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Biomedical subjects

O Hornykiewicz

Publications and source records attributed to O Hornykiewicz.

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

Brain gamma-aminobutyric acid and benzodiazepine receptor binding in dialysis encephalopathy.

We measured gamma-aminobutyric acid (GABA) and benzodiazepine binding in autopsied frontal cortex of 8 patients dying with dialysis encephalopathy (DE). No alteration in [3H] GABA binding was observed. However, a mild reduction (-23%, P less than 0.05) of [3H] flunitrazepam-binding density was found in DE cortex. The magnitude of this reduction was similar to that observed in frontal cortex of amygdala-kindled rats [10]. We suggest that a reduction in benzodiazepine receptor number, in combination with markedly reduced GABA concentration in DE cerebral cortex may contribute to some of the clinical features (especially seizures) characteristically observed in this syndrome.

Benzodiazepinones↗
PubMed1985

Alpha 2-adrenoceptors modulate kainic acid-induced limbic seizures.

We have tested several compounds interfering with the brain monoamine (noradrenaline, dopamine, serotonin) and acetylcholine systems for their effects on limbic seizures produced by systemically (s.c.) injected kainic acid as well as on neurochemical changes in amygdala/pyriform cortex resulting from the kainic acid treatment. The characteristic neurochemical changes induced by s.c. kainic acid were a decrease in noradrenaline and an increase in 5-hydroxyindoleacetic acid in the acute (3 h after kainic acid injection) suggesting strongly increased neurotransmitter turnover in noradrenergic and serotonergic neurons. This was followed by a reduction of glutamic acid decarboxylase and choline acetyltransferase activities during the chronic phase (3 days) of the kainic acid action, indicating destruction of GABAergic and cholinergic neurons. The compounds tested in this model of limbic epilepsy included 1-propranolol, prazosin, clonidine, yohimbine, metergoline, atropine and haloperidol. Among these compounds the alpha 2-adrenergic agonist clonidine (0.1 mg/kg, i.p.) exhibited a powerful protective action on kainic acid-induced limbic seizures as well as on the neurochemical changes in the amygdala and pyriform cortex. In addition, the adrenoceptor antagonists prazosin (alpha 1) and propranolol (beta) as well as the dopamine receptor antagonist haloperidol had significant but less potent - protective actions upon kainic acid-induced seizures and subsequent neurochemical changes. On the other hand, yohimbine (alpha 2-antagonist) and metergoline (serotonin-antagonist) potentiated the limbic seizure syndrome and no effect was found with atropine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Kainic acid-induced seizures: dose-relationship of behavioural, neurochemical and histopathological changes.

Behavioural, neurochemical and histopathological changes induced by systemic injection of kainic acid were investigated at various doses of the neurotoxin (3, 6 and 10 mg/kg s.c.). There was a positive correlation between the dose of kainic acid and the extent of both the acute neurochemical changes 3 h after the injection (increases of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid levels and a decrease in noradrenaline levels in all brain regions investigated), the acute histopathological changes (shrinkage and condensation of nerve cells and brain oedema in the entire forebrain) and the extent of behavioural alterations (immobility, 'wet dog shakes' and limbic seizures). However, the slope of the dose-response curves was very steep. Late and irreversible alterations included losses of the enzyme markers glutamic acid decarboxylase and choline acetyltransferase and, histopathologically, incomplete parenchymal necrosis and haemorrhages. These changes, however, were restricted to a few brain regions, the most important being the hippocampus, amygdala, entorhinal and pyriform cortex, and olfactory bulb, and they were seen only in animals which had undergone severe convulsions. It is suggested that the irreversible brain lesions in this animal model of limbic (temporal lobe) epilepsy are not solely induced by a direct action of kainic acid, but may be caused--at least in part--by additional, secondary pathogenetic mechanisms.

Animals↗
PubMed1985

Brain benzodiazepine receptor binding and purine concentration in Lesch-Nyhan syndrome.

