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Biomedical subjects

M Ingvar

Publications and source records attributed to M Ingvar.

At least 19 recordsLinked to original sources
PubMed1992

Positron emission tomographic studies of central cholinergic nerve terminals.

The aim of this study was to develop a quantitative method for the study of cholinergic nerve terminals in vivo. An 18F-labeled analogue of vesamicol ([18F]FMV) that binds with high affinity to synaptic vesicles from Torpedo electric organ was synthesized and evaluated in vivo in rats and monkeys by positron emission tomography (PET). In rats, the tracer was rapidly cleared from the blood and highly extracted into the brain, where it was specifically and irreversibly bound. In monkeys, a specific binding of the tracer was observed in brain regions known to contain cholinergic nerve terminals. Preinjection of non-labeled vesamicol prevented the cerebral binding of [18F]FMV to a high affinity site in both species. Our results are a major step towards quantitative human in vivo studies of presynaptic cholinergic functions.

Animals↗
PubMed1992

In vivo distribution of [11C]-busulfan in cynomolgus monkey and in the brain of a human patient.

The in vivo distribution of the antileukemic agent busulfan labeled with the positron-emitting radionuclide carbon 11 was investigated in cynomolgus monkeys and in a human patient using positron emission tomography. After i.v. injection of the radiotracer, its regional uptake was monitored for about 1 h in the monkey's body and, in a separate experiment, in the monkey's brain. The concentration of radioactivity in the liver, which showed the highest levels of all the organs scanned, increased throughout the experiment and was 9-fold that in the brain at the end of the experiment. [11C]-Busulfan rapidly crossed the blood-brain barrier. The radioactivity peaked in both the cortex and the white matter showing a ratio of 1.25, at 3 min but declined quickly to yield a ratio of approximately 1 after 30 min. In the human brain, radioactivity in the cerebellum, cortex, and white matter reached a maximum within 5 min showing a cortex:white matter ratio of 1.6. The activity in the cortex declined to yield a ratio of 1 within 30 min. Of the delivered dose, 20% penetrated into the brain.

Adult↗
PubMed1992

Frontal cortex lesion prior to hyperglycemic ischemia: no decrease in ensuing substantia nigra pars reticulata damage or fatal post-ischemic seizures.

Preischemic hyperglycemia worsens brain damage after ischemia, and characteristically leads to post-ischemic seizures and a pan-necrotic lesion in substantia nigra pars reticulata (SNPR). The excitatory input to SNPR could contribute to the damage observed. By performing a unilateral frontal cortex lesion 6-19 days prior to the ischemia, we wanted to explore whether a decrease in excitatory input to the ipsilateral SNPR ameliorate the seizures or alter the light microscopical damage in SNPR. Our results demonstrate that unilateral frontal cortex lesion did not alter the development of fatal post-ischemic seizures after 10 min of ischemia in hyperglycemic subjects. Thus, 7/8 animals developed seizures and died within 20 h of recovery. This study also failed to show any difference between the left and right side in post-ischemic SNPR damage after 15 h of recovery in animals with preischemic unilateral frontal cortex lesion. Furthermore, no side difference was observed in any other brain region evaluated. The results thus suggest that the pan-necrotic lesion in SNPR after hyperglycemic ischemia is not caused by excessive excitatory input from frontal cortex. A decrease in the GABA-ergic inhibitory input from caudoputamen to SNPR may be a more important mechanism for the ensuing excitotoxic post-ischemic SNPR damage, and for seizure development.

Amino Acids↗
PubMed1991

Rapid feasibility studies of tracers for positron emission tomography: high-resolution PET in small animals with kinetic analysis.

