) after embolization. The increase in T2 in the control group was significantly higher at 24 hours and 168 hours than in the rt-PA—treated group ( P < 0.05). Significant correlations ( r ≥ 0.80, P < 0.05) were found between lesion volume measured 1 week after embolization and CBF and ADCw obtained 1 hour after injection of rt-PA. Within a coronal section of brain, MRI cluster analysis, which combines ADCw and T2 data maps, indicated a significant reduction ( P < 0.05) in the lesion 24 hours after thrombolysis compared with nontreated animals. These data demonstrate that the values for CBF and ADCw obtained 1 hour after injection of rt-PA correlate with histologic outcome in the tissue, and that the beneficial effect of thrombolysis of an intracranial embolus by means of rt-PA is reflected in an increase of CBF and ADCw, a reduction in the increase of T2, and a reduction of the ischemic lesion size measured using MRI cluster analysis.
Low Extracellular Dopamine Levels Are Maintained in the Anoxic Turtle (Trachemys scripta) Striatum
Authors: Milton Sarah L. , Lutz Peter L.
Published: November 2003

The uncontrolled increase of extracellular dopamine (DA) has been implicated in the pathogenesis of hypoxic/ischemic damage in the mammalian brain. But unlike the harmful release of excitatory neurotransmitters such as glutamate and aspartate, which occurs on brain depolarization, excessive extracellular DA levels occur even with mild hypoxia in the mammalian brain. The purpose of this study was to determine whether hypoxia/anoxia provokes a similar increase in the anoxic tolerant turtle brain. Extracellular DA was measured in the striatum of the turtle using microdialysis followed by high-performance liquid chromatography analysis. Results show that extracellular DA was held to normoxic levels over 4 hours of anoxia. Treatment with the specific DA transport blocker GBR 12909 during anoxia resulted in a significant increase in DA to 236% over basal levels. The ability to maintain low striatal extracellular DA may be an important adaptation for anoxic survival in the turtle brain; a contributing factor is the continued functioning of DA uptake mechanisms during anoxia.
Reduction of Ischemic Damage by Application of Vascular Endothelial Growth Factor in Rat Brain after Transient Ischemia
Authors: Hayashi Takeshi , Abe Koji , Itoyama Yasuto
Published: November 2003

Vascular endothelial growth factor (VEGF) is a secreted polypeptide and plays a pivotal role in angiogenesis in vivo. However, it also increases vascular permeability, and might exacerbate ischemic brain edema. The effect of this factor on the brain after transient ischemia was investigated in terms of infarct volume and edema formation, as well as cellular injury. After 90 minutes of transient middle cerebral artery occlusion, VEGF (1.0 ng/μL, 9 μL) was topically applied on the surface of the reperfused rat brain. A significant reduction of infarct volume was found in animals with VEGF application ( P < 0.001) at 24 hours of reperfusion as compared with cases with vehicle treatment. Brain edema was significantly reduced in VEGF-treated animals ( P = 0.01), and furthermore, extravasation of Evans blue was also decreased in those animals ( P < 0.01). Terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling and immunohistochemical analysis for 70-kDa heat shock protein showed an amelioration of the stainings at 24 and 48 hours after reperfusion with VEGF treatment, which indicated reduction of neuronal damage. These results indicate that treatment with topical VEGF application significantly reduces ischemic brain damage, such as infarct volume, edema formation, and extravasation of Evans blue, and that the reductions were associated with that of neuronal injury.
Elucidating Dynamic Brain Interactions with Across-Subjects Correlational Analyses of Positron Emission Tomographic Data: The Functional Connectivity of the Amygdala and Orbitofrontal Cortex during Olfactory Tasks
Authors: Zald David H. , Donndelinger Michael J. , Pardo José V.
Published: November 2003

Covariance analyses of positron emission tomography (PET) data are used increasingly to elucidate the functional connectivity between brain regions during different cognitive tasks. Functional connectivity may be estimated by examining the covariance between regions over time or across subjects. In functional brain-mapping studies, across-subjects covariance matrices derived from within-task (nonsubtracted) and between-task (subtracted) data characterize different, complementary aspects of functional interactions. The authors study amygdala-orbitofrontal interactions during three task conditions (aversive olfaction, odor detection, and resting with eyes closed) to illustrate the strengths and limitations of across-subjects covariance analyses based on subtracted and nonsubtracted data. This example underscores the dynamic nature of connectivity between the amygdalae and orbitofrontal cortices and highlights the importance of including data from resting conditions in covariance analyses.
Evaluation of Focal Cerebral Ischemia in Rats by Magnetic Resonance Imaging and Immunohistochemical Analyses
Authors: Ishii Hisanari , Arai Toshiyuki , Morikawa Shigehiro , Inubushi Toshiro , Tooyama Ikuo , Kimura Hiroshi , Mori Kenjiro
Published: November 2003