Benzodiazepine receptor [( 3H]flunitrazepam) binding and purine concentration were measured in autopsied cerebral cortex of 4 patients who died with Lesch-Nyhan syndrome. Receptor density was normal in all 4 regions of Lesch-Nyhan cortex examined. However, an enhancement of benzodiazepine receptor affinity (25% reduction in Kd) was found in well-washed parietal and occipital cortex homogenates. Maximal gamma-aminobutyric acid (GABA) stimulation of [3H]flunitrazepam binding was normal in temporal, parietal and occipital cortex but markedly reduced (by 50-80%) in frontal cortex. Increased sensitivity to hypoxanthine inhibition (30% reduction in Ki) was also observed in parietal cortex. The concentrations of the purines hypoxanthine, xanthine and inosine in Lesch-Nyhan parietal cortex were about twice the values measured in control material matched for postmortem time. We suggest that the above-normal concentrations of purines estimated to be present in Lesch-Nyhan brain may be sufficient to significantly affect the ability of the benzodiazepine receptor to modulate GABA-mediated brain mechanisms.

Adolescent↗
PubMed1985

[The life history of brain dopamine].

Neurochemical studies in Parkinson's disease have greatly contributed to the understanding of the neurobiology of the meso-telencephalic dopamine (DA) system; in addition, these studies have significantly influenced our concepts regarding the general principles of brain function. The primary role of DA in striatal function can be seen in its ability to initiate complex patterns of motor activity. The nigro-striatal DA system shows in the face of partial damage an extraordinarily high degree of plasticity, i.e. capacity for functional compensation. The two most important mechanisms of plasticity of the nigro-striatal DA system are: compensatory activation of the presynaptic remaining DA neurons (through increase in DA turnover); and increase in the number of postsynaptic DA receptors. The DA loss which occurs during normal ageing is not of sufficient magnitude to cause clinically overt Parkinson's disease. On the other hand, the observations pertaining to the Parkinsonian syndrome produced by NMPTP suggest the participation of environmental factors in the aetiology of idiopathic Parkinson's disease. The remarkable results of nigral cell transplants into the striatum of animals with experimental "parkinsonism", as well as the high therapeutic efficacy of DA substitution in patients with Parkinson's disease point toward a neurohumoral, rather than neurotransmitter, function of brain DA.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Brain neurotransmitter abnormalities in neuronal intranuclear inclusion body disorder.

Biochemical markers for the major neurotransmitter systems were measured in the brain of a patient who died with neuronal intranuclear inclusion disease. A severe nigrostriatal dopamine deficiency constitutes the basis for the parkinsonian features in the patient. A marked loss of brain norepinephrine and serotonin was found in the basal ganglia and hypothalamus. Brain amino acid (gamma-aminobutyric acid and glutamate) and cholinergic (choline acetyltransferase activity) systems were either normal or less severely affected.

Adolescent↗
PubMed1985

Progressive supranuclear palsy: relationship between extrapyramidal disturbances, dementia, and brain neurotransmitter markers.

Biochemical markers for the major neurotransmitter systems were measured in the brains of 5 patients who had died with neuropathologically confirmed progressive supranuclear palsy. A marked nigrostriatal dopamine deficiency, observed in 4 of the 5 patients, was sufficient to explain the parkinsonian features (especially bradykinesia) observed in patients with progressive supranuclear palsy. Dopamine concentrations, however, were normal in the nucleus accumbens, hypothalamus, and temporal cortex. Brain noradrenalin, serotonin, gamma-aminobutyric acid, and aspartic acid levels were generally normal. Normal brain choline acetyltransferase activity (the marker enzyme for cholinergic neurons) in the 2 patients with severe dementia suggests that, at least in some patients, the cognitive impairment in this disorder is likely to be related to noncholinergic neurotransmitter system changes. The glutamic acid concentration was elevated in many brain areas in 3 of the 5 patients studied.

Aged↗
PubMed1984

B-HT 958--an antagonist at alpha 2-adrenoceptors and an agonist at dopamine autoreceptors in the brain.