The development of methods for production of a radiotracer for use in human studies with positron emission tomography (PET) is often a time-consuming process of optimizing radiolabelling yields and handling procedures. Sometimes the radiotracer is not the original drug, but rather a derivative with unknown in vivo pharmacological properties. We have developed a fast and simple method of testing putative new PET tracers in vivo in small animals. The procedure has been validated in rats with different PET tracers with known kinetic and pharmacological properties ([2-18F]2-fluoro-2-deoxy-D-glucose, [N-methyl-11C]Ro 15-1788, and [15O]butanol). The tracer concentration in arterial blood was continuously measured to obtain the brain input function. Following image reconstruction of the scans, time-activity curves of selected regions of interest were generated. Estimations of CMRglc (1.0 +/- 0.2 mumol g-1 min-1), CBF (1.4 +/- 0.4 ml g-1 min-1) and transport rate constants for [N-methyl-11C]Ro 15-1788 (K1 = 0.44 +/- 0.01 ml g-1 min-1 and k2 = 0.099 +/- 0.005 min-1) as well as calculated first pass extraction (0.32 +/- 0.1) are in reasonable agreement with literature values. Small animal studies require minimal amounts of radioactivity and can be performed without sterility and toxicology tests. They may serve as a preliminary basis for radiation safety calculations because whole body scans can be performed even with a head scanner.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Emulation of seizure induced brain damage in neural tissue transplants to the anterior chamber of the eye.

We have developed a model system in which the mechanisms of neuronal damage due to hyperexcitation can be studied in isolation and where extended observation periods can be used. Substantia nigra pars reticulata (SNPR) develops a hypermetabolic necrosis following status epilepticus (Nevander et al. 1985; Auer et al. 1986). We transplanted rat fetal nigral area alone or together with fetal frontal neocortex to the anterior chamber of the eye in adult rats. Following 3 months of transplant maturation the hosts were subjected to status epilepticus for 60 min. In single nigral transplants no sign of structural damage was found. In the double transplants of frontal cortex and the substantia nigra a tissue necrosis had developed in the nigral part. This was demonstrated by a total loss of glial fibrillary acidic protein (GFA) immunoreactivity within a circumscribed necrotic region in the nigral part of the double transplant. Such a loss of GFA immunofluorescence had also developed in the host SNPR, as we have earlier shown (Eriksdotter-Nilsson et al. 1987). Thus, intraocular brain tissue transplants provide a unique model for studies on the development of neuronal damage and functional dependence between different neuronal structures for the development of such damage.

Animals↗
PubMed1989

Seizure-induced damage in the substantia nigra pars reticulata: lesions in the frontal cortex prior to the seizure period mitigate the damage.

Flurothyl-induced status epilepticus in the rat causes a hypermetabolic necrosis in the substantia nigra pars reticulata (SNPR). We studied if cortically generated excitatory input into the SNPR was causative of the structural damage. Rats were subjected to a unilateral frontal cortex lesion prior to induction of 40 min status epilepticus. A distinct mitigation in the size of the necrotic region in the ipsilateral SMPR was noted when compared to the contralateral side of the same animals (N = 10). No side difference was noted in animals where a lesion of similar size was placed in the parietal cortex region (N = 2) or in unlesioned animals subjected to seizures (N = 4). Neither analyses of energy metabolites in the cerebral cortex nor EEG revealed any side differences during seizures in the animals with lesions in the frontal cortex. This suggests that difference in seizure intensity was not the explanation for the mitigation of SNPR damage. It is suggested that the excitatory input from the frontal cortex was necessary for development of neuronal necrosis in the SNPR due to seizures.

Amino Acids↗
PubMed1988

Local cerebral glucose consumption during ethanol withdrawal in the rat: effects of single and multiple episodes and previous convulsive seizures.

Local cerebral glucose consumption (l-CMRgl) was studied using [14C]2-deoxyglucose autoradiography in minimally restrained rats during acute (12 or 18 h postwithdrawal (p.w.] and late (14 days p.w.) ethanol withdrawal, as well after 10 previous, weekly withdrawal episodes as after a similar period of isocalorical feeding. A period of two days of intoxication was established by gastric intubation. Spontaneous incomplete convulsive seizures were observed during the 8th to 10th withdrawal episode. Audiogenic seizures occurred following stimulation during the 6th and 10th withdrawal episode. Animals with previous spontaneous or audiogenic seizure were distributed randomly and evenly among the groups. l-CMRgl values were adjusted to a temperature of 38 degrees C. During acute withdrawal, l-CMRgl was significantly reduced by 18-32% in cortical and most limbic regions, but unchanged in cerebellum and subcortical structures as compared with the neutral state (late withdrawal and control groups). l-CMRgl was relatively more lowered in the amygdala in animals with previous spontaneous withdrawal seizures and in structures belonging to the auditory system in animals with previous audiogenic seizures. l-CMRgl did not differ among neutral groups. The lowered l-CMRgl in cortical and limbic regions during withdrawal contrasts to the results of previous studies. This difference may be attributed to the minimal restraint of animals in this study. The pattern of l-CMRgl in acute and late withdrawal animals with previous spontaneous withdrawal seizures is consistent with a mechanism comparable to electrical amygdala kindling contributing to seizure genesis.

Animals↗
PubMed1988

The nature and timing of excitotoxic neuronal necrosis in the cerebral cortex, hippocampus and thalamus due to flurothyl-induced status epilepticus.

Flurothyl-induced status epilepticus was studied by light and electron microscopy (LM, EM) to determine the time course and structural features of neuronal necrosis in the vulnerable brain regions in epilepsy. The cerebral cortex, hippocampus and thalamus were examined after closely spaced recovery periods of up to 1 week. The results showed that acidophilic neurons appeared simultaneously in neurons of the neocortex, hippocampus and thalamus, and that this occurred within 1 h following the end of the epilepsy. The corresponding features of acidophilic neurons by EM were mitochondrial flocculent densities and large discontinuities in cell and nuclear membranes. Dark neurons were ubiquitous during the epilepsy, but recovered almost universally. A few dark neuronal forms persisted and underwent cytorrhexis after 12-h recovery or longer. Axon-sparing dendritic lesions characteristic of excitotoxic neuronal death were found in the neuropil of the neocortex, and in both vulnerable CA1 and resistant CA3 neurons of the hippocampus. Other than acute edema, glial changes were absent. The findings support an excitotoxic mechanism in epilepsy-induced selective neuronal necrosis also in brain regions outside the hippocampus, and contrast with previous reports in ischemia and hypoglycemia in that neuronal necrosis occurs virtually immediately after an epileptic insult. No "maturation" of cell damage, as described in ischemia, was seen. Furthermore, even exceedingly dark neuronal forms and massive dendritic swelling must be considered sub-lethal or prelethal cellular changes. Lethal cellular changes include acidophilia by LM, cell membrane breaks, and mitochondrial flocculent densities by EM.

Animals↗
PubMed1987

Sustained seizures cause circumscribed cerebral changes in glial fibrillary acidic protein, neurofilament and laminin immunofluorescence.

Sustained experimental seizures in rats have previously been shown to cause an extensive necrosis in pars reticulata of substantia nigra (SNPR) and globus pallidus (GP). In the present paper we have studied the effects of hexafluorodiethyl ether-induced seizures on the immunoreactivity seen with antibodies directed against glial fibrillary acidic protein, GFA, used to visualize astrocytes, antibodies to the glycoprotein laminin as a marker for blood vessel walls and neurofilament (NF) antibodies to monitor neuronal disturbances. Already 12 h after a 20-min seizure period a reduction in GFA immunofluorescence intensity was observed in SNPR. After 3 days, marked lesions were noted in SNPR and GP as seen with cresyl violet staining. The lesions contained almost no GFA-positive structures. In the proximity of the lesions, an increase in GFA-immunoreactivity was noted. Such an increase, although less pronounced, was also seen in the major projection areas of SNPR. Two months post-seizure, the gliotic reaction had disappeared, and only a thin and elongated gliotic scar was observed. In spite of the development of a profound central necrosis especially evident in SNPR, both laminin- and NF-immunoreactivity was slightly increased within the lesioned areas. NF-immunoreactivity was also increased in the superior colliculus and in the reticular formation. Two months post-experiment NF-immunofluorescence was normalized but the former lesion sites showed signs of hypervascularization. We conclude that hexafluorodiethyl ether-induced 20-min seizures lead to rapid, localized glial and neuronal changes in the rat brain as evidenced by GFA and NF immunohistochemistry, while the vascular network remains intact.

Animals↗
PubMed1987

Metabolic alterations underlying the development of hypermetabolic necrosis in the substantia nigra in status epilepticus.

The substantia nigra pars reticulata (SNPR) has previously been shown to undergo tissue necrosis following status epilepticus induced by flurothyl in the rat. Even if the rat is ventilated, the SNPR develops necrosis if the epileptic period lasts more than 30 min. Rat brains were frozen in situ after 20 and 60 min of seizure activity and after 60 min of seizure activity followed by 60 min recovery. Labile energy metabolites were then analyzed in the SNPR and in the periaqueductal grey matter (PAG, control region). In the PAG, the metabolite changes during status epilepticus were similar to those reported for cerebral cortex and hippocampus. Measurements showed an unchanged ATP content and energy charge (97% and 98% of control, respectively) and an accumulation of lactate to 9.2 +/- 0.6 mumol/g in the 60-min group. In the PAG, all metabolites measured had returned to control values after 60 min of recovery. In the SNPR, the perturbation of the energy metabolites was much more pronounced during status epilepticus. The concentration of ATP decreased to 75 +/- 3%, the energy charge to 91% +/- 12% and the adenylate pool to 86.7 +/- 5.7% of control. Lactate accumulated to concentrations of 16.1 +/- 1.8 mumol/g and 24.9 +/- 2.3 mumol/g in the 20-min and 60-min groups, respectively. The concentration of lactate was still increased above control after 60 min recovery, whereas the concentration of ATP and the energy charge were lower than control. The findings demonstrate that sustained and intense neuronal activation can cause metabolic disturbance and thereby lead to necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1986

Mechanisms of epileptic brain damage: evidence for a protective role of the noradrenergic locus coeruleus system in the rat.

This study explores the possibility that the noradrenergic locus coeruleus system influences epileptic brain damage. Bilateral 6-hydroxydopamine lesions of the locus coeruleus projection to the forebrain were found to aggravate neuronal necrosis in the neocortex following 60 min of flurothyl-induced status epilepticus. We propose that the activation of the inhibitory locus coeruleus system during status epilepticus counteracts a deleterious neuronal hyperexcitation, probably induced by excessive release of excitatory amino acids, thereby limiting neuronal necrosis.

Adrenergic Fibers↗
PubMed1986

Short term status epilepticus in rats causes specific behavioral impairments related to substantia nigra necrosis.

Status epilepticus (SE) was induced for 40 min by flurothyl in well oxygenated rats. This insult resulted in selective destruction of up to 65% of the substantia nigra pars reticulata. We investigated the short and long term behavioral effects of this damage. No deficits were observed in sensorimotor reactivity, locomotor coordination, spontaneous or apomorphine-stimulated locomotor activity in the rats with induced epilepsy. However, these rats exhibited a long-lasting enhancement of amphetamine-stimulated locomotor activity. We propose that this selective impairment is caused by the necrosis of the pars reticulata. This damage might lead to deficient regulation either of mesostriatal dopamine neurons innervating nc. accumbens, or of neurons in the mesencephalic reticular formation mediating the locomotor response initiated in the nc. accumbens.

Animals↗
PubMed1986

Early axonal lesion and preserved microvasculature in epilepsy-induced hypermetabolic necrosis of the substantia nigra.

The time course of structural change in epilepsy-induced necrosis of the substantia nigra was studied by light and electron microscopy, and was correlated with previous metabolic studies. By light microscopy, tinctorial pallor appeared early, followed by pan-necrosis and macrophage infiltration. Mild lesions showed neuropil vacuolation but sparing of neurons, rather than a selective neuronal vulnerability. Electron microscopy of the evolving necrosis revealed an orderly sequence of structural damage involving first axons, then dendrites, neurons, and glia. No necrotic endothelial cells could be found, even in areas of apparent pan-necrosis by light microscopy. Pericytes near the vascular lumen were spared, whereas those in outer locations were necrotic. Edema, measured densitometrically, was absent. Previous metabolic studies of this lesion have demonstrated a pronounced focal lactic acidosis due to anaerobic hypermetabolism. Although the lesions resemble infarcts, hypermia rather than ischemia has been shown to accompany their development. Structural preservation of endothelial cells and inner pericytes likely stems from proximity to the moving blood stream, away from the site of lactic acid production in the neuropil. The findings indicate that the perfusion of necrotic tissue occurs via a persisting, intact microcirculation. The relative neuronal sparing and the early axonal rather than dendritic lesion show a clear distinction from excitotoxic pathology.

Animals↗
PubMed1986

Regional differences in brain glucose content in graded hypoglycemia.

Graded hypoglycemia was induced with insulin in anesthetized and artificially ventilated rats. The brains were frozen in situ, and the regional glucose concentration was determined in different areas of the brain with the bioluminescent technique. In all nine brain structures analyzed, brain tissue glucose content assessed with the bioluminescent technique correlated closely with the plasma glucose levels; the tissue/plasma glucose concentration ratios approximating 0.3. There were, however, relatively marked regional differences. For example, whereas glucose concentrations in the neocortex, caudoputamen, hippocampus, and cerebellum were very low in rats having a plasma glucose concentration of less than 4 mumol/mL, higher glucose concentrations were present in these animals in the thalamus, hypothalamus, and brainstem. The lowest glucose content was found in the caudoputamen, which was depleted of glucose in animals with plasma levels below 3 mumol/mL. It is concluded that regional inhomogeneities in the glucose levels observed during hypoglycemia may, at least in part, explain differences in the vulnerability of different brain structures following reversible hypoglycemia.

Animals↗
PubMed1986

Carbon dioxide narcosis: influence of short-term high concentration carbon dioxide inhalation on EEG and cortical evoked responses in the rat.

The effects of 1 min exposure to 80% CO2 inhalation was studied in rats under light general anaesthesia with N2O. It was found that 80% CO2 gave a rapid slowing of the EEG as well as a rapid decrease of the amplitude of cortical somatosensory evoked potentials. Only minor influences upon the blood pressure and heart rate were seen. The changes were found to be transient and most of the EEG effects had disappeared about 2-3 min following the end of the CO2 exposure. The findings are related to current procedures for preslaughter anaesthesia in swine using 80% CO2. The present experiments show that 80% CO2 rapidly induces an interruption of afferent sensory transmission to the cortex as well as slowing of the EEG. Both findings indicate that 80% CO2 is an effective agent for inducing adequate anaesthesia for slaughter procedures. However, the transient nature of the CO2 effects upon the central nervous system revealed here has to be taken into account to optimize the slaughter house procedures.

Anesthesia, Inhalation↗
PubMed1986

Cerebral blood flow and metabolic rate during seizures. Relationship to epileptic brain damage.

UNLABELLED: After long periods of status epilepticus, selective neuronal necrosis is incurred in the neocortex (layer III-IV), in the hippocampus (CA1 and CA4), and in the thalamus (VPL-VPM). In these areas the cerebral metabolic rate for glucose is increased to between 200-300% of control, indicating a correlation between neuronal damage and enhanced neuronal activity. Measurements of local cerebral blood flow indicate that the damage is not due to insufficient supply of oxygen. In most rats with status epilepticus lasting longer than 30 minutes, an infarction develops in the substantia nigra pars reticulata. In this region the metabolic rate is first increased but later during the seizure activity falls to very low values indicating cell necrosis. CONCLUSION: prolonged neuronal hyperactivity with a concomitant increase in the metabolic rate for glucose is a prerequisite for the development of neuronal damage. However, the necrosis of the SNPR demonstrates that other factors determine the vulnerability of neurons to hyperexcitation, e.g., the type of agonist acting on the neuron.

Animals↗
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↗