Correlation of focal ischemia-induced brain damage evidenced by magnetic resonance imaging (MRI) and by staining with microtubule-associated protein 2 (MAP2) was studied in rats. Ischemia was produced by transient occlusion of the middle cerebral artery (MCAO). The damage was assessed at 6 to 8 hours after MCAO and 1 week later. The area of damage assessed by MRI agreed with that by MAP2 staining at 6 to 8 hours after MCAO, which was smaller ( P < 0.001) than that defined by MAP2 staining 1 week after MCAO. Glial staining indicated that glial infiltration affected the signal intensity of MRI in the area of damage.
Magnetic Resonance Imaging Assessment of Cerebral Hemodynamics during Spreading Depression in Rats
Authors: de Crespigny Alexander , Röther Joachim , van Bruggen Nick , Beaulieu Christian , Moseley Michael E.
Published: November 2003

High-speed magnetic resonance imaging was used to perform simultaneous measurements of relative cerebral blood volume (rCBV) and water diffusion changes during spreading depression (SD) induced by cortical potassium chloride application. Rats were fitted epidurally with a rubber chamber. Potassium chloride was perfused through the chamber until SD was indicated by a negative direct current (DC) potential shift. Magnetic resonance imaging scans used echo planar diffusion and T2-weighted images. Iron dextran was injected as a blood pool contrast agent to make subsequent changes in T2 (or T2*) directly proportional to changes in CBV. Multislice maps of apparent diffusion coefficient (ADC) and rCBV were generated with 6- to 16-second time resolution, which revealed transient ADC and rCBV changes propagating over the cortex after potassium chloride application. Transient ADC declines appeared simultaneously with the DC shift, whereas rCBV increase followed with a delay of 16.4 ± 14.9 seconds. Prolonged rCBV decrease was observed after the initial increase during the SD in half of the animals. The delayed rCBV response after the ADC change supports the observation of increased energy demand because of repolarization. Simultaneous DC potential recording and ADC measurements in corresponding sites of the cortex indicate that transient ADC decreases during SD reflect water shifts associated with cell depolarization.
Stimulation of β2-Adrenoceptors Inhibits Apoptosis in Rat Brain after Transient Forebrain Ischemia
Authors: Zhu Yuan , Culmsee Carsten , Semkova Irina , Krieglstein Josef
Published: November 2003

We have previously demonstrated that the neuroprotective effect of the β2-adrenoceptor agonist clenbuterol in vitro and in vivo was most likely mediated by an increased nerve growth factor (NGF) expression. In the present study, we examined whether clenbuterol was capable of inhibiting apoptosis caused by ischemia. Transient forebrain ischemia was performed in male Wistar rats (300 to 350 g) by clamping both common carotid arteries and reducing the blood pressure to 40 mm Hg for 10 minutes. Clenbuterol(0.1, 0.5, and 1.0 mg/kg intraperitoneally) was administered 3 hours before ischemia or immediately after ischemia. The brains were removed for histologic evaluation 7 days after ischemia. The time course of DNA fragmentation was determined 1, 2, 3 and 4 days after ischemia. Staining with terminal deoxynucleotidyl transferase(TdT)-mediated dUTP nick end-labeling (TUNEL) was used for further analysis of DNA fragments in situ 3 days after ischemia. The NGF protein was assayed by enzyme-linked immunosorbent assay. Ten-minute forebrain ischemia damaged 80% to 90% of the neurons in the hippocampal CA1 region evaluated 7 days after ischemia. Pretreatment with clenbuterol (0.5 and 1.0 mg/kg) reduced the neuronal damage by 18.1% ( P< 0.01) and 13.1% ( P < 0.05), respectively. The neuroprotective effect also was found when clenbuterol (0.5 mg/kg) was administered immediately after ischemia ( P < 0.05). The DNA laddering appeared in striatum 1 day and in hippocampus 2 days after ischemia and peaked on the third day in both regions. The DNA laddering was nearly abolished in the hippocampus and partially blocked in striatum and cortex by 0.5 mg/kg clenbuterol. These results were confirmed by TUNEL staining. Clenbuterol (0.5 mg/kg intraperitoneally) elevated the NGF protein level by 33% ( P < 0.05) in the hippocampus and 41% ( P < 0.05) in the cortex 6 hours after ischemia. Three days after ischemia, the NGF levels in these regions were no longer different between the clenbuterol-treated and control groups. This study clearly demonstrates that clenbuterol possesses a neuroprotective activity and a marked capacity to inhibit DNA degradation after global ischemia. The results suggest that clenbuterol increases NGF expression during the first hours after global ischemia and thereby protects neurons against apoptotic damage.
Evaluation of a Motor Deficit after Chronic Focal Cerebral Ischemia in Rats
Authors: Yonemori Fumihiko , Yamaguchi Tohru , Yamada Hideki , Tamura Akira
Published: November 2003

It is well known that hemiplegia is frequently observed in cerebral ischemia. It is important for the pathophysiologic study and development of drug therapies to establish a precise method investigating impairment of motor function with animal models. To develop a quantitative and objective method for evaluating impairment of motor function, we examined an inclined plane test after chronic focal cerebral ischemia in the rat. Standard scoring of neurologic deficits has limitations, including problems with quantification and objectivity. The purpose of this study was to establish a novel method for evaluating impairment of motor function in middle cerebral artery (MCA) occluded rats. The left MCA was permanently occluded at a proximal site, and sensorimotor performance was evaluated at the fifth day and every week for 11 weeks thereafter. The ability to maintain body position on an inclined plane was measured when rats were placed on a stainless steel slope in left-headed, right-headed, and up-headed positions. Neurologic examination based on hemiparesis and abnormal posture was also performed. After all behavioral examinations were completed, the degree of shrinkage of the left hemisphere to the contralateral was measured. The ability of MCA-occluded rats to maintain position on an inclined plane in the left-headed position was significantly restricted when compared with that of sham-operated rats throughout the test period (maximum angle of 37° versus 45°, respectively). Minimal natural recovery was observed for all position measurements. MCA-occluded rats showed a significantly higher neurologic score with natural recovery. The ability to maintain position on an inclined plane after MCA occlusion (MCAO) was significantly correlated with the degree of the shrinkage of the ischemic hemisphere and neurologic score. The angle for the left-headed position was most strongly correlated with ipsilateral shrinkage. In the present study, long-lasting impairment of motor function was detected in rats with MCAO, which correlated with the shrinkage of the ischemic hemisphere. Furthermore, a difference in performance depending on body position (left-headed versus right-headed) was also detected. The left-headed position was found to be most sensitive for evaluating this model. The inclined plane test is a quantitative, objective, and sensitive method for evaluating motor deficits after chronic focal cerebral ischemia in rats, and this method may be useful to investigate changes in motor function in hemiplegia.
Muscarinic Cholinergic Receptor Measurements with [18F]FP-TZTP: Control and Competition Studies
Authors: Carson Richard E. , Kiesewetter Dale O. , Jagoda Elaine , Der Margaret G. , Herscovitch Peter , Eckelman William C.
Published: November 2003

[18F]Fluoropropyl-TZTP (FP-TZTP) is a subtype-selective muscarinic cholinergic ligand with potential suitability for studying Alzheimer's disease. Positron emission tomography studies in isofluorane-anesthetized rhesus monkeys were performed to assess the in vivo behavior of this radiotracer. First, control studies (n = 11) were performed to characterize the tracer kinetics and to choose an appropriate model using a metabolite-corrected arterial input function. Second, preblocking studies (n = 4) with unlabeled FP-TZTP were used to measure nonspecific binding. Third, the sensitivity of [18F]FP-TZTP binding to changes in brain acetylcholine (ACh) was assessed by administering physostigmine, an acetylcholinesterase (AChE) inhibitor, by intravenous infusion (100 to 200 μg·kg−1·h−1) beginning 30 minutes before tracer injection (n = 7). Tracer uptake in the brain was rapid with K1 values of 0.4 to 0.6 mL·min−1·mL−1 in gray matter. A model with one tissue compartment was chosen because reliable parameter estimates could not be obtained with a more complex model. Volume of distribution ( V) values, determined from functional images created by pixel-by-pixel fitting, were very similar in cortical regions, basal ganglia, and thalamus, but significantly lower ( P < 0.01) in the cerebellum, consistent with the distribution of M2 cholinergic receptors. Preblocking studies with unlabeled FP-TZTP reduced V by 60% to 70% in cortical and subcortical regions. Physostigmine produced a 35% reduction in cortical specific binding ( P < 0.05), consistent with increased ACh competition. The reduction in basal ganglia (12%) was significantly smaller ( P < 0.05), consistent with its markedly higher AChE activity. These studies indicate that [18F]FP-TZTP should be useful for the in vivo measurement of muscarinic receptors with positron emission tomography.
Collateral Inhibition of Transcallosal Activity Facilitates Functional Brain Asymmetry
Authors: Karbe Hans , Herholz Karl , Halber Marco , Heiss Wolf-Dieter
Published: November 2003

The corpus callosum is the largest connection between the functionally asymmetric cerebral hemispheres. The objective of this study was to measure functional activity of callosal fiber tracts during speech processing. We analyzed the regional glucose metabolism of the corpus callosum and of speech-relevant cortical areas in 10 normal individuals at rest and during word repetition. We used three-dimensionally registered magnetic resonance imaging to visualize the individual brain morphology and high-resolution positron emission tomography for metabolic measurements. The task-induced metabolic changes of the callosal midbody and isthmus had a significant negative correlation with key regions of language processing in the left inferior frontal cortex (Brodmann's area 44) and in the right superior temporal cortex (Brodmann's area 22) (e.g., correlation of metabolic changes in the surface aspects of the right Brodmann's area 22 and the callosal midbody/isthmus: r = −0.91, P < 0.001). The study indicates that language processing in asymmetrically organized cortical areas inhibits the reciprocal transcallosal information exchange in favor of the lateralized mental operation. Our data agree with anatomic, electrophysiologic, and pharmacologic experiments that point to the important role of collateral inhibition for the transcallosal information exchange.
Use of Suppression Subtractive Hybridization Strategy for Discovery of Increased Tissue Inhibitor of Matrix Metalloproteinase-1 Gene Expression in Brain Ischemic Tolerance
Authors: Wang Xinkang , Yaish-Ohad Shoshanit , Li Xiang , Barone Frank C. , Feuerstein Giora Z.
Published: November 2003

Brief occlusion of the middle cerebral artery (i.e., ischemic preconditioning; PC) induces significant brain protection to subsequent severe ischemic events. In an effort to discover genes responsible for ischemic tolerance, we have applied a new technique, suppression subtractive hybridization (SSH), to identify genes that are upregulated by PC. Using this SSH approach, a cDNA that encodes tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) was identified. Time course studies using Northern analysis revealed that TIMP-1 mRNA was significantly elevated at 24 hours (3.3-fold over controls, P < 0.05, n = 5) and 2 days (4.3-fold increase, P < 0.01) after PC, corresponding to the onset of significant ischemic tolerance. Our data not only demonstrate the utility of this new polymerase chain reaction—based SSH strategy for discovery of genes differentially expressed in PC, but also suggest a potential role of TIMP-1 in PC-induced ischemic tolerance.
Moderate Hypothermia Reduces Hypotensive, But Not Hypercapnic Vasodilation of Pial Arterioles in Rats
Authors: Irikura Katsumi , Miyasaka Yoshio , Nagai Shigeki , Yuzawa Izumi , Morii Seiji , Fujii Kiyotaka
Published: November 2003

Two types of acid—base strategies are available for the blood gas management of patients during hypothermia: alpha-stat and pH-stat management However, the more suitable strategy for therapeutic hypothermia is unclear. We studied the effects of hypothermia (30°C) and acid—base management on reactivity to hypercapnia and hypotension in rat pial arterioles, using a closed cranial window, The baseline diameter during hypothermia decreased in the alpha-stat (Paco2 was maintained at 35 mm Hg when measured at 37°C, n = 8), but not in the pH-stat (Paco2 was maintained at 35 mm Hg when corrected to the animal's actual temperature, n = 7), Vasodilation induced by hypotension was significantly reduced in hypothermic groups compared with the normothermic group (n = 7), whereas responses to hypercapnia were preserved, Moreover, hypotensive vasodilation was more attenuated in the pH-stat, than the alpha-stat, management These findings show that moderate hypothermia and acid-base management alter cerebrovascular autoregulation.
An Adiabatic Approximation to the Tissue Homogeneity Model for Water Exchange in the Brain: II. Experimental Validation
Authors: Lawrence Keith S. St. , Lee Ting-Yim
Published: November 2003

A frequently reported limitation to using water as a tracer for measuring CBF has been the dependence of the CBF estimate on the experimental time (referred to as the failing flow phenomenon, FFP), To eliminate the FFP, we have developed the adiabatic solution of the tissue homogeneity model to replace the solution of the single-compartment Kety model. In Part I, the derivation of the adiabatic solution was presented, In this second part, the adiabatic solution was applied to measure CBF in rabbits using nuclear magnetic resonance spectroscopy and the tracer deuterium oxide, It was shown that the FFP, observable when the 2H clearance data were analyzed with the Kety equation, was significantly reduced when the same data were analyzed with the adiabatic solution of the tissue homogeneity model. By concurrently measuring CBF with radioactive microspheres, it was determined that the CBF estimates from the adiabatic solution were accurate for true blood flow values less than 60 mL·100 g−1·min−1, Above this value the CBF estimate was progressively underestimated, which was attributed to the diffusion limitation of water in the brain.
The Progression and Topographic Distribution of Interleukin-1β Expression after Permanent Middle Cerebral Artery Occlusion in the Rat
Authors: Davies Christine A. , Loddick Sarah A. , Toulmond Sylvie , Stroemer R. Paul , Hunt Joanne , Rothwell Nancy J.
Published: November 2003

The cytokine interleukin-1 (IL-1) has been implicated in the exacerbation of ischemic damage in the brains of rodents. This study has ascertained the cellular localization and chronologic and topographic distribution of pro/mature interleukin-1β (IL-1β) protein 0.5, 1, 2, 6, 24, and 48 hours after ischemia by subjecting rats to permanent unilateral occlusion of the middle cerebral artery. Interleukin-1β was localized immunocytochemically in vibratome sections of perfusion-fixed brains. The cells that expressed IL-1β had the morphologic features of microglia and macrophages. Interleukin-1β was first detected 1 hour after occlusion in ipsilateral meningeal macrophage-like cells. By 6 hours, pro/mature IL-1β-immunoreactive (IL-1βir) putative microglia were present in the ischemic cerebral cortex, corpus callosum, caudoputamen, and surrounding tissue. By 24 and 48 hours after ischemia, the number and spread of IL-1βir cells increased greatly, including those resembling activated microglia and macrophages, as the core of the infarct became infiltrated. Interleukin-1βir cells also were present in apparently undamaged tissue, adjacent to the lesion ipsilaterally, and contralaterally in the cerebral cortex, dorsal corpus callosum, dorsal caudoputamen, and hippocampus. These results support the functional role of IL-1 in ischemic brain damage and reveal a distinct temporal and spatial expression of IL-1β protein in cells believed to be microglia and macrophages.
The Trigeminovascular System in Humans: Pathophysiologic Implications for Primary Headache Syndromes of the Neural Influences on the Cerebral Circulation
Authors: May Arne , Goadsby Peter J.
Published: November 2003

Primary headache syndromes, such as cluster headache and migraine, are widely described as vascular headaches, although considerable clinical evidence suggests that both are primarily driven from the brain. The shared anatomical and physiologic substrate for both of these clinical problems is the neural innervation of the cranial circulation. Functional imaging with positron emission tomography has shed light on the genesis of both syndromes, documenting activation in the midbrain and pons in migraine and in the hypothalamic gray in cluster headache. These areas are involved in the pain process in a permissive or triggering manner rather than as a response to first-division nociceptive pain impulses. In a positron emission tomography study in cluster headache, however, activation in the region of the major basal arteries was observed. This is likely to result from vasodilation of these vessels during the acute pain attack as opposed to the rest state in cluster headache, and represents the first convincing activation of neural vasodilator mechanisms in humans. The observation of vasodilation was also made in an experimental trigeminal pain study, which concluded that the observed dilation of these vessels in trigeminal pain is not inherent to a specific headache syndrome, but rather is a feature of the trigeminal neural innervation of the cranial circulation. Clinical and animal data suggest that the observed vasodilation is, in part, an effect of a trigeminoparasympathetic reflex. The data presented here review these developments in the physiology of the trigeminovascular system, which demand renewed consideration of the neural influences at work in many primary headaches and, thus, further consideration of the physiology of the neural innervation of the cranial circulation. We take the view that the known physiologic and pathophysiologic mechanisms of the systems involved dictate that these disorders should be collectively regarded as neurovascular headaches to emphasize the interaction between nerves and vessels, which is the underlying characteristic of these syndromes. Moreover, the syndromes can be understood only by a detailed study of the cerebrovascular physiologic mechanisms that underpin their expression.
Nitric Oxide Modulates Endothelin 1-Induced Ca2+ Mobilization and Cytoskeletal F-Actin Filaments in Human Cerebromicrovascular Endothelial Cells
Authors: Chen Ye , McCarron Richard M. , Bembry Joliet , Ruetzler Christl , Azzam Nabil , Lenz Fred A. , Spatz Maria
Published: November 2003

A functional interrelation between nitric oxide (NO), the endothelial-derived vasodilating factor, and endothelin 1 (ET-1), the potent vasoconstrictive peptide, was investigated in microvascular endothelium of human brain. Nor-1 dose-dependently decreased the ET-1–stimulated mobilization of Ca2+. This response was mimicked with cGMP and abrogated by inhibitors of guanylyl cyclase or cGMP-dependent protein kinase G. These findings indicate that NO and ET-1 interactions involved in modulation of intracellular Ca2+ are mediated by cGMP/protein kinase G. In addition, Nor-1–mediated effects were associated with rearrangements of cytoskeleton F-actin filaments. The results suggest mechanisms by which NO–ET-1 interactions may contribute to regulation of microvascular function.
Loss of D2 Receptor Binding with Age in Rhesus Monkeys: Importance of Correction for Differences in Striatal Size
Authors: Morris Evan D. , Chefer Svetlana I. , Lane Mark A. , Muzic Raymond F. , Wong Dean F. , Dannals Robert F. , Matochik John A. , Bonab Ali A. , Villemagne Victor L. , Grant Steven J. , Ingram Donald K. , Roth George S. , London Edythe D.
Published: November 2003

The relation between striatal dopamine D2 receptor binding and aging was investigated in rhesus monkeys with PET. Monkeys (n = 18, 39 to 360 months of age) were scanned with 11C-raclopride; binding potential in the striatum was estimated graphically. Because our magnetic resonance imaging analysis revealed a concomitant relation between size of striatum and age, the dynamic positron emission tomography (PET) data were corrected for possible partial volume (PV) artifacts before parameter estimation. The age-related decline in binding potential was 1% per year and was smaller than the apparent effect if the age-related change in size was ignored. This is the first in vivo demonstration of a decline in dopamine receptor binding in nonhuman primates. The rate of decline in binding potential is consistent with in vitro findings in monkeys but smaller than what has been measured previously in humans using PET. Previous PET studies in humans, however, have not corrected for PV error, although a decline in striatal size with age has been demonstrated. The results of this study suggest that PV correction must be applied to PET data to accurately detect small changes in receptor binding that may occur in parallel with structural changes in the brain.
Mitochondria in Neurodegeneration: Bioenergetic Function in Cell Life and Death
Authors: Murphy Anne N. , Fiskum Gary , Beal M. Flint
Published: November 2003

The biochemical pathways to cell death in chronic and acute forms of neurodegeneration are poorly understood, limiting the ability to develop effective therapeutic approaches. As details of the apoptotic and necrotic pathways have been revealed, an appreciation for the decisive role that mitochondria play in life-death decisions for the cell has grown. As a result, the need has arisen to reevaluate the significance to cell viability of mitochondrial Ca2+ sequestration, reactive oxygen species generation, and the membrane permeability transition. This review provides basic information on these mitochondrial functions as they relate to control over cell death.
Brief Vibrotactile Stimulation Does Not Increase Cortical Oxygen Consumption When Measured by Single Inhalation of Positron Emitting Oxygen
Authors: Ohta Shinsuke , Reutens David C. , Gjedde Albert
Published: November 2003

Vibrotactile stimulation of the hand elicits no increase in oxygen consumption commensurate with the increase in blood flow measured in human sensory cortex. To test the hypothesis that previous failures to detect a proportionate increase in oxygen consumption could be an artefact of the sequential bolus, or three-step, method used to measure this parameter in the human brain in vivo, the authors compared the measurements with the results of a novel single bolus, or one-step, method of measuring oxygen consumption. The time of completion of the three-step method was 40 to 50 minutes, whereas the one-step method lasted only 3 minutes. The baseline whole-brain oxygen consumption averaged 185 ± 32 μmol hg−1 min−1 by the three-step method and 153 ± 15 μmol hg−1 min−1 by the one-step method. Vibrotactile stimulation did not elicit a significant increase in oxygen consumption measured by either method. This finding rejects the hypothesis that failure to detect an increase of oxygen consumption could be an artefact caused by limitations of the method used previously. Conversely, it also rejects the hypothesis that observations of an increase of oxygen consumption by the new method are artefacts caused by limitations of the one-step method.
Frequency-Dependent Changes in Cerebral Metabolic Rate of Oxygen during Activation of Human Visual Cortex
Authors: Vafaee Manouchehr S. , Meyer Ernst , Marrett Sean , Paus T. , Evans Alan C. , Gjedde Albert
Published: November 2003

To test the hypothesis that brain oxidative metabolism is significantly increased upon adequate stimulation, we varied the presentation of a visual stimulus to determine the frequency at which the metabolic response would be at maximum. The authors measured regional CMR O2 in 12 healthy normal volunteers with the ECAT EXACT HR+ (CTI/Siemens, Knoxville, TN, U.S.A.) three-dimensional whole-body positron emission tomograph (PET). In seven successive activating conditions, subjects viewed a yellow-blue annular checkerboard reversing its contrast at frequencies of 0, 1, 4, 8, 16, 32, and 50 Hz. Stimulation began 4 minutes before and continued throughout the 3-minute dynamic scan. In the baseline condition, the subjects began fixating a cross hair 30 seconds before the scan and continued to do so for the duration of the 3-minute scan. At the start of each scan, the subjects inhaled 20 mCi of 15O-O2 in a single breath. The CMR O2 value was calculated using a two-compartment, weighted integration method. Normalized PET images were averaged across subjects and coregistered with the subjects' magnetic resonance imaging in stereotaxic space. Mean subtracted image volumes (activation minus baseline) of CMR O2 then were obtained and converted to z statistic volumes. The authors found a statistically significant focal change of CMR O2 in the striate cortex (x = 9; y = −89; z = −1) that reached a maximum at 4 Hz and dropped off sharply at higher stimulus frequencies.
Lack of Histamine Synthesis and Down-Regulation of H1 and H2 Receptor mRNA Levels by Dexamethasone in Cerebral Endothelial Cells
Authors: Karlstedt Kaj , Sallmén Tina , Eriksson Krister S. , Lintunen Minnamaija , Couraud Pierre-Olivier , Joó Ferenc , Panula Pertti
Published: November 2003

The purpose of this work was to determine whether cerebral endothelial cells have the capacity to synthesize histamine or to express mRNA of receptors that specifically respond to available free histamine. The histamine concentrations and the expression of L-histidine decarboxylase (HDC) and histamine H1 and H2 receptor mRNA, both in adult rat brain and in cultured immortalized RBE4 cerebral endothelial cells, were investigated. In this study endothelial cells were devoid of any kind of detectable histamine production, both in vivo and in the immortalized RBE4 cells in culture. Both the immunostainings for histamine and the in situ hybridizations for HDC were negative, as well as histamine determinations by HPLC, indicating that endothelial cells do not possess the capacity to produce histamine. Also, glucocorticoid (dexamethasone) treatment failed to induce histamine production in the cultured cells. Although the cerebral endothelial cells lack histamine production, a nonsaturable uptake in RBE4 cells is demonstrated. The internalized histamine is detected both in the cytoplasm and in the nucleus, which could indicate a role for histamine as an intracellular messenger. Histamine H1 and H2 receptor mRNA was expressed in RBE4 cells, and glucocorticoid treatment down-regulated the mRNA levels of both H1 and H2 receptors. This mechanism may be involved in glucocorticoid-mediated effects on cerebrovascular permeability and brain edema.
Spatial Assessment of the Dynamics of Lactate Formation in Focal Ischemic Rat Brain
Authors: Dijkhuizen Rick M. , de Graaf Robin A. , Garwood Michael , Tulleken Kees A. F. , Nicolay Klaas
Published: November 2003

Early identification of the potentially salvageable penumbra is critical for the determination of therapeutic intervention strategies in acute focal cerebral ischemia. This study differentiates the ischemic penumbra from the core on the basis of the dynamics of lactate formation. This was tested in a rat model of focal cerebral ischemia by infusion of [1-13C]-glucose, using lactate-edited magnetic resonance spectroscopic imaging techniques. The authors detected essentially no enrichment of lactate with 13C-label from the infused 13C-glucose in the ischemic core. However, in borderzone areas, 13C was incorporated into lactate, which could point toward compromised but potentially viable tissue. The authors' findings suggest that this combination of 13C-glucose infusion with the proposed magnetic resonance methods may aid in differentiating the penumbra from the core in cerebral ischemia.
Rapid Efflux of Lactate from Cerebral Cortex during K+-Induced Spreading Cortical Depression
Authors: Cruz Nancy F. , Adachi Keiji , Dienel Gerald A.
Published: November 2003

Rapid transport of lactate from activated brain regions to blood, perhaps reflecting enhanced metabolite trafficking, would prevent local trapping of labeled metabolites of [6-14C]glucose and cause underestimation of calculated CMRglc. Because the identities of glucose metabolites lost from activated structures and major routes of their removal are not known, arteriovenous differences across brains of conscious normoxic rats for derivatives of [6-14C]glucose were determined under steady-state conditions in blood during K+-induced spreading cortical depression. Lactate was identified as the major labeled product lost from brain. Its entry to blood was detected within 2 minutes after a pulse of [6-14C]glucose, and it accounted for 96% of the 14C lost from brain within approximately 8 minutes. Lactate efflux corresponded to 20% of glucose influx, but accounted for only half the magnitude of underestimation of CMRglc when [14C]glucose is the tracer, suggesting extensive [14C]lactate trafficking within brain. [14C]Lactate spreading within brain is consistent with (1) relatively uniform pattern labeling of K+-treated cerebral cortex by [6-14C]glucose contrasting heterogeneous labeling by [14C]deoxyglucose, and (2) transport of 14C-labeled lactate and inulin up to 1.5 and 2.4 mm, respectively, within 10 minutes. Thus, newly synthesized lactate exported from activated cells rapidly flows to blood and probably other brain structures.
Robustness of Anatomically Guided Pixel-by-Pixel Algorithms for Partial Volume Effect Correction in Positron Emission Tomography
Authors: Strul Daniel , Bendriem Bernard
Published: November 2003

Several algorithms have been proposed to improve positron emission tomography quantification by combining anatomical and functional information in a pixel-by-pixel correction scheme. The precision of these methods when applied to real data depends on the precision of the manifold correction steps, such as full-width half-maximum modeling, magnetic resonance imaging-positron emission tomography registration, tissue segmentation, or background activity estimation. A good understanding of the influence of these parameters thus is critical to the effective use of the algorithms. In the current article, the authors present a monodimensional model that allows a simple theoretical and experimental evaluation of correction imprecision. The authors then assess correction robustness in three dimensions with computer simulations, and evaluate the validity of regional SD as a correction performance criterion.
Comparison of PET [15O]Water Studies with 6-Minute and 10-Minute InterScan Intervals: Single-Subject and Group Analyses
Authors: Chmielowska Jolanta , Coghill Robert C. , Carson Richard E. , Ishii Kenji , Chen Robert , Hallett Mark , Herscovitch Peter
Published: November 2003

The authors recently showed that [15O]water PET data obtained with a short interscan interval (6 minutes) produced similar results whether or not the residual background from the previous scan is subtracted. The purpose of the present study was to compare scans obtained during motor activation using a short (6-minute) interscan interval protocol with those obtained with a standard (10-minute) protocol in the same scanning session. Single-subject and group analyses were performed using Worsley's method, which uses a pooled variance estimate and statistical parametric mapping with a local variance estimate. High consistency in both the activation maps, i.e., the number of activated motor brain structures and the Talairach coordinates of peak intensities of the activated regions, was obtained in the 6- and 10-minute studies in both single-subject and group analyses. However, in comparison to the 6-minute studies, a larger cluster size of activated brain regions and an approximately 20% higher peak activation in these regions were observed in the 10-minute studies with the same number of replicates. Analysis of these results suggests that using a 6-minute interval with an increased number of replications, i.e., without changing the subject's total study duration, should produce comparable statistical power to that of the 10-minute interval for group analysis and increased statistical power for single-subject analyses that use a local variance estimate because of increased degrees of freedom. Alternatively, with a small increase in the number of scans and the use of a 6-minute interscan interval, a comparable level of statistical significance may be achieved for single-subject experiments that use a local variance estimate, with an overall shortening of the study duration.
Excitotoxins in Neuronal Apoptosis and Necrosis
Authors: Nicotera Pierluigi , Lipton Stuart A.
Published: November 2003

Neuronal loss is common to many neurodegenerative diseases. Although necrosis is a common histopathologic feature observed in neuropathologic conditions, evidence is increasing that apoptosis can significantly contribute to neuronal demise. The prevalence of either type of cell death, apoptosis or necrosis, and the relevance for the progression of disease is still unclear. The debate on the occurrence and prevalence of one or the other type of death in pathologic conditions such as stroke or neurotoxic injury may in part be resolved by the proposal that different types of cell death within a tissue reflect either partial or complete execution of a common death program. Apoptosis is an active process of cell destruction, characterized morphologically by cell shrinkage, chromatin aggregation with extensive genomic fragmentation, and nuclear pyknosis. In contrast, necrosis is characterized by cell swelling, linked to rapid energy loss, and generalized disruption of ionic and internal homeostasis. This swiftly leads to membrane lysis, release of intracellular constituents that evoke a local inflammatory reaction, edema, and injury to the surrounding tissue. During the past few years, our laboratories have studied the signals and mechanisms responsible for induction or prevention of apoptosis/necrosis in neuronal injury and this is the subject of this review.
Measuring Cerebral Blood Flow Using Magnetic Resonance Imaging Techniques
Authors: Calamante Fernando , Thomas David L. , Pell Gaby S. , Wiersma Jonna , Turner Robert
Published: November 2003

Magnetic resonance imaging techniques measuring CBF have developed rapidly in the last decade, resulting in a wide range of available methods. The most successful approaches are based either on dynamic tracking of a bolus of a paramagnetic contrast agent (dynamic susceptibility contrast) or on arterial spin labeling. This review discusses their principles, possible pitfalls, and potential for absolute quantification and outlines clinical and neuroscientific applications.
Ubiquitin Stress Response in Postischemic Hippocampal Neurons under Nontolerant and Tolerant Conditions
Authors: Ide Takafumi , Takada Koji , Qiu Jian Hua , Saito Nobuhito , Kawahara Nobutaka , Asai Akio , Kirino Takaaki
Published: November 2003

Ubiquitin, an essential protein in nonlysosomal proteolytic system, is expressed after metabolic stress to the cell, The authors investigated stress response of ubiquitin in the hippocampus of the Mongolian gerbil after forebrain ischemia, The level of hippocampal ubiquitin was compared with that under ischemic tolerance induced by ischemic preconditioning, The authors also studied ubiquitin gene expression using in situ hybridization method, Transient ischemia resulted in consumption of free ubiquitin and an increase of multiubiquitin chains, These changes were transient in the hippocampus outside of the CA1 region where neurons survived, whereas it was persistent in the CA1 region where neurons were destined to die after ischemia. Under tolerant condition, subsequent ischemia provoked rapid recovery and further increase of free ubiquitin. The signal of ubiquitin messenger ribonucleic acid was continuously detected after ischemia, not only under tolerant conditions, but without tolerance induced by preconditioning. Thus, ubiquitin stress response takes place, at least at a transcriptional level, in dying CA1 neurons. Under tolerant conditions, however, subsequent ischemia in the CA1 region induces the stress response of ubiquitin up to the translational level, leading to the rapid restoration of protein synthesis and to eventual neuronal survival.
Increased Vulnerability of NFH-LacZ Transgenic Mouse to Traumatic Brain Injury-Induced Behavioral Deficits and Cortical Damage
Authors: Nakamura Michio , Saatman Kathryn E. , Galvin James E. , Scherbel Uwe , Raghupathi Ramesh , Trojanowski John Q. , McIntosh Tracy K.
Published: November 2003

The authors evaluated the neurobehavioral and neuropathologic sequelae after traumatic brain injury (TBI) in transgenic (TG) mice expressing truncated high molecular weight neurofilament (NF) protein fused to beta-galactosidase (NFH-LacZ), which develop Lewy body-like NF-rich inclusions throughout the CNS. TG mice and their wild-type (WT) littermates were subjected to controlled cortical impact brain injury (TG, n=19; WT, n=17) or served as uninjured controls (TG, n =11; WT, n =11). During a 3-week period, mice were evaluated with an array of neuromotor function tests including neuroscore, beam balance, and both fast and slow acceleration rotarod. Brain-injured WT and TG mice showed significant motor dysfunction until 15 days and 21 days post-injury, respectively ( P < .025). Compared with brain-injured WT mice, brain-injured TG mice had significantly greater motor dysfunction as assessed by neuroscore ( P < .01) up to and including 15 days post-injury. Similarly, brain-injured TG mice performed significantly worse than brain-injured WT mice on slow acceleration rotarod at 2, 8, and 15 days post-injury ( P < .05), and beam balance over 2 weeks post-injury ( P < .01). Histopathologic analysis showed significantly greater tissue loss in the injured hemisphere in TG mice at 4 weeks post-injury ( P < .01). Together these data show that NFH-LacZ TG mice are more behaviorally and histologically vulnerable to TBI than WT mice, suggesting that the presence of NF-rich inclusions may exacerbate neuromotor dysfunction and cell death after TBI.