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]az epine), a compound chemically related to clonidine-like drugs of the azepine type, was described previously as a mixed agonist-antagonist at peripheral alpha 2-adrenoceptor sites. In the present experiments the actions of B-HT 958 on brain noradrenergic and dopaminergic mechanisms were examined using behavioural, pharmacological and biochemical methods. (i) In the dog, intracisternally injected B-HT 958 (300 micrograms/kg) abolished the reflex bradycardia facilitated by the alpha 2-agonist B-HT 920 (10 micrograms/kg i.ci.). (ii) In the whole mouse brain as well as in the rat hypothalamus and neocortex, but not in the hippocampus, amygdala and nucleus accumbens B-HT 958 (5-20 mg/kg s.c.) accelerated the alpha-methyltyrosine (alpha-MT)-induced disappearance of noradrenaline. (iii) B-HT 958 decreased in a dose-dependent manner the exploratory activity of mice (ED50: 6.3 mg/kg s.c.) and slightly enhanced the motor activity of reserpine-treated mice only in high doses. (iv) B-HT 958 (20 mg/kg s.c.) lowered the level of homovanillic acid in the striatum and nucleus accumbens and dose dependently (1-20 mg/kg) slowed the alpha-MT-induced disappearance of dopamine in these 2 brain regions of the rat as well as in the whole mouse brain. (v) The gamma-butyrolactone-induced increase in DOPA levels was effectively antagonized by B-HT 958 (1 and 5 mg/kg s.c.) in the rat striatum and nucleus accumbens. These behavioural, pharmacological and biochemical observations indicate that B-HT 958 possesses central alpha-adrenoceptor blocking activity and exerts a strong agonistic effect on brain dopamine autoreceptors.

Adrenergic alpha-Antagonists↗
PubMed1984

Cerebellar norepinephrine in patients with Parkinson's disease and control subjects.

Norepinephrine was measured in postmortem cerebellar cortex of 22 non-neurological control subjects and nine patients with Parkinson's disease, using the high-performance liquid chromatography method with amperometric detection. In all control subjects, substantial amounts of norepinephrine was found in cerebellar cortex. There was a moderate negative correlation between age of control subjects and cerebellar norepinephrine concentration. In the patients with Parkinson's disease, the cerebellar cortical norepinephrine levels were significantly below normal. This is in accord with previously reported reduced norepinephrine levels in locus ceruleus and other regions of the parkinsonian brain. Although the main symptoms of Parkinson's disease are primarily caused by disturbed basal ganglia (dopamine) function, cerebellar dysfunction related to norepinephrine may contribute to some abnormalities of motor performance in this disorder.

Aged↗
PubMed1984

The role of brain edema in epileptic brain damage induced by systemic kainic acid injection.

Edema formation and blood-brain barrier permeability was studied in animals with epileptic seizures induced by subcutaneous injection of kainic acid. Brain edema was most pronounced between 3 and 24 h after kainic acid injection. It was reflected by massive swelling of perineuronal and perivascular astroglia. Three hours after kainic acid perivascular astroglia swelling resulted in disturbance of local microcirculation in the affected brain areas. In addition, compression of drainage veins by the edematous brain induced focal perivenous hemorrhages similar to herniation damage in human brain edema. Tracer studies with sodium fluorescein, Evans blue, albumin and horseradish peroxidase revealed only a mild increase in the permeability of cerebral vessels, topographically unrelated to areas of brain edema. This finding indicates the presence of cytotoxic brain edema in kainic acid-induced epileptic brain damage. Treatment of brain edema with dexamethasone did not influence the incidence and severity of kainic acid-induced epileptic brain damage. However, in 54% of animals injected with kainic acid, lesions were completely prevented by treatment of brain edema with mannitol. The present results indicate that brain edema plays an important role in the pathogenesis of epileptic brain damage following systemic kainic acid intoxication. It is suggested that in this model of limbic epilepsy the brain edema is due to the massive ionic imbalance elicited in the affected brain regions by the kainic acid-induced persistent neuronal excitation.

Animals↗
PubMed1984

Neurochemical basis of dementia in Parkinson's disease.

According to their mental status, patients with Parkinson's disease can be subdivided into three groups: (1) mentally normal patients; (2) patients with severe cognitive impairment and Alzheimer-type brain pathology (neuritic plaques, neurofibrillary tangles, granulovacuolar changes); and (3) demented patients without any evidence of Alzheimer changes. Neurochemically, irrespective of the presence or absence of Alzheimer-type brain pathology, demented Parkinson patients seem to have the same disturbance of cortical cholinergic neuron function as patients with Alzheimer-type dementia (Alzheimer's disease), namely, reduced levels of cortical acetylcholine esterase and choline acetyltransferase activity. At present, the question whether the "cortical cholinergic deficiency" is the only (or sufficient) neurochemical basis for the cognitive impairment in Parkinson patients with dementia cannot be answered with certainty; the additional role of other neurotransmitter changes known to occur in the Parkinson brain, especially loss of cortical, hippocampal and subcortical noradrenaline and/or dopamine cannot be ruled out.

Alzheimer Disease↗
PubMed1984

Benzodiazepine receptor binding in cerebellar cortex: observations in olivopontocerebellar atrophy.

Benzodiazepine receptor binding was measured in cerebellar cortex of 15 patients with dominantly inherited olivopontocerebellar atrophy (OPCA). The majority of these patients had a moderate to marked Purkinje cell loss, as judged by the lowered levels of dentate nucleus gamma-aminobutyric acid (GABA), a marker of Purkinje cells. Despite the reduction in Purkinje cell number cerebellar cortical benzodiazepine receptor density was either normal or slightly elevated in the OPCA patients. These results are in contrast to the findings in a mutant strain of mice deficient in Purkinje cells in which the concentration of benzodiazepine receptors in cerebellum is greatly reduced. Our data indicate that in the human, cerebellar cortical benzodiazepine receptors are either not significantly associated with Purkinje cells or that in OPCA Purkinje cell loss triggers a de novo synthesis of extra benzodiazepine binding sites. It is concluded that, in contrast with the rodent, in the human benzodiazepine receptor binding may not serve as a marker for cerebellar Purkinje cells.

Atrophy↗
PubMed1984

Reduction of noradrenaline in cerebellum of patients with olivopontocerebellar atrophy.

Noradrenaline (NA) was measured in postmortem cerebellar cortex of 15 patients with dominantly inherited olivopontocerebellar atrophy (OPCA). The mean cerebellar cortical NA level was significantly reduced (by 40%) in OPCA as compared with control values. The NA deficit most likely reflects a degeneration of the locus caeruleus noradrenergic system that is known to occur in some patients with OPCA. The relationship between the altered cerebellar NA levels and the clinical symptomatology of OPCA remains to be determined.

Atrophy↗
PubMed1983

Increased GABA receptor binding in dominantly-inherited cerebellar ataxias.

We measured gamma-aminobutyric acid (GABA) receptor binding in the cerebellar cortex of 14 patients with dominantly-inherited cerebellar ataxias. Most of these patients had moderate to marked Purkinje cell loss as judged from the subnormal dentate nucleus GABA levels. Mean GABA receptor binding (at 25 nM GABA concentration) was elevated significantly by 37% in the total group of 14 patients studied and by 60% in the largest subgroup (n=6) analyzed. Possible explanations for the enhanced binding include glial proliferation, exposure of normally unexposed receptor sites consequent to neuronal degeneration, and/or denervation supersensitivity.

Cerebellar Ataxia↗
PubMed1983

Alterations in benzodiazepine and GABA receptor binding in rat brain following systemic injection of kainic acid.

The binding of gamma-aminobutyric acid (GABA) and benzodiazepine to receptors was examined in regions of rat brain at various times after subcutaneous injection of kainic acid (KA, 15 mg/kg). The animals exhibited pronounced convulsions 90 min-4 hr after this treatment. During this period (2 hr after the injection of kainic acid) no alterations in the binding of [3H]-GABA or [3H]flunitrazepam to receptors were detected in the frontal cortex, the hippocampus or the amygdala-pyriform cortex. After recovery from the acute convulsive phase, the rats appeared to be hyperexcitable, hyperactive, and displayed marked aggression and occasional clonic convulsions one to 80 days later. During this period a marked increase (80-200%) in the number of binding sites for GABA in the amygdala-pyriform cortex occurred but this was associated with a slow decrease in the number of binding sites for [3H]flunitrazepam to 70% control value at 3 weeks. Binding of the "peripheral"-type of benzodiazepine ligand, [3H]-Ro5-4864, was increased to 450% of control 3 weeks after injection. In addition, the ability of GABA to stimulate the binding of [3H]flunitrazepam was reduced when measured 3 days after the injection of kainic acid. It is suggested that the long-term behavioural syndrome observed in kainic acid-treated rats, as well as the reduced effectiveness of diazepam in preventing seizures in animals treated with kainic acid, (Czuczwar, Turski, Turski and Kleinrock, 1981) may be explained in part by a reduction in the number of neuronal benzodiazepine receptors and a "desensitization" of the GABA receptors which are coupled to benzodiazepine receptors.

Animals↗
PubMed1983

Kainic acid induced seizures: neurochemical and histopathological changes.

Behavioural, histopathological and neurochemical changes induced by systemic injection of kainic acid (10 mg/kg, s.c.) were investigated in rats. The most pronounced behavioural changes were strong immobility ("catatonia"), increased incidence of "wet dog shakes", and long-lasting generalized tonic-clonic convulsions. The behavioural symptoms were fast in their onset and lasted for several hours. Two distinct phases of histopathological and neurochemical changes were observed. (1) Early partially reversible changes were seen up to 3 h after kainic acid injection. They consisted of shrinkage and pyknosis of neuronal perikarya together with swelling of dendrites and axon terminals. These changes were accompanied by generalized signs of edema throughout the whole brain. Neurochemically, there was a marked decrease in noradrenaline levels (up to 70%) and an increase in levels of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid and homovanillic acid (up to 200%) in all analysed brain regions, suggesting a strongly increased firing rate of aminergic neurones during the period of generalized seizures. These histological and neurochemical changes were found in all the brain regions examined; they were greatly reduced or only sporadically seen after 1-3 days, when the animals had recovered from the seizures. (2) Late irreversible changes developed 24 h and later following kainic acid injection. They consisted of incomplete tissue necrosis with loss of nerve cells and oligodendrocytes, demyelination, astroglial scar formation, small perivenous hemorrhages and extensive vascular sprouting. The changes were restricted to the pyriform cortex, amygdala, hippocampus (most pronounced in the CA1 sector), gyrus olfactorius lateralis, bulbus olfactorius and tuberculum olfactorium. Neurochemically, a selective decrease was seen in choline acetyltransferase activity (40%) of the amygdala/pyriform cortex area, and of glutamate decarboxylase activity in the dorsal hippocampus (45%) and amygdala/pyriform cortex (55%). No such changes were found in the frontal cortex and the striatum/pallidum. Since at these later time periods the widespread early changes in monoamine metabolism were mostly normalized, loss of acetylcholine and gamma-aminobutyric acid neurons in the affected brain regions represented a selective neurochemical change typical for this stage of kainic acid action. The observed neurochemical and histopathological changes may be directly related to the excitotoxic and convulsive properties of kainic acid. However, brain edema resulting in herniation damage of the basal portions of the brain in addition to disturbances of microcirculation and +

Amygdala↗
PubMed1983

Neuronal [3H]benzodiazepine binding and levels of GABA, glutamate, and taurine are normal in Huntington's disease cerebellum.

Alterations in one subunit of the proposed GABA receptor complex, namely, the GABA receptor, have been observed in Huntington's disease cerebellum. We measured binding to a second subunit, the benzodiazepine binding site, in the autopsied cerebellum of 12 patients dying with adult-onset Huntington's disease. Neuronal benzodiazepