bluuebunny/crossref_metadata_2025 huggingface dataset:
Attenuation of Brain Free Fatty Acid Liberation during Global Ischemia: A Model for Screening Potential Therapies for Efficacy?
Authors: Nemoto Edwin M. , Shiu Gerald K. , Nemmer Joseph , Bleyaert Achiel L.
Published: April 2011

Whole brain free fatty acids (FFA) continue to rise appreciably even 1 h after decapitation, which may reflect the evolution of ischemic brain injury at least during global ischemia. If so, the attenuation of FFA liberation by various drugs may reflect their efficacy in ischemic brain injury. Rats were pretreated with either 0.9% NaCI (controls), ketamine, halothane, lofentanil, etomidate, Y-9179, R41-468, Innovar-Vet®, pentobarbital, thiopental, or phenytoin and decapitated 15 to 30 min thereafter. The brains were kept normothermic for 10 min until they were frozen in liquid nitrogen. Whole brain FFAs were quantitated by gas–liquid chromatography. After 10 min of ischemia in controls, total FFAs and arachidonic, stearic, oleic, and palmitic acids increased by 8- to 10-fold. The drugs, in order of decreasing effectiveness in attenuating FFA liberation, fell into the following three groups: (1) phenytoin, thiopental, pentobarbital, and Innovar-Vet; (2) R41-468, Y-9179, and etomidate; and (3) lofentanil, halothane and ketamine. The three groups reduced total FFAs by about 23%, 13%, and 8%, respectively. The effectiveness of the drugs in attenuating FFA liberation appears to correlate with their efficacy in ischemic brain injury. However, a cause and effect relationship between FFA liberation and the evolution of ischemic brain injury must be established before accurate predictions of efficacy can be made by this method. The limitations of the proposed method of evaluation are discussed.
Neurophysiological Recovery after Hypoglycemic Coma in the Rat: Correlation with Cerebral Metabolism
Authors: Agardh C.-D. , Rosén I.
Published: April 2011

Recovery of electroencephalographic activity and somatosensory evoked responses was studied in paralyzed and lightly anesthetized (70% N2O) rats in which profound hypoglycemia had been induced by insulin administration. The duration of severe hypoglycemia was defined as the duration of a flat electroencephalogram (EEG) recording (5, 30, and 60 min, respectively) before restitution with glucose. The restitution period was followed by continuous EEG monitoring and repeated tests for evoked potentials. After 180 min of recovery, the brains were frozen in situ with liquid nitrogen and analyzed for energy metabolism. In accordance with earlier metabolic studies from this laboratory, the recovery after 60 min of severe hypoglycemia was incomplete, with signs of permanent failure of energy metabolism. There was persistent ATP reduction proportional to the duration of the hypoglycemia. The short-term recovery of EEG and sensory evoked responses was proportional to the duration of severe hypoglycemia. The neurophysiological recovery after 5 min of severe hypoglycemia was complete. After 30 min of severe hypoglycemia, the evoked responses recovered but showed a significant prolongation of latency, compared with normal. After 60 min of severe hypoglycemia, no early evoked response and scanty EEG activity were observed. The neurophysiological observations indicate a persistent deficit of synaptic transmission in the somatosensory pathway, including the cortical projection. This can be correlated with neuropathologic changes that are particularly prominent in intermediate cortical layers, as previously shown.
The Cortical Ischaemic Penumbra Associated with Occlusion of the Middle Cerebral Artery in the Cat: 1. Topography of Changes in Blood Flow, Potassium Ion Activity, and EEG
Authors: Strong A. J. , Venables G. S. , Gibson G.
Published: April 2011

The gyral topography of the ischaemic penumbra associated with middle cerebral artery occlusion was studied in cats; local blood flow (hydrogen clearance, 2-min initial slope analysis), pial surface potassium activity (Kp), and electroencephalogram (EEG) amplitude were recorded on the ectosylvian, suprasylvian, and marginal gyri. Penumbral conditions were defined as a reduction of EEG amplitude in the absence of a major increase in Kp. Whole hemisphere cerebral blood flow prior to occlusion was 35.6 ± 11.4 (SD) ml 100 g−1 min−1 (n = 25), and fell significantly (p < 0.001) to 13.0 ± 4.7 (SD), 14.1 ± 6.6, and 23.8 ± 9.3 on ectosylvian, suprasylvian, and marginal gyri, respectively. Pre-occlusion Kp was 3.0 ± 0.59 m M (n = 53); sustained, steady-state increases in excess of 11.5 m M occurred in 5 of 7 (71%) experiments on ectosylvian gyrus, in 13 of 22 (59%) experiments on suprasylvian gyrus, and in 2 of 24 experiments on marginal gyrus. Transient increases in Kp occurred at ocdusion and resolved to baselines significantly higher than control in 5 (23%) experiments in suprasylvian gyrus and in 15 (63%) on marginal gyrus. In 7 experiments on the marginal gyrus (29%), no increase in Kp grealer than 1 m M occurred. In contrast EEG amplitude on this gyrus was reduced by middle cerebral artery occlusion in 25 of 26 experiments, and it is concluded that this gyrus is the principal site of ischae mic penumbra in the model; in 41% of experiments similar conditions were also present on the suprasylvian gyrus.
The Cortical Ischaemic Penumbra Associated with Occlusion of the Middle Cerebral Artery in the Cat: 2. Studies of Histopathology, Water Content, and in vitro Neurotransmitter Uptake
Authors: Strong A. J. , Tomlinson B. E. , Venables G. S. , Gibson G. , Hardy J. A.
Published: April 2011

The nature of the ischaemic penumbra, as defined by suppression of electroencephalogram amplitude in the absence of increase in steady state pial surface potassium activity in excess of 13 m M, was examined in the marginal gyrus of cats subjected to middle cerebral artery occlusion. In vitro synaptosomal neurotransmitter uptake, water content (specific gravity), and histopathology at the light and electron microscopic level were studied and the results compared with those obtained at deeper, critical levels of ischaemia (less than 15 ml 100 g−1 min−1). [3H]4-Aminobutyric acid uptake was 104% of control in the marginal gyrus (NS), and 61 and 48% (p < 0.05) in critical ischaemia. It is concluded that impairment of in vivo synaptosomal uptake is a marker of simultaneous widespread damage to neurones, rather than of a change restricted to the synaptic compartment, although the present findings cannot exclude reversible, substrate-limited impairment of uptake in vivo. Reductions in specific gravity were seen only with critical ischaemia. In 5 of 6 experiments, early or classical ischaemic neuronal cell changes and reactive glia were seen on light microscopy in restricted areas in the marginal gyrus, either in microfoci or scattered more diffusely. Ultrastructural changes were more frequent but were considered to affect only a minority of neurones. Hypotheses for selective electrophysiological suppression in penumbra are discussed.
Effect of OKY-1581, a Thromboxane Synthesis Inhibitor, on the Platelet Aggregation and Vasodilation Induced by Injury of Mouse Pial Arterioles
Authors: Rosenblum William I. , El-Sabban Farouk
Published: April 2011

OKY-1581 (sodium [E]-3-[4-(3-pyridylmethyl)-phenyl]-2-methylacrylate) is a known inhibitor of thromboxane synthesis, a class of agents thought potentially useful in treating conditions characterized by platelet aggregation. Doses of 10, 100, and 300 mg/kg were administered intraperitoneally to mice 1 h before their pial vessels were injured by a combination of light from a filtered mercury lamp and intravascular sodium fluorescein. In this model platelet aggregation and arterial dilation are produced. Pretreatment with OKY-1581 had no effect except at the 300-mg/kg dose, which enhanced aggregation as manifested by a decrease in the time required for the noxious stimulus to initiate aggregation. In addition the dilation increased in magnitude as compared with that in controls. The latter result is compatible with a decreased synthesis of thromboxane, a known constrictor of cerebral vessels. However, the enhancement of aggregation by a high dose of OKY-1581 was unexpected and paradoxical. The data do not support the use of thromboxane synthesis inhibitors as therapy for conditions caused by platelet aggregation, but the results may be dependent upon the species, the vascular bed, or the method used to induce aggregation.
Innervation of the Cerebral Veins as Compared with the Cerebral Arteries: A Histochemical and Electron Microscopic Study
Authors: Nakakita Kazuo , Imai Harumichi , Kamei Ichiro , Naka Yutaka , Nakai Kunio , Itakura Toru , Komai Norihiko
Published: April 2011

The distribution of nerve fibers in the cerebral veins was studied by catecholamine fluorescence simultaneously with acetylcholinesterase (AChE) histochemistry. A comparison of nerve fibers in the cerebral arteries was made, The ultrastructure of terminal boutons in the veins fixed with potassium permanganate was also studied, In the adventitia of the cerebral artery, green fluorescent aminergic fibers and brownish AChE-reactive (probably cholinergic) fibers were observed. In contrast, the cerebral venous system showed no AChE-positive fibers. Catecholamine fluorescent varicose fibers were detected in the dural sinus, the internal cerebral vein, and the superficial vein of Labbé. The highest density of aminergic fibers was found in the dural sinus and the second highest in the internal cerebral vein. Most of the terminal boutons in the adventitia of the cerebral veins were found adjacent to a muscle-like cell and showed only cored vesicles under electron microscopy. Results of our study suggest that the cerebral venous system has a neurogenic innervation, mainly from aminergic fibers, which is different from the neurogenic supply to the cerebral arterial system.
Measurement of Local Cerebral Blood Flow by Xenon-Enhanced Computerized Tomography Imaging: A Critique of an Error Assessment
Authors: Gur David , Shabason Leonard , Wolfson Sidney K. , Yonas Howard , Good Walter F.
Published: April 2011

A review of an error assessment of local cerebral blood flow values derived from xenon-enhanced computerized tomography imaging indicates that the authors have failed to consider the appropriate parameters, thereby yielding errors that are larger than the true errors.
Local Cerebral Glucose Metabolism in Rats with Chronic Portacaval Shunts
Authors: Cruz Nancy F. , Duffy Thomas E.
Published: April 2011

Local cerebral glucose utilization was measured with the autoradiographic [14C]deoxyglucose method in rats at 2 days and 1, 4, 8, and 12 weeks after the construction of a portacaval shunt, and in weight-matched controls. Local glucose utilization in brain was altered in shunted animals, but the magnitude and direction of the changes differed among 36 neuroanatomical structures, depending upon the length of time that the animals had been shunted. In rats shunted for 4 weeks or less, glucose utilization did not differ from control (30 of 36 structures) or was decreased (6 structures). The largest decreases of glucose utilization, noted at 1 week, occurred in the parietal (– 25%) and frontal cortices (– 28%) and subcortical white matter (– 50%). In rats shunted for 8 weeks, however, glucose utilization was higher than control in many brain structures (13 of 36), and after 12 weeks it was higher than control in most structures (25 of 36). Only the parietal cortex did not follow this trend; it exhibited a decreased rate of glucose utilization in rats shunted for 8 weeks (–21%) that normalized in animals shunted for 12 weeks. Portal-systemic shunting of blood increased arterial blood ammonia concentrations to twice the control value of 85 ± 3 μ M in animals shunted for 1 week, and to ∼2.5 times control in animals shunted for 4–12 weeks. Kety-Schmidt measurements of cerebral blood flow and arterial–venous (torcular) differences for ammonia across the brains of control rats and rats with portacaval shunts for 8 weeks revealed an increased cerebral uptake of ammonia in the shunted animals. The late-developing morphological changes known to occur in astrocytes and the delayed increases in local glucose consumption in rats with portacaval shunts may be related, and represent an adaptive response to sustained hyperammonemia.
Effects of Topical Application of a Calcium Antagonist (Nifedipine) on Feline Cortical Pial Microvasculature under Normal Conditions and in Focal Ischemia
Authors: Brandt Lennart , Ljunggren Bengt , Andersson Karl-Erik , Edvinsson Lars , MacKenzie Eric , Tamura Akira , Teasdale Graham
Published: April 2011

Cat cortical arterioles and venules were exposed in vivo to the Ca2+ antagonist nifedipine under normal conditions and in focal ischemia. Topical application of nifedipine caused a marked, concentration-dependent arteriolar dilatation. The dilatatory responses increased significantly with decreasing arteriolar size. Perivenular microapplication of nifedipine invariably caused dilatation that was less pronounced but more long-lasting than that on the arteriolar side. Arterioles, which constricted after middle cerebral artery occlusion, invariably dilated following nifedipine application. These dilatatory responses were transient but could be repeated, and on some occasions were accompanied by a return of flow in vessels in which stasis had been present. The results suggest that nifedipine is able to dilate cerebral vessels both under normal conditions and when contracted during focal ischemia.
in vitro Effects of Calcium Antagonists PN 200-110, Nifedipine, and Nimodipine on Human and Canine Cerebral Arteries
Authors: Müller-Schweinitzer E. , Neumann P.
Published: April 2011

PN 200–110 [4-(2, 1, 3-benzoxadiazol - 4 -) - 1,4-dihydro - 2,6 - dimethyl - pyridine - 3,5 - dicarboxylic acid methyl 1-methylethyl ester], a new dihydropyridine derivative, was investigated by recording isometric tension on spiral strips from human and canine arteries in tissue baths at 37°C. Responses to increasing concentrations of CaCl2 were investigated in calcium-free depolarizing solution (60 mmol/L KCl in equimolar replacement for NaCl, 50 mmol/L TRIZMA buffer, pH 7.4). Comparison of those concentrations that reduced the vasoconstrictor response to 1.6 mmol/L CaCl2 by 50% revealed the following order of potencies on both human and canine arteries: PN 200–110 > nimodipine > nifedipine. Responses to 5-hydroxytryptamine (5-HT) and blood were investigated in Krebs–Henseleit solution (NaHCO3 buffer). On canine arteries, PN 200–110 antagonized responses to 5-HT when used at 10–30 pmol/L; it was ∼70 times more potent on basilar than on mesenteric arteries, whereas both nifedipine and nimodipine were, respectively, ∼10 and 6 times more potent on basilar than on mesenteric arteries. When canine basilar arteries were constricted by the addition of blood to the organ bath, each of the investigated dihydropyridine derivatives elicited concentration-dependent relaxation, producing the following order of potencies: PN 200–110 > nifedipine = nimodipine. On human anterior cerebral arteries, the blood-induced contractions were counteracted in the following rank order: PN 200–110 = nimodipine > nifedipine. The results suggest that due to its potent calcium-blocking activity on cerebral arteries, PN 200–110 might be of value for the prevention and treatment of cerebrovascular spasms following subarachnoid hemorrhage.
Effects of Arterial Pco2 and Cerebrospinal Fluid Volume Flow Rate Changes on Choroid Plexus and Cerebral Blood Flow in Normal and Experimental Hydrocephalic Cats
Authors: Nakamura S. , Hochwald G. M.
Published: April 2011

The effect of changes in brain blood flow on cerebrospinal fluid (CSF) volume flow rates, and that of changes in CSF volume flow rates on brain blood flow were determined in both normal and kaolin-induced hydrocephalic cats. In both groups of cats, blood flow in grey and white matter, cerebral cortex, and choroid plexus was measured with 105Ru microspheres during normocapnia, and again with 141Ce microspheres after arterial Pco2 was either increased by 300% or decreased by 50%. Blood flow measurements were also made during perfusion of the ventricular system with mock CSF and repeated during perfusion with anisosmotic mannitol solutions to alter CSF volume flow rate. In 30 normal and 26 hydrocephalic cats, blood flow to the cerebral cortex, white matter, and choroid plexus was similar; only blood flow to the caudate nucleus was greater in normal cats. The weight of the choroid plexus from hydrocephalic cats decreased by 17%. Blood flow in the choroid plexus of all cats decreased by almost 50% following hypercapnia or hypocapnia, without a change in the CSF volume flow rate. There was no change in cerebral or choroidal blood flow when CSF volume flow rate was either increased by 170% or decreased by 80%. These results suggest that choroid plexus blood flow does not limit or affect the volume flow rate of CSF from the choroid plexus. CSF volume flow rate can be altered without corresponding blood flow changes of the brain or choroid plexus. Choroid plexus blood flow and the reactivity of both brain and choroidal blood flow to changes in arterial Pco2 were not affected by the hydrocephalus. The lower CSF formation rate of hydrocephalic cats can be attributed in part to the decrease in the mass of choroid plexus tissue.
Effect of the Organic Calcium Antagonist D-600 on Cerebrocortical Vascular and Redox Responses Evoked by Adenosine, Anoxia, and Epilepsy
Authors: Kovách Arisztid G. B. , Dóra Eörs , Szedlacsek Sándor , Koller Ákos
Published: April 2011

The purpose of this study was to investigate the role of calcium ions in cerebrocortical vasodilatation and oxidized and reduced nicotinamide adenine dinucleotide (NAD/NADH) redox responses evoked by adenosine, anoxia, and epileptic seizures. The brain cortex of chloralose-anaesthetized cats was treated locally with gallopamil-hydrochloride (D-600) and verapamil (Isoptin®). These organic calcium antagonists decrease the inward movement of calcium ions into vascular smooth muscle cells. Cerebrocortical vascular volume (CVV) and NADH fluorescence were measured in vivo by fluororeflectometry. Adenosine and calcium antagonists were dissolved in artificial cerebrospinal fluid (mock CSF) and applied topically to the brain cortex by superfusion. Adenosine (10−8 to 10−3 M) resulted in concentration-dependent increases in CVV. The NAD/NADH redox state was not altered below adenosine concentrations of 10−5 M. However, in the concentration range of 10−5 to 10−3 M, significant NAD reduction was obtained. Both calcium antagonists increased CVV markedly, but did not bring about significant changes in NAD/NADH ratio and local electrical activity of the exposed brain cortex. D-600 (2 × 10−6 M) increased CVV as much as did 10−4 M adenosine, but it failed to diminish the vascular and metabolic effects of the adenosine. D-600 (2 × 10−4 M) resulted in an increase in CVV approximately 2.5 times greater than that caused by 10−4 M adenosine alone. However, the adenosine-induced CVV response was inhibited by only about 70%, compared with the control response. After pretreating the brain cortex with 2 × 10−3 M D-600, adenosine had no effects on CVV and NAD/NADH redox state; the NAD reduction accompanying anoxia and epileptic seizures was considerably diminished. These results suggest that the inhibition of transmembrane calcium influx could have a minor role in the vasodilatatory mechanism of adenosine. Since the vascular effect of adenosine vanished only at very high concentration of D-600, which might also inhibit the release of calcium from intracellular binding sites, it is presumed that adenosine dilates the cerebrocortical vessels by interacting with intracellular calcium-sequestrating mechanisms. Furthermore, since adenosine had a marked NAD reducing effect and since it is well known that it increases the activity of adenylate cyclase and phosphorylase enzymes, accumulation of 3′,5′-cyclic adenosine monophosphate (cAMP) and substrate mobilization might be involved also in the vasodilatatory mechanism of adenosine. Our results concerning the inhibitory effect of D-600 on epilepsy- and anoxia-induced cerebrocortical NAD reduction unambiguously demonstrate the significance of calcium fluxes in glycogen and glucose metabolism under these conditions.
Metabolic Mapping in the Sympathetic Ganglia and Brain of the Spontaneously Hypertensive Rat
Authors: Kadekaro Massako , Savaki Helen E. , Kutyna Francis A. , Davidsen Leslie , Sokoloff Louis
Published: April 2011

Local rates of glucose utilization in the superior cervical, cardiac, and coeliac ganglia were measured by means of the autoradiographic 2-deoxy-d-[14C]glucose method in male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY), 32–34, 46–48, and 78–87 days old. Brain glucose utilization was examined in 78–87-day-old SHR and WKY. At 32–34 days (at which time mean arterial blood pressure was normal and similar in both groups of rats), the rates of glucose utilization of all three sympathetic ganglia were the same in both groups. At 46–48 days, despite the fact that blood pressure had risen significantly in SHR (mean ± SEM, 136 ± 3 mm Hg, n = 5, compared to 113 ± 3 mm Hg, n = 5, in the control WKY), glucose utilization was decreased in the cardiac and coeliac ganglia but not in the superior cervical ganglia of the SHR. At 78–87 days, glucose utilization was reduced in all the sympathetic ganglia of the hypertensive rats. These results suggest that the sympathetic system is less active in SHR and indicate that hyperactivity of the sympathetic nervous system is not part of the mechanism of the hypertension. Of 44 structures examined in the central nervous system, only the external cuneate, vestibular, and fastigial nuclei of the SHR exhibited increased rates of glucose utilization, and no changes were found in any of the other structures. These increases are probably not related to the origin or maintenance of the hypertension, inasmuch as lesioning of the vestibular or fastigial nuclei did not decrease blood pressure in the SHR.
Metabolic and Histological Reversibility of Thiamine Deficiency
Authors: Hakim Antoine M. , Carpenter Stirling , Pappius Hanna M.
Published: April 2011

The rapid improvement in the clinical manifestations of thiamine deficiency with thiamine supplementation is well known. To study this process in more detail, we rendered rats thiamine deficient either by dietary deprivation alone (DD) or, in addition, by daily pyrithiamine administration (DD + PT). We observed the cerebral metabolic and histological responses of these rats after 1 or 7 days of thiamine supplementation both prior to and at the onset of clinical sequelae. The cerebral metabolic response to thiamine deficiency and replenishment was determined with the [14C]deoxyglucose technique for measurement of local cerebral glucose utilization (LCGU). Our results indicate that thiamine replenishment reverses the LCGU changes resulting from thiamine deprivation of short duration. However, prolonged thiamine deprivation may result in LCGU changes that are not completely reversible by thiamine replenishment, before the appearance of the clinical or histological consequences of thiamine deficiency.
Regional Differences in Vascular Autoregulation in the Rat Brain in Severe Insulin-Induced Hypoglycemia
Authors: Siesjö Bo K. , Ingvar Martin , Pelligrino Dale
Published: April 2011

The present experiments were undertaken to determine if loss of vascular autoregulation during severe hypoglycemia shows regional differences that could help to explain the localization of hypoglycemic cell damage. Artificially ventilated rats (70% N2O) were subjected to a 30-min insulin-induced hypoglycemic coma (with cessation of EEG activity), with mean arterial blood pressure being maintained at 140, 120, 100, and 80 mm Hg. After 30 min of hypoglycemia, local cerebral blood flow (CBF) in 25 brain structures was measured autoradiographically with a [14C]iodoantipyrine technique. Since local CBF values did not differ between the 120 and the 100 mm Hg groups, the animals of these groups were pooled (110 mm Hg group). The results showed that at a blood pressure of 140 mm Hg, CBF was increased in 22 of 25 structures analysed, the maximal values approximating 300% of control. At 110 mm Hg, cerebral cortical structures had CBF values that were either decreased, normal, or slightly increased; however, many subcortical structures (and cerebellum) showed markedly increased flow rates. Although a lowering of blood pressure to 80 mm Hg usually further reduced flow rates, some of these latter structures also had well-maintained CBF values at that pressure. Thus, there were large interstructural variations of local CBF at any of the pressures examined. Analysis of the pressure–flow relationship showed loss of autoregulation in some structures, whereas others had remarkably well-preserved CBF values at low pressures. The results indicate that during severe hypoglycemia, even relatively moderate arterial hypotension may add a circulatory insult to the primary one, and they strongly suggest that any such insult affects some brain structures more than others.
Effect of Glucose on Recovery of Energy Metabolism following Hypoxia—Oligemia in Mouse Brain: Dose-Dependence and Carbohydrate Specificity
Authors: Welsh Frank A. , Sims Renee E. , McKee Ann E.
Published: April 2011

Unilateral cerebral hypoxia–oligemia was produced in anesthetized mice using carotid artery occlusion combined with systemic hypoxia (10% O2). In the cerebral cortex ipsilateral to the carotid occlusion, ATP levels were depleted during a 30-min insult, but were restored to 64% of control during 60 min of recovery. Pretreatment of animals with glucose diminished the restoration of ATP in a dose-dependent manner. Thus, when blood glucose levels exceeded 12–13 m M (225 mg/dl), ATP recovery was greatly impaired. Neither galactose nor 3- O-methylglucose mimicked the detrimental effect of glucose. However, pretreatment with mannose, which is readily metabolized by brain, impaired restoration of ATP. The impairment, therefore, appears to be specific for substrates of cerebral metabolism. The ischemic accumulation of lactate in the ipsilateral cortex was augmented by only 30% at blood glucose levels well above the threshold for ATP recovery. Thus, unless recovery of energy metabolism is sensitive to small increments in brain lactate, it is difficult to explain the glucose-induced energy failure on the basis of enhanced lactic acidosis. Ipsilateral cerebral blood flow (CBF), measured with [14C]iodoantipyrine during hypoxia and recovery, was lower in glucose-pretreated than in saline-pretreated animals. However, the poor correlation between CBF and ATP, measured in the same tissue samples at 15 min recovery, failed to substantiate that regeneration of ATP was flow-limited early in recovery.
Lactate Reverses Insulin-Induced Hypoglycemic Stupor in Suckling—Weanling Mice: Biochemical Correlates in Blood, Liver, and Brain
Authors: Thurston Jean Holowach , Hauhart Richard E. , Schiro James A.
Published: April 2011

The recovery of weanling mice from insulin-induced hypoglycemic stupor–coma after injection of sodium -l(+)-lactate (18 mmol/kg) was as rapid (10 min) as in litter-mates treated with glucose (9 mmol/kg). Stimulated by this dramatic action, we studied the effects of lactate injection on brain carbohydrate and energy metabolism in normal and hypoglycemic mice; blood and liver tissue were also studied. Ten minutes after lactate injection in normal mice, plasma lactate levels increased by 15 mmol/L; plasma glucose levels were unchanged, but the β-hydroxybutyrate concentration fell 59%. In the brains of these animals, glucose levels increased 2.3-fold, and there were significant increases in brain glycogen (10%), glucose-6-phosphate (27%), lactate (68%), pyruvate (37%), citrate (12%), and malate (19%); the increase in α-ketoglutarate (32%) was not significant. Lactate injection reduced the cerebral glucose-use rate 40%. These changes were not due to lactate-induced increases in blood [HCO−3] and pH (examined by injection of 15 mmol/kg sodium bicarbonate). Although lactate injection of hypoglycemic mice doubled levels of glucose in plasma and brain (not significant) and most of the cerebral glycolytic intermediates, values were far below normal (still in the range seen in hypoglycemic animals). By contrast, citrate and α-ketoglutarate levels returned to normal; the large increase in malate was not significant. Reduced glutamate levels increased to normal, and elevated aspartate levels fell below normal. Thus, recovery from hypoglycemic stupor does not necessarily depend on normal levels of plasma and/or brain glucose (or glycolytic intermediates). Near normal levels of the Krebs citric acid cycle intermediates suggest that changes in these metabolites, amino acids, or derived substrates relate to the dramatic recovery of hypoglycemic mice after lactate injection.
Effect of the Calcium Antagonist Nimodipine on the Delayed Hypoperfusion following Incomplete Ischemia in the Rat
Authors: Smith Maj-Lis , Kågström Erik , Rosén Ingmar , Siesjö Bo K.
Published: April 2011

Regional cerebral blood flow (CBF) was measured autoradiographically in the recovery period following 15 min of forebrain ischemia in rats pretreated with either nimodipine (0.1 mg kg−1) or vehicle. The results showed that although nimodipine increased postischemic CBF, the flow enhancement was regionally heterogeneous, sometimes resulting in zones of gross hypoperfusion and overt hyperemia within the same structures. This patchy improvement of delayed postischemic hypoperfusion was not accompanied by recovery of sensory evoked responses, and return of EEG activity was not enhanced.
Cerebral Blood Flow and Neurologic Outcome When Nimodipine is Given after Complete Cerebral Ischemia in the Dog
Authors: Steen Petter A. , Newberg Leslie A. , Milde James H. , Michenfelder John D.
Published: April 2011

Ten minutes of complete cerebral ischemia was produced in 26 dogs by temporary ligation of the aorta and the venae cavae. Twenty dogs received nimodipine, a calcium entry blocker, 10 μg kg−1 i. v. 2 min after the ischemic period, followed by 1 μg kg−1 min−1 for 2–3 h. Six dogs received only the solvent used for nimodipine. Fourteen dogs received nimodipine for 3 h and were subsequently evaluated neurologically up to 48 h postischemia. In the 12 other dogs, CBF and metabolism were followed for 2 h postischemia while either nimodipine or the solvent only was infused. The results were compared to previously published results for untreated dogs and dogs given nimodipine before the ischemic event. Nimodipine had the same effect on postischemic CBF whether started before or after the ischemic event, nearly doubling the flow when compared with untreated controls, whereas the solvent alone caused only a slight increase in CBF over control. By contrast, nimodipine initiated in the preischemic period significantly improved the neurologic outcome, but when initiated in the post-ischemic period the results were equivocal, such that the outcome was not significantly different from either the untreated group or the group in which nimodipine was initiated preischemia. Metabolic measurements did not give any indication of a specific effect of nimodipine, nor could the metabolic results be used as an indicator of neurologic outcome. The results are consistent with a beneficial effect of nimodipine following complete cerebral ischemia; however, evaluation of neurologic functional effects will require a more sensitive model.
Local Interrelationships of Cerebral Oxygen Consumption and Glucose Utilization in Normal Subjects and in Ischemic Stroke Patients: A Positron Tomography Study
Authors: Baron J. C. , Rougemont D. , Soussaline F. , Bustany P. , Crouzel C. , Bousser M. G. , Comar D.
Published: April 2011

With the use of positron emission tomography (PET) and the 15O steady-state-[18F]fluorodeoxyglucose combined method, the local interrelationships between the cerebral metabolic rate for oxygen (CMRO2) and the cerebral metabolic rate for glucose (CMRGlc) were investigated in control subjects and in stroke patients. In addition to the classic in vivo autoradiographic approach, a kinetic method was used to measure CMRGlc because it was expected to be more reliable in cerebral ischemia. In control subjects local coupling between CBF, CMRO2, and CMRGlc was confirmed, and acceptable values for the CMRO2/CMRGlc ratio were found; the latter, however, was lower in white matter than in gray. Uncoupling between CMRO2 and CMRGlc was observed in all stroke patients, suggesting that (1) enhanced anaerobic glycolysis occurred both in reperfused recent infarcts and in chronically ischemic tissue, and (2) substrates other than blood-borne glucose were being oxidized at the borders of recent infarcts. However, methodological uncertainties presently make such observations only tentative. Finally, a coupled depression of CMRO2 and CMRGlc was found in the contralateral cerebellum.
Measurement of Cerebral Blood Flow in the Rat with Intravenous Injection of [11C]Butanol by External Coincidence Counting: A Repeatable and Noninvasive Method in the Brain
Authors: Takagi Shigeharu , Ehara Kazumasa , Kenny Peter J. , Finn Ronald D. , Kothari Paresh J. , Gilson Albert J.
Published: April 2011

No method has been reported for measuring CBF, repeatedly and noninvasively, in the rat brain. A new method is described, which is noninvasive to the brain, skull, or cervical large vessels. Two pairs of coincidence detectors were positioned, one over the rat brain and the other at the loop of a catheter inserted into the femoral artery. The coincidence head curve and arterial curve were recorded after intravenous injection of 1-[11C]butanol in 15 rats. CBF was calculated by one-compartment curve fitting (CBFo) from 1-min data and with the recirculation corrected height/area method from 3-min data (CBFh · 3min) and 5-min data (CBFh · 5min). CBFo agreed well with CBFh · 5min, although a slight overestimation was observed in CBFh · 3min. The normal CBFo in the normocapnic group (n = 6, paco2 36.7 ± 2.3 mm Hg) was 1.76 ± 0.49 ml/g min (mean ± SD). A good correlation was observed between CBFo ( y) and Paco2 ( x), and the regression line was y = 0.0629 x – 0.715 (r = 0.88, p < 0.0001). We concluded that this method gives the stable blood flow values noninvasively and with a minimum loss of blood (<0.28 ml per measurement). Applications of this method include activation studies, studies on the effect of drugs and treatments, and water and oxygen extraction fraction studies using different tracers in the same rat.
Strategy for the Measurement of Regional Cerebral Blood Flow Using Short-Lived Tracers and Emission Tomography
Authors: Alpert N. M. , Eriksson L. , Chang J. Y. , Bergstrom M. , Litton J. E. , Correia J. A. , Bohm C. , Ackerman R. H. , Taveras J. M.
Published: April 2011

This report describes a strategy for measurement of regional CBF that rigorously accounts for differing tracer partition coefficients and recirculation, and is convenient for use with positron emission tomography. Based on the Kety model, the measured tissue concentration can be expressed in terms of the arterial concentration, the rate constant K, and the blood flow f. The local partition coefficient may be computed as p = f/K. In our approach, maps of K and f are computed from two transverse section reconstructions. The reconstructions are based on weighted sums of projection data measured frequently during the observation period. Theoretical studies of noise propagation in the estimates of K and f were carried out as a function of tomographic count rate, total measurement time, and tracer half-life for varying input functions. These calculations predict that statistical errors in f of between 5 and 10% at a resolution of 1 cm full width at half maximum can be obtained with existing tomographs following i. v. injection. To compare theory and experiment, a series of flow studies were carried out in phantoms using a positron tomograph. These measurements demonstrate close agreement between computed flow and noise estimates and those measured in a controlled situation. This close agreement between theory and experiment as well as the low statistical errors observed suggest that this approach may be a useful tool in clinical investigation.
Intense Furosemide-Sensitive Potassium Accumulation in Astrocytes in the Presence of Pathologically High Extracellular Potassium Levels
Authors: Walz Wolfgang , Hertz Leif
Published: April 2011

An intense K+ accumulation in primary cultures of astrocytes, occurring when external K+ was increased from 5.4 to 54 m M, was investigated. This increase resulted in a doubling of the K+ content within 10 s. Thirty percent of the accumulation was inhibited by furosemide (2 m M). This drug had no effect on the unidirectional influx of K+ at 5.4 m M K+, but when the extracellular K+ concentration was increased, there appeared to be a furosemide-sensitive component of the influx. This component increased with increasing external K+ levels, reaching 44% of the total influx at 72 m M. These results show that astrocytes exhibit an intense furosemide-sensitive K+ accumulation which is activated by K+ levels resembling those occurring in the extracellular compartment during pathological events. Previous studies on a furosemide-sensitive Cl− pump in cultured astrocytes suggest that this accumulation might be via KCl cotransport, which in other systems is involved in volume control.
In vivo Measurement of Regional Cerebral Haematocrit Using Positron Emission Tomography
Authors: Lammertsma Adriaan A. , Brooks David J. , Beaney Ronald P. , Turton David R. , Kensett Malcolm J. , Heather Jon D. , Marshall John , Jones Terry
Published: April 2011

A method is described for measuring the regional cerebral-to-large vessel haematocrit ratio using inhalation of carbon-11-labelled carbon monoxide and the intravenous injection of carbon-11-labelled methyl-albumin in combination with positron emission tomography. The mean value in a series of nine subjects was 0.69. This is ∼20% lower than the value of 0.85 previously reported. It is concluded that previous measurements of regional cerebral blood volume using a haematocrit ratio of 0.85 will have underestimated the value of regional cerebral blood volume by 20%.
Measurement of Blood—Brain Barrier Permeability with Positron Emission Tomography and [68Ga]EDTA
Authors: Kessler R. M. , Goble J. C. , Bird J. H. , Girton M. E. , Doppman J. L. , Rapoport S. I. , Barranger J. A.
Published: April 2011

Positron emission tomography (PET) was employed to examine time-dependent changes in blood–brain barrier (BBB) permeability to [68Ga]ethylenediaminetetraacetate (EDTA) in the rhesus monkey, following reversible barrier opening by intracarotid infusion of a hypertonic mannitol solution. The PET technique, when combined with measurements of plasma radioactivity, provided a quantitative measure of the cerebrovascular permeability-area product ( PA) at different times following mannitol infusion. Hypertonic mannitol treatment reversibly increased PA to [68Ga]EDTA more than 10-fold; much of the barrier effect was over by 10 min after mannitol treatment. The results show that PET can be used to measure transient changes in BBB integrity in specific brain regions, under in vivo, noninvasive conditions.
Alternative Approach to Single-Scan Estimation of Cerebral Glucose Metabolic Rate Using Glucose Analogs, with Particular Application to Ischemia
Authors: Hutchins G. D. , Holden J. E. , Koeppe R. A. , Halama J. R. , Gatley S. J. , Nickles R. J.
Published: April 2011

In the glucose analog method for determining local glucose utilization rates, time courses of tissue and plasma radioactivity are measured and then analyzed in terms of first-order exchange of label between tissue compartments. The rate of glucose utilization is assumed to have a fixed, linear relationship to the analog phosphorylation rate calculated from the fitted rate constants. Accurate estimation of the rate constants requires many hours of dynamic data acquisition. Therefore, techniques assuming a linear relationship between analog phosphorylation rate and total tissue concentration of label were developed to predict glucose utilization rates from a single scan. Previously reported linearizations differ in their sensitivity to differences between current and average kinetic rate constants, and thus in their accuracy. We have developed a method that is insensitive to the presumed value of the blood flow–capillary wall transport parameter k1. This new single-scan approach has been validated by comparison of the single-scan metabolic rate values with the values calculated from the dynamic measurements.
Calcium Overload in Selectively Vulnerable Neurons of the Hippocampus during and after Ischemia: An Electron Microscopy Study in the Rat
Authors: Simon R. P. , Griffiths T. , Evans M. C. , Swan J. H. , Meldrum B. S.
Published: April 2011

Light and electron microscopy has been used to study the cytopathological changes in the rat hippocampus directly after a 30-min period of forebrain ischemia and after 30 or 120 min of reperfusion. The fine structural localization of calcium has been demonstrated using the oxalate/pyroantimonate procedure. Cellular changes considered typical of ischemia (swelling of astrocytic processes, distention of mitochondria, condensation of cytoplasm, “ischemic cell change”) are most prominent after 30 min of reperfusion. At this time, dense calcium pyroantimonate deposits are evident in swollen mitochondria in pyramidal and hilar neurons. After 120 min of reperfusion, substantial restitution has occurred; most mitochondria appear normal and there are few calcium deposits. However, a small number of selectively vulnerable neurons (hilar and pyramidal neurons) show dense condensation (ischemic cell change) with multiple vacuoles containing calcium deposits. The role of excessive calcium entry and mitochondrial calcium overload during the reperfusion period in determining the death of selectively vulnerable neurons is discussed.
Retroglenoid Venoconstriction and its Influence on Canine Intracranial Venous Pressures
Authors: Pearce William J. , Bevan John A.
Published: April 2011

Using standard in vitro techniques, we found that the canine retroglenoid vein, a vessel that drains a significant fraction of canine cerebral venous effluent, demonstrated the following: an average wall thickness of ∼240 μm; a norepinephrine (NE) content of ∼3 μg/g tissue; a NE uptake capacity (uptake 1) of ∼8 nmol/g tissue; an ED50 for NE of 1.9 × 10−8 M; and a phentolamine-sensitive constriction during electric transmural stimulation that had a median effective frequency of ∼3 Hz and a maximum response that was ∼84% of the maximum response to exogenous NE. In a separate series of in vivo experiments conducted in six α-chloralose-anesthetized dogs, we found that electrical stimulation of the left superior cervical ganglion produced a phentolamine-sensitive, frequency-dependent increase in cerebral venous pressure (CVP) of up to 19 mm Hg when all cerebral venous effluent was diverted through the left retroglenoid vein. Taken together, our findings suggest that the canine retroglenoid vein undergoes a marked vasoconstriction during physiological frequencies of electric sympathetic nerve stimulation in vivo. Although our data further suggest that the retroglenoid is not a dominant influence on CVP in the intact dog, they do encourage a cautious interpretation of cerebral venous outflow data obtained with techniques in which cerebral effluent is drained primarily by extracranial veins.
Influence of the Input Function on the Calculation of the Local Cerebral Metabolic Rate for Glucose in the Deoxyglucose Method
Authors: Kato Amami , Menon Devidas , Diksic Mirko , Yamamoto Y Lucas
Published: April 2011

We describe here a modification of Sokoloff's deoxyglucose method which requires fewer blood samples but does not diminish accuracy. To calculate the local cerebral metabolism for glucose (LCMRglu), the input function containing the initial peak must be known. This requires many blood samples for accurate definition. To estimate the influence of the peak on the LCMRglu, a dummy input function was generated by extrapolating the data points after 2 min back to 0 min. Next, a biexponential curve, fitted to a reduced number of samples, was applied for the input function. The error introduced into the LCMRglu by using these different approximations was analyzed with an error function derived from an operational equation. The results indicate that the error of LCMRglu caused by neglecting the peak is <3%. Furthermore, the error of LCMRglu resulting from use of the biexponential approximation is a function of LCMRglu: the error decreases as the LCMRglu increases and remains at <3% even when only seven data points are used (half the usual number of the standard method). Finally, the LCMRglu was calculated by the biexponential curve-fitting, using the experimental data, and compared with that calculated by Sokoloff's computer program. Both methods were in good agreement. This modified method offers great advantage for simultaneous measurement of CMRglu, CBF, and other physiological parameters by means of the multiple tracer autoradiographic technique in the small laboratory animal.
Cerebral Metabolic Relationships for Selected Brain Regions in Alzheimer's, Huntington's, and Parkinson's Diseases
Authors: Metter E. Jeffrey , Riege Walter H. , Kameyama M. , Kuhl David E. , Phelps Michael E.
Published: April 2011

Local CMRGlc values were determined for 13 regions in each hemisphere from tomographs of patients with Alzheimer's, Huntington's, and Parkinson's diseases who were studied using [18F]fluorodeoxyglucose with positron emission computed tomography. Intercorrelations among the 26 regional measures were calculated for each disease state and for normal controls, and were accepted as reliable at p < 0.01, uncorrected for the number of comparisons. The number of reliable correlations was found to be decreased in Parkinson's and Huntington's diseases, two primarily subcortical disorders, and increased in Alzheimer's disease, a primarily cortical disorder. The changes suggest that one role of the basal ganglia involves coordinating or pacing the ability of cortical brain regions to function as a unit.
A Kinetic Evaluation of Blood—Brain Barrier Permeability in Human Brain Tumors with [68Ga]EDTA and Positron Computed Tomography
Authors: Hawkins Randall A. , Phelps Michael E. , Huang Sung-Cheng , Wapenski Joseph A. , Grimm Peter D. , Parker Robert G. , Juillard Guy , Greenberg Peter
Published: April 2011

Twelve patients with primary and metastatic brain tumors were evaluated with [68Ga]ethylenediaminetetraacetate (EDTA) and positron computed tomography. Using a two-compartment tracer kinetic model, foward ( K1) and reverse ( k2) rate constants for molecular diffusion across the blood–brain barrier (BBB) were obtained and averaged 0.0029 ± 0.0016 (mean ± SD) ml/min/g for K1 and 0.0310 ± 0.0156 min−1 for k2. Most tracer kinetic models are based on the assumption that tissue radioactivity contains no vascular component or require independent measures of cerebral blood volume (CBV) which are then subtracted from the measure tissue activity. The model in this work differs from that approach by assuming a vascular compartment in the tissue kinetic data. This vascular parameter is estimated from sequential measurements of activity concentrations in regions with an intact BBB or from measurements of 68Ga concentrations in the plasma (the input function). Thus, this approach does not require the assumption of a zero vascular contribution, does not require a separate measurement of CBV, and uses the criteria of constrained estimation to provide estimates of the local CBV and molecular diffusion through the BBB. Estimates of the relative CBV of the lesions in four studies (three subjects) with [68Ga]EDTA correlated well with those obtained with the C15O hemoglobin technique (correlation coefficient of 0.97).