Iodoamphetamine as a new tracer for local cerebral blood flow in the rat: comparison with isopropyliodoamphetamine.

Rats were injected with iodoamphetamine synthesized and labeled with 125I or with 125I- isopropyliodoamphetamine , a molecule of established value for the determination of local cerebral blood flow. The blood kinetics, tissue distribution, and brain uptake index for each tracer exhibited practically no differences. Autoradiographic quantification of the local cerebral blood flow, calculated according to the microsphere model, produced identical results for both molecules. However, compared with the values reported for other tracers, our values constituted an underestimation of white matter blood flow and a more real estimation of hippocampal flow. It is concluded from the brain uptake of the derivatives of both amphetamines during the first minutes following their injection that these tracers can be used as a chemical microembolus for the measurement of local cerebral blood flow.

Multiparametric imaging of blood flow and metabolism after middle cerebral artery occlusion in cats.

In anesthetized adult cats, acute stroke was produced by transorbital occlusion of the left middle cerebral artery. A battery of imaging techniques was used for simultaneous evaluation of regional blood flow, glucose utilization, protein synthesis, pH, and the regional tissue content of glucose, ATP, and potassium. The electrophysiological impact of stroke was monitored by EEG frequency analysis and recording of somatosensory evoked potentials. Two hours after vascular occlusion, a close correlation existed between the degree of electrophysiological changes and biochemical alterations, in particular with the extent of tissue acidosis, ATP depletion, decrease of tissue potassium content, and suppression of protein synthesis. However, there was only a poor correlation with blood flow and glucose utilization. Both of these exhibited a greatly inhomogeneous pattern with regions of reduced, normal, or increased rates. In areas remote from the infarct, the content of biochemical substrates was normal but blood flow was reduced globally by approximately 50% and glucose utilization by approximately 20%. An anatomically defined regional pattern of cerebral or cerebellar diaschisis was not observed. It is concluded that during the acute phase of stroke, imaging of blood flow and glucose utilization does not provide an accurate estimate of the actual functional or metabolic disturbance. For the clinical evaluation of the development or treatment of stroke, in consequence, alternative noninvasive techniques such as imaging of protein synthesis and/or pH may be more relevant.

Cerebral blood-flow tomography: xenon-133 compared with isopropyl-amphetamine-iodine-123: concise communication.

Tomographic maps of local cerebral blood flow (CBF) were obtained with xenon-133 and with isopropyl-amphetamine-iodine-123 (IMP) in 11 subjects: one normal, two tumor cases, and eight cerebrovascular cases. A highly sensitive four-face, rapidly rotating, single-photon emission tomograph was used. The Xe-133 flow maps are essentially based on the average Xe-133 concentration over the initial 2 min during and after an inhalation of the inert gas lasting 1 min. These maps agreed very well with the early IMP maps obtained over the initial 10 min following an i.v. bolus injection. The subsequent IMP tomograms showed a slight decrease in contrast amounting to appr. five percentage points in the CBF ratio between diseased and contralateral areas. It is concluded that Xe-133 is more practical: low cost, available on a 7-day basis, easily repeatable, quantifiable without the need for arterial sampling, and with low radiation exposure to patient and personnel. On the other hand, IMP gives an image of slightly higher resolution. It also introduces a new class of iodinated brain-seeking compounds allowing, perhaps, imaging of other functions more important than mere blood flow.

Blockade of the different enzymatic steps in the synthesis of brain amines and memory (CAR) in hypobaric hypoxic rats treated and untreated with L. dopa.

L. Dopa associated with an extracerebral inhibitor of dopadecarboxylase is able to protect the rat against the deleterious effects of hypobaric hypoxia on a conditioned avoidance response. L. Dopa loses its protective effect against hypoxia if tyrosine hydroxylase, dopadecarboxylase, or dopamine beta hydroxylase is previously blocked. L. Dopa's protective effect must therefore be due to an indirect action on the endogenous catecholamine metabolism.

[Cerebral blood flow, metabolism and learning after a cerebral infarction in the rat (author's transl)]. / Débit cérébral, métabolisme et comportement a la suite d'un infarctus cérébral chez le rat.

Experimental microembolization of the rat brain has been used as a model for the production of cerebral microinfarction which resulted in a decrease in blood flow and secondary brain edema with changes in the oxidative metabolic pathways. The use of radioactive microspheres as embolizing agents allowed to determine the number of microinfarctions and their localization. In every microinfarct, oedema developed and it could be quantified by measuring the water percentage as soon as the fourth hour following the microembolization. The activity of oxygen-dependent enzymes was severely reduced in the ischemic area around which hyperemia was present. A quick decrease in the ATP and glucose levels and an increase in the lactate levels were observed, showing that the energetic metabolism was deviated towards the anaerobic pathway. On the fifth day following the microembolization, the oedema disappeared. The cellular metabolic activity and the cerebral blood flow almost returned to normal values within the same time. The simultaneously study of an avoidance response in a conditioned learning test showed a correlation between the reappearance of this response and the regression of the oedema.

[Cerebral glucose consumption. The effect of Ginkgo biloba extract]. / Consommation cérébrale du glucose. Effet de l'extrait de Ginkgo biloba.

Deoxyglucose is transported under the same conditions as glucose from blood to cerebral tissue. Deoxyglucose-6-phosphate, which cannot be neither metabolized nor eliminated, accumulates in cells. This accumulation is correlated with glucose consumption. In this study, two parameters, transfer rate of deoxyglucose and glucose consumption were measured by means of quantitative autoradiography in two experimental models: normobaric hypoxia and carotid clamping in rats. Normobaric hypoxia induced a decrease in both transfer rate and glucose consumption. Ligature of the carotid artery induced a diminution of glucose consumption greater than that of transfer rate. After administration of Ginkgo biloba extract, glucose consumption was partly reestablished in both experimental models, but the transfer rate of deoxyglucose was increased only in normobaric hypoxia.

[Protective effects of Ginkgo biloba extract on the early rupture of the hemato-encephalic barrier in the rat]. / Effets protecteurs de l'extrait de Ginkgo biloba sur la rupture précoce de la barrière hémoencéphalique chez le rat.

During the hours immediately following an hypertensive burst or a cerebral ischemia induced by the intracarotid administration of microspheres, damage to the blood brain barrier can be observed with molecules of low molecular weight, such as angiotensin, whereas albumin or large proteins will not yet have been able to cross over and there is virtually no edema. Gingko biloba extract causes the brain uptake index of angiotensin hypertensive animals. This effect is proportional to the dose of extract used (500-100 mg/kg). A similar effect can be observed in animals showing embolism in one hemisphere. The process can therefore doubtlessly be explained by the stabilizing effect of Ginkgo biloba on membranes.

[Learning, hemodynamic and metabolic attendant effects in aged animals after an acute ischemic accident]. / Apprentissage et concomitances hémodynamiques et métaboliques chez l'animal âgé après un accident ischémique aigu.

The effects of ageing in normal and pathological rats were studied. Learning (spatio-temporal test) was measured simultaneously with the local cerebral blood flow, determined by a diffusible indicator (iodoantipyrine) and with the uptake and consumption of glucose, determined by the deoxyglucose. Normal ageing disturbs the learning with a decrease in acquisition speed and an increase in the number of errors. Furthermore, normal ageing induces a decrease in glucose uptake and in glucose consumption in the brain structures such as hippocampus or corpus striatum, with only a slight decrease in local cerebral blood flow. Dihydroergotoxine partially reestablishes the performances of the rats and increases the glucose consumption in the areas involved in learning. Pathological ageing, produced by the administration of microspheres and corresponding to the multi-infarct dementia, is correlated to a large decrease in glucose consumption and local blood flow. Dihydroergotoxine treatment partially suppresses the micro-infarct effects before the reestablishment of rat performance in behavioral tests.

[Effect of citidoline on hemodynamics in the normobaric hypoxic dog]. / Influence d'un traitement par la citidoline sur les effets hémodynamiques de l'hypoxie normobare chez le chien.

In dogs submitted to a normobaric hypoxia, we found an elevation of the arterial blood pressure, of the heart rate, of the cardiac output and of the regional blood flows, the total peripheral resistance remaining unchanged. Treatment with citidoline abolishes these hemodynamic responses and the authors hypothetize that this effect is correlated with the agonist dopaminergic effect of the drug.

Age and learning: experimental and clinical aspects.

Memory loss and similar cognitive associated dysfunctions are commonly recognized as being the most serious symptoms of ageing and dementia. In this work, a deterioration of cognitive function which is appreciated in old rats (learning test in a maze--or, in aged humans, memory verbal test) is determined during the measurement of local cerebral blood flow and metabolism. In the animal, the disturbance by the learning test is observed by a decrease of blood flow in the hippocampus, diencephalon, and corpus striatum. In man, the cognitive dysfunctions appear although there is an increase of blood flow in the frontal cortex. These data show a new organization in the ageing brain which only appears during cerebral stimulation.

Simultaneous study of cerebral blood flow, vascular bed and deoxyglucose in aged rats. Effects of two dihydrogenated rye ergot alkaloids.

The influence of aging and the effects of treatment with dihydrogenated rye ergot alkaloid on cerebral hemodynamics and metabolism were studied in Long-Evans rats. Cerebral blood flow (CBF) was not affected by aging whereas the vascular bed and the uptake of deoxyglucose were significantly lower in aged than in young rats. 20 days after ligation of a carotid artery the blood flow on the same side of the brain, the vascular bed and the uptake of deoxyglucose were significantly lowered in aged rats as opposed to young rats. The second carotid artery was ligated 1 h before the animals were sacrificed: in the corresponding cerebral hemisphere the blood flow was found to be significantly lowered in young rats and even more so in aged rats. These results show that young rats are more likely to adapt to an acute or chronic circulatory deficiency than aged rats. Dihydroergocryptine ( DHEC , 0.1 mg/kg/day for 5 days, p.o.) reduces CBF and the vascular bed in aged rats, as opposed to dihydroergotoxine ( DHET , 5 X 0.1 mg/kg/day p.o.). The uptake of deoxyglucose was not influenced by the treatments. After ligation of the carotid arteries, treatment with DHEC and DHET induced an increase in CBF without any change in the vascular bed and, in the case of DHEC only, there was a significant increase in the uptake of deoxyglucose in the cerebral hemisphere submitted to acute circulatory deficiency. DHEC and DHET thus exerted significant effects on cerebral metabolism and hemodynamics in the aged rats after repeated oral treatment.

[Experimental model of cerebral ischemia preventive activity of Ginkgo biloba extract (author's transl)]. / Modèle expérimental d'ischémie cérébrale. Action préventive de l'extrait de Ginkgo.

Unilateral embolization of the brain was performed in rats by intracarotid injection of 4 000 radioactive microspheres (50 mu). Local blood flow in hippocampus, striatum, hypothalamus and remainder of the brain were determined using the iodoantipyrine technique. Embolization resulted in a decreases in blood flow and modificationof the distribution of microflow. Furthermore, embolization produces changes in energy metabolism : particularly a fall in ATP and glucose levels and an increase in lactate level. Subsequently, severe vasogenic edema developed. There was a correlation between the number of microspheres injected and the amount of edema. Pretreatment using an extracted of Ginkgo biloba leaves partially suppressed the effect of embolization. An improvement of the flow in the ischemic areas associated with an improvement of the energy metabolism explain the decreases of the edema.

[Hemodynamic, functional and biochemical effects of hypobaric hypoxia in rats treated with cytidine diphosphocholine]. / Effets hémodynamiques, fonctionnels et biochimiques de l'hypoxie hypobare chez le rat traité par la cytidine diphosphocholine.

Treatment with cytidine diphosphocholine (20 mg/kg i.p.) in rats induces, during acute hypoxia, a reduction of vegetative responses (no modification of cerebral blood flow), a protection of conditioned avoidance response and a stabilization of dopamine and noradrenaline cerebral levels.

[Cerebral blood flow metabolism and behavior following cerebral infarction in the awake rat (author's transl)]. / Conséquences d'un infarctus cérébral chez le rat vigile, sur le débit sanguin cérébral, le métabolisme et le comportement.

In the awake rats, a cerebral ischemia was performed by means of 2,000 microspheres administered into the internal carotid via a chronic catheter. After a coma lasting for a few minutes and a 24-48 h palsy, the Long Evans rats gradually recover a normal behavior. The acquisition of an avoidance response is deeply disturbed by microembolization but the capacities of memorization reappeared with the regression of oedema. 7 days after embolization, the cerebral blood flow in ischemized hemisphere was still significantly decreased, and in spite the glucose consumption was identical in ischemized and non ischemized side. This latter parameter is a better index of the cell activity. This model in the awake rat was proposed for the study of molecules used in cerebral ischemia without interference of anesthetics drugs.

Deoxyglucose uptake in pathological conditions.

In case of quick physiological variations or in pathological conditions, it is impossible to measure the deoxyglucose consumption by means of the deoxyglucose technique and we propose a method for the study of the deoxyglucose uptake by the cerebral tissue. It is simultaneously measured with the blood flow, 3 min following the intravenous administration of deoxyglucose (2-deoxyglucose-14C). Hypercapnia induces an increase in the flow but does not modify the deoxyglucose uptake and moderate hypoxia results in a decrease in the deoxyglucose uptake without modifying the flow. In pathological conditions such as ischemia or stricture, the blood flow and deoxyglucose uptake variations are not parallel. These results show that the 2-deoxyglucose uptake does not follow the blood flow and that it depends on the cell activity. It is therefore possible to use this method when the consumption studies cannot be implemented.

Effects of Ginkgo Biloba on changes induced by quantitative cerebral microembolization in rats.

Unilateral embolization of the brain was performed in rats by the intracarotid injection of 4000 radioactive microspheres (50 micron). The local blood flow was determined using the iodoantipyrine technique in the hippocampus, hypothalamus, striatum and remainder of the brain. Embolization resulted in a decrease in the blood flow and a modification of the distribution of microflow. Besides, the embolization produced changes in energy metabolism, specially a fall in ATP and glucose levels and an increase in lactate level. Subsequently severe vasogenic cerebral edema developed. There was a correlation between the number of microspheres injected and the extent of edema. Pretreatment with an extract of Ginkgo Biloba leaves partially suppressed the effects of the embolization. An increase in the blood flow associated with normalization of cellular energy metabolism explained the decrease in brain edema.

Age-associated changes in deoxyglucose uptake in whole brain.

Cerebral blood flow, studied by means of a diffusible indicator, remains unchanged in the aging process (developmental changes). On the contrary, brain activity, evaluated by deoxyglucose uptake, is significantly reduced. Papaverine, which increases cerebral blood flow, and vincamine, slightly but significantly, act on this parameter in the older animals.

Learning and cholinergic neurotransmission in old animals: the effect of Hydergine.

In the present work, a study of the number of functional receptors has been made with 3HQNB given to resting awaken animals during a learning process. Ageing leads to a decrease in the ability of learning associated with an increase in the number of large movements. The number of cholinergic receptors is also reducel if we compare 22 month old animals with 4 month old animals maintained under usual conditions. Learning conditioning leads to a stimulation of the cholinergic system with a release of acetylcholine. The mediator takes the 3HQNB out of its fixation areas which causes an apparent decrease in the number of receptors. This result is more significant in young animals than in aged ones because of the possibility of activation in the cholinergic system. The treatment by dihydroergotoxine partially re-establishes the learning abilities in animals and, at the same time, increases the number of cholinergic receptors This effect could explain the actions of this drug on the memory process in ageing persons.

Simultaneous study of haemodynamic, metabolic and behavioural sequelae in a model of cerebral ischaemia in aged rats: effects of nicergoline.

Unilateral cerebral ischaemia was induced in 18-month-old Long-Evans rats by injection of 2,000 labelled microspheres (phi 50 microns) into the carotid blood stream. This results in an ipsilateral decrease in cerebral blood flow, development of severe oedema and modifications of glucose uptake and consumption. Furthermore, this ischaemia led to a deterioration of the avoidance response in conditioned animals. All these disturbances, including the cerebral oedema, diminished with nicergoline pretreatment.

Demonstration of vascular redistribution after carotid clamping in rats.

In Long Evans rats, the vertebral arteries supply only the brain stem. Simultaneous application of clamps to both carotid arteries results in a considerable fall of cerebral blood flow and eventually death. If an interval of about 4 days is allowed between the clamping of the 2 carotids, redistribution of blood flow takes place. Owing to this mechanism, 50% of the rats survive with a satisfactory restoration of cerebral blood flow.