Search PubMed⌕ Search

Biomedical subjects

M Ingvar

Publications and source records attributed to M Ingvar.

At least 91 records · Page 5Linked to original sources
PubMed1985

Convulsive and non-convulsive ethanol withdrawal behaviour in rats with lesions of the noradrenergic locus coeruleus system.

The ascending noradrenergic pathways from the locus coeruleus were lesioned bilaterally in 10 rats by intracerebral 6-hydroxydopamine injections. Ten rats were sham-operated. All animals were subjected to a 4-day ethanol intoxication period using intragastric intubation. Intoxication and withdrawal assessments were performed blindly. The 6-hydroxydopamine lesions did not appear to affect tolerance to ethanol. During withdrawal, however, lesioned animals showed minor, but statistically significant changes in scores of certain non-convulsive withdrawal signs, but incidence and intensity of spontaneous and audiogenic convulsive seizures were not different between the groups.

Acoustic Stimulation↗
PubMed1985

Status epilepticus in well-oxygenated rats causes neuronal necrosis.

Neuronal necrosis in the brain resulting from status epilepticus of 15 to 120 minutes duration in ventilated and well-oxygenated rats was assessed. Seizures were induced by inhalation of the convulsant gas flurothyl, and terminated by withdrawal of flurothyl and a single injection of thiopental. The animals were allowed to recover for one week, and neuronal damage was assessed by cell counts following subserial sectioning of the brain and microscopical examination of the sections. Infarction of the pars reticulata of the substantia nigra occurred in 5 of the 6 animals with seizure duration of 30 minutes, and in all animals with longer seizure durations. There also was a common affectation of the central parts of the globus pallidus. The pars compacta of the substantia nigra was never affected. After 45 to 120 minutes of seizures, moderate neuronal necrosis was observed in the neocortex (layers 3 and 4), and after 60 to 120 minutes was seen in amygdaloid and thalamic nuclei, as well as in CA4 and CA1 hippocampal pyramidal cells. Notably, CA3 neurons were not damaged nor were dentate granule cells affected. After 120 minutes of seizures, damage regularly affected the neocortex and the ventral-posterior nuclei of the thalamus. A conspicuous feature was the localization of neuronal necrosis at sites close to the ventricles.

Animals↗
PubMed1985

Functional reactivation of the deafferented hippocampus by embryonic septal grafts as assessed by measurements of local glucose utilization.

Transection of the septo-hippocampal connections through fimbria-fornix damage in the rat results in profound hippocampal cholinergic deafferentation, and, when applied bilaterally, leads to severe and long-lasting impairments in learning and memory. Previous studies have shown that intrahippocampal septal grafts can reestablish a new cholinergic in the initially denervated hippocampal formation and at least partly compensate for the lesion-induced learning impairments in fimbria-fornix lesioned rats. The purpose of the present study was to determine the magnitude of lesion-induced alterations in cerebral function as reflected in local glucose use measured by (14C)-2-deoxyglucose (2-DG) autoradiography, and the degree to which this index of functional activity could be normalized following reinnervation from transplants of fetal cerebral tissue from the primordial septal region. Six months after unilateral fimbria-fornix transection the rate of glucose utilization was reduced markedly throughout the ipsilateral hippocampus when compared to the intact contralateral side, while in the neocortex only the cingulate cortex showed long-lasting reductions in glucose use. Rats that received a transplant of fetal septal-diagonal band tissue at the time of fimbria-fornix transection, and were sacrificed 6 months later, displayed significantly greater glucose utilization in the ipsilateral hippocampus and cingulate cortex than was measured in these areas in rats with lesion alone. The recovery in glucose use was paralleled by a significant increase in acetylcholinesterase (AChE) staining in several areas of the ipsilateral hippocampal formation and cingulate cortex. This index of graft-induced cholinergic reinnervation was, moreover, significantly correlated with the rate of glucose use. Thus, in the fimbria-fornix transected animals the magnitude of glucose depression correlated with the extent of reduction in AChE staining, and in the grafted animals the degree of normalization of glucose use was correlated with the graft-induced increase in AChE-staining density. These results thus indicate that the 2-DG autoradiographic technique can provide a unique opportunity to map both altered functional activity in localized areas of the brain following specific lesions and the extent to which transplant-derived reinnervation of the host may induce a return to normal functional levels in the target site.

Acetylcholinesterase↗
PubMed1985

11C-labeled 4-isopropylantipyrine: preparation and biological evaluation as a blood flow tracer in positron emission tomography (PET).

Radiolabeled 4-isopropylantipyrine (1) has been synthesized and evaluated as a tracer for the measurement of cerebral blood flow (CBF). Methylation of 4-isopropyl-3-methyl-1-phenylpyrazol-5-one (2) with [14C]methyl iodide in acetonitrile gave [14C]-1 in radiochemical yields of 10-20%. Its blood-brain partition coefficient in rats was determined to be 0.62 +/- 0.03 (mean +/- SE). Autoradiographic determination of regional cerebral blood flow under normal flow conditions indicated that [14 C]-1 gives results essentially identical with those obtained with the widely used tracer [14C]-4-iodoantipyrine ( [14C]-IAP). Studies performed in high-flow states indicated that [14C]-1 is not more diffusion limited than [14C]-IAP. A rapid synthesis was therefore developed for the preparation of [11C]-1. Radiochemical yields were increased to 40-50% when the alkylation of 2 with [11C]methyl iodide was performed in dimethyl sulfoxide using solid potassium hydroxide as a base. Since the 11C-labeled compound can easily be produced in large quantities and since the tracer is not diffusion limited at flow rates commonly observed in normal and most pathological states in man, [11C]-4-isopropylantipyrine will be used for in vivo studies of CBF using positron emission tomography.

Animals↗
PubMed1985

Extra- and intracellular pH in the brain during seizures and in the recovery period following the arrest of seizure activity.

The objective of the study was to estimate changes in extracellular pH (pHe) and intracellular pH (pHi) during seizures and in the recovery period following the arrest of seizure activity. Seizures of 5- and 20-min duration were induced in rats by fluorothyl added to the insufflated gas mixture, and recovery for 5, 15, and 45 min was instituted by withdrawal of the fluorothyl supply following 20 min of continuous seizures. Changes in pHe were measured by double-barreled, liquid ion-exchange pH microelectrodes, and in pHi by the CO2 method, following estimation of tissue PCO2 and extracellular fluid (ECF) volume. The animals were either normoxic or rendered moderately hypoxic (arterial PO2 40-50 mm Hg). Upon induction of seizures in normoxic animals, pHe decreased by a mean of 0.36 unit, the values being identical at 5 and 20 min. In moderate hypoxia, seizures sustained for 20 min were accompanied by a further fall in pHe (mean decrease 0.51 unit). The changes in pHe seemed mainly to reflect the nonionic diffusion of lactic acid from cells to the ECF (tissue lactate levels approximately 10 and 15 mumol g-1 during seizures in normoxic and hypoxic animals, respectively). However, the gradual fall in pHe attributable able to lactic acid production was preceded by rapid acidification, sometimes exceeding the steady-state values subsequently attained. This acidification was interpreted to reflect spreading depression and fast transcellular Na+/H+ exchange. Following cessation of seizure discharge, pHe normalized at a surprisingly slow rate, with some acidosis persisting even after 45 min. The difference between cerebrovenous and arterial PCO2 was reduced during seizures and increased in the recovery period, probably reflecting alterations in the blood flow/metabolic rate coupling. Impedance changes were slight, indicating only minor changes in ECF volume. Changes in pHi after 5 min of seizures ranged from 0.20 (normoxic animals) to 0.32 (hypoxic animals) unit, the pHi values after 20 min being 0.07-0.08 unit higher. The results suggest the regulation of pHi during ongoing seizures. Upon arrest of seizure activity, pHi rapidly increased to normal and subsequently to supranormal values. Postepileptic intracellular alkalosis occurred at a time when pHe was still reduced and in spite of the fact that tissue lactate values had not normalized. It is concluded that the rapid normalization of pHi and overt alkalosis were caused by the simultaneously occurring oxidation of lactate, with the removal of a stoichiometrical amount of H+, and the extrusion of H+ from cells, possibly via a Na+/H+ exchanger, the latter probably delaying normalization of pHe.

Acid-Base Equilibrium↗
PubMed1985

Cerebral metabolic changes during and following fluorothyl-induced seizures in ventilated rats.

The objective of the present study was to assess metabolic changes in the neocortex and hippocampus of well-oxygenated or moderately hypoxic rats in which fluorothyl-induced seizures were sustained for 5 or 20 min, or which were allowed recovery periods of 5, 15, or 45 min following cessation of 20-min seizure activity by withdrawal of the convulsant gas. Sustained fluorothyl-induced seizures were found to cause metabolic alterations qualitatively and quantitatively similar to those previously observed with other commonly used convulsants. Thus, although the phosphorylation state of the adenine nucleotide pool remained only moderately perturbed, if at all, there were decreases in tissue concentrations of phosphocreatine and glycogen, and increases in those of cyclic AMP, lactate, and pyruvate, with a calculated fall in intracellular pH of about 0.15 units and a rise in the cytoplasmic NADH/NAD+ ratio. The enhanced metabolic rate was reflected in a marked reduction in the tissue-to-plasma glucose concentration ratio. Induced moderate hypoxia (arterial PO2 40-50 mm Hg) had no metabolic effect after 5 min of seizures but moderately increased lactate concentrations after 20 min (from about 10 to about 15 mumol X g-1). On cessation of seizure discharge cyclic AMP and phosphocreatine concentrations normalized already within 5 min, whereas glycogen and lactate concentrations normalized more slowly. In the neocortex (but not the hippocampus) postepileptic tissue-to-plasma glucose concentration ratios rose above control, probably reflecting metabolic depression. The results suggest that intracellular pH promptly returned to control, and that postepileptic alkalosis developed. They also suggest that some elevation of the NADH/NAD+ ratio persisted even after 45 min of recovery.

Adenine Nucleotides↗
PubMed1984

Cerebral metabolic and circulatory effects of 1,1,1-trichloroethane, a neurotoxic industrial solvent. 1. Effects on local cerebral glucose consumption and blood flow during acute exposure.

The effects of inhaled 1,1,1-trichloroethane (3500, 6000, and 7800 ppm) on behavior, local cerebral blood flow, and local cerebral glucose consumption were studied in awake rats. The effect of the solvent inhalation on the EEG pattern and local cerebral blood flow was also studied in paralyzed animals under N2O analgesia. Exposure of awake animals to 6000 ppm 1,1,1-trichloroethane induced a decrease in motility and exploratory behavior. At 7800 ppm the rats were clearly ataxic. The local cerebral glucose consumption in 23 brain regions was studied by the [14C]deoxyglucose technique. A decrease was observed ranging from 14 to 55% of control values. The inferior colliculus and substantia nigra displayed the largest reductions. In exposed animals the local cerebral blood flow increased in 11 brain structures by 28-45%. In animals under N2O analgesia, 7400 ppm 1,1,1-trichloroethane induced a depression of the EEG activity. In these animals the local cerebral blood flow increased by 12-99%, with a large variability in blood flow between the different structures. It is concluded that exposure of rats to subanesthetic doses of 1,1,1-trichloroethane induces an increase in cerebral blood flow in spite of a concomitant decrease in glucose consumption and depression of cerebral function.

Anesthesia↗
PubMed1984

Regional cerebral blood flow in conscious stroke-prone spontaneously hypertensive rats.

Regional cerebral blood flow (rCBF) was measured autoradiographically with [14C]iodoantipyrine as a diffusible tracer in two strains of conscious normotensive rats (Wistar Kyoto and local Wistar) and in two groups of spontaneously hypertensive stroke-prone rats (SHRSP) with a mean arterial pressure (MAP) below or above 200 mm Hg. In spite of the large differences in arterial pressure, rCBF did not differ significantly between the hypertensive and the normotensive groups in any of the 14 specified brain structures measured. However, rCBF increased asymmetrically within part of the caudate-putamen in two of nine SHRSP with a MAP above 200 mm Hg, indicating a regional drop in the elevated cerebrovascular resistance.

Animals↗
PubMed1984

Metabolic, circulatory, and structural alterations in the rat brain induced by sustained pentylenetetrazole seizures.

Previous studies have demonstrated that bicuculline-induced seizures of 1-2 h in duration lead to structural, metabolic, and circulatory alterations in the rat brain. Such alterations were observed even though cerebral oxygenation seemed adequate. In the present study, we explored whether pentylenetetrazole, a convulsant which interferes with gamma-aminobutyric acid inhibition by mechanisms other than that of bicuculline, leads to similar structural alterations and to similar cerebral metabolic and circulatory changes. The drug was given to paralyzed and artificially ventilated rats in a dose of 100 mg/kg i.v., and seizures were allowed to continue for 1-120 min. The onset of seizures was accompanied by a small perturbation of cerebral cortical energy state, but sustained changes were confined to decreases in phosphocreatine, glycogen, and glucose and increases in lactate, pyruvate, and cyclic nucleotides. A sustained increase in free fatty acid concentration was observed, with the largest change occurring in arachidonic acid concentration. In the cerebellum, metabolic perturbation was clearly less pronounced, but cyclic nucleotide concentrations rose substantially. Local cerebral blood flow increased in all but two structures (frontal cortex and caudoputamen), but pronounced interstructural changes occurred. Nerve cell changes and astrocytic swelling were observed in the cerebral cortex. There was marked status spongiosus due to edema, which was mainly astrocytic and most prominent in cortical layer 3 and in parts of hippocampus. Nerve cell changes were of two basic types. The type 1 injured neurons, condensed and triangular in shape, were mainly confined to the edematous areas. Many of them had cytoplasmic vacuoles which on electron microscopy proved to be mainly dilated Golgi cisternae or mitochondria. As compared with bicuculline-induced epilepsy such abnormal mitochondria appeared to be more frequent. The type 2 neurons had slit-formed intracytoplasmic and perinuclear vacuoles resulting from dilatation of the endoplasmic reticulum cisternae and the nuclear envelope. The cerebellum looked normal by light microscopy. We conclude that, in the rat, sustained seizure activity induced by pentylenetetrazole is accompanied by alterations in EEG activity, in cerebral metabolism and circulation, and in cell structure similar to those elicited by bicuculline.

Animals↗
PubMed1984

Models for studying long-term recovery following forebrain ischemia in the rat. 1. Circulatory and functional effects of 4-vessel occlusion.

The article describes findings obtained by the application of the Pulsinelli-Brierley 4-vessel occlusion ischemic model in 2 rat strains. In one, a high incidence of respiratory arrest was observed after carotid occlusion. In the other, no such problems were encountered but a large fraction of the animals failed to lose consciousness upon arterial occlusion. In these "stuporous" animals, CBF values of major forebrain structures, as measured by a tissue sampling 14C-iodoantipyrine technique, showed considerable scatter with some values approaching 75% of control. However, even in animals which became comatose, flow was variable and occasionally approached 50% of control, the variability being especially pronounced in the hippocampus and the thalamus. It is concluded that the variability in ischemic flow rates must be taken into account when the model is used for studies of pathophysiological events and therapeutic interventions.

Animals↗
PubMed1983

Influence of lesions of the noradrenergic locus coeruleus system on the cerebral metabolic response to bicuculline-induced seizures.

The objective of the present study was to explore if lesions of the ascending noradrenergic pathways, originating in the locus coeruleus, modulate the cerebral metabolic response to bicuculline-induced seizures in rats. Bilateral noradrenergic lesions were performed by 6-hydroxydopamine injections in the caudal mesencephalon, 12-22 days before seizures were induced in animals ventilated on N2O:O2 (75:25). After 5 min of seizures the brain was frozen in situ and cerebral cortex and hippocampus were sampled for analysis. Labile phosphates, glycolytic metabolites, cyclic nucleotides, and free fatty acids were measured. In another series, lesioned animals were used for measurements of cerebral oxygen consumption. The noradrenergic lesions neither modified the electroencephalographically recorded seizure discharge, nor did they alter cerebral oxygen consumption or cerebral energy state. However, when compared to sham-operated animals, those with noradrenergic lesions had significantly higher (115% and 68%) glycogen concentrations and lower (50% and 52%) cyclic AMP concentrations in cerebral cortex and hippocampus, respectively, demonstrating the marked influence of noradrenergic activity on adenylate cyclase activity and glycogenolysis. The lesions failed to modulate the rise in free fatty acids in the cerebral cortex, or the cyclic GMP concentrations in the cerebral cortex and hippocampus. Thus, increased noradrenergic activity during status epilepticus does not seem responsible for lipolysis or for activation of guanylate cyclase.

Animals↗
PubMed1983

Apomorphine-induced changes in local cerebral blood flow in normal rats and after lesions of the dopaminergic nigrostriatal bundle.

Systemic administration of the dopamine (DA) receptor agonist apomorphine leads to a general increase in cerebral blood flow (CBF) as determined by the autoradiographic iodoantipyrine technique. The magnitude of the increase varies between different regions but shows no obvious relation to the density of either DA terminals or receptors. The circulatory response is much more prominent in the lateral than in the medial caudate-putamen. Apomorphine seems to increase CBF both via a change in metabolic rate and via stimulation of dilatory vascular receptors. In animals with unilateral 6-hydroxydopamine lesions of the ascending DA pathways apomorphine induces an augmented CBF response in some denervated structures, notably caudate-putamen and globus pallidus. It is concluded that this is partly due to stimulation of denervated supersensitive vascular receptors, suggesting a direct dopaminergic control of the blood vessels in these areas.

Animals↗
PubMed1983

Regional differences in vascular autoregulation in the rat brain in severe insulin-induced hypoglycemia.

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 analyzed, 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.

Animals↗
PubMed1983

Local blood flow and glucose consumption in the rat brain during sustained bicuculline-induced seizures.

The present study addresses the problem of whether brain structures which have been shown to develop neuronal cell damage in recurrent or prolonged epileptic seizures have higher metabolic rates and/or less pronounced increases in blood flow rates than others during sustained seizures. To that end, local cerebral blood flow (CBF) and glucose utilization (CMRgl) were measured autoradiographically in ventilated rats, in which seizures of 20, 60, or 120 min duration were induced by i.v. bicuculline. After 20 and 60 min of seizure activity, local CBF increased 2- to 4-fold in most of the 21 structures analysed. However, there was a marked heterogeneity with CBF values varying between 150% (caudoputamen) and 500% (globus pallidus) of control. After 120 min, CBF in several structures, notably cortical and limbic regions, fell in spite of unchanged blood pressure and continued seizure activity. Changes in local CMRgl were equally heterogenous, and correlated poorly with blood flow rates. Some structures (the cerebral cortices and 3 limbic areas) showed a sustained 2-4 fold increase in CMRgl. In these, metabolic rate and blood flow were initially matched but CBF subsequently fell to yield a pattern of relative hypoperfusion. Other structures showed no, or only moderate, increases in CMRgl. In spite of this, CBF increased markedly to yield a pattern of relative hyperemia. It is concluded that bicuculline-induced seizures represent a condition in which structures, observed to be prone to develop cell damage, show grossly enhanced metabolic rate and develop relative underperfusion. Furthermore, the results suggest that structures with a large increase of the metabolic rate during seizures, develop a striking mismatch between local metabolic rate and blood flow.

Animals↗
PubMed1982

Effect of nitrous oxide on local cerebral glucose utilization in rats.

The influence of 70-80% N2O on local local cerebral glucose utilization (CMRg1) in the rat brain was studied with the [14C]deoxyglucose method in minimally restrained, spontaneously breathing animals 75 min following discontinuation of halothane anaesthesia. Nitrous oxide was found to have only small effects on local CMRg1 in the majority of the 25 structures analyzed. When corrections were made for a small difference in body temperature between nitrous oxide--breathing animals and those breathing air nitrous oxide was found to significantly increase local CMRg1 in some subcortical structures by 15-25% (red nucleus, thalamus, geniculate bodies, and superior colliculus), and to decrease local CMRg1 in nucleus accumbens and sensorimotor cortex by comparable amounts. Thus, although nitrous oxide does not alter overall glucose utilization in the brain, it differentially affects CMRg1 in some brain structures.

Animals↗
PubMed1982

The influence of bicuculline-induced seizures on free fatty acid concentrations in cerebral cortex, hippocampus, and cerebellum.

Using ventilated rats maintained on N2O-O2 (70:30, vol/vol) we induced continuous seizures with i.v. bicuculline and analysed free fatty acids (FFA) in cerebral cortex, hippocampus, and cerebellum after seizures durations of 1-120 min. In the cerebral cortex, peak FFA concentrations were observed after 5 min, with a threefold increase in total FFA content. The values then remained unchanged for the next 15-20 min, but decreased thereafter. At 60 and 120 min, total FFA contents were only moderately increased above control. In the initial period, arachidonic acid increased about 10-fold and stearic acid 2- to 3-fold, with little change in palmitic acid and linoleic acid concentrations. At all times, the docosahexenoic acid concentration was markedly increased. Following its massive accumulation at 1 min, arachidonic acid gradually decreased in concentration. Pretreatment of animals with indomethacin did not alter this behaviour. After 20 and 120 min of seizure activity, changes in total and individual FFA concentrations in the hippocampus were similar to those observed in the cerebral cortex. The cerebellum behaved differently. Thus, at 20 min the only significant change was a 5- to 10-fold increase in arachidonic acid concentration and, after 120 min, total and individual FFA concentrations were similar to control values. Furthermore, since the control values for arachidonic acid were much lower in the cerebellum, the 20-min values were only about 20% of those observed in the cerebral cortex and the hippocampus.

Animals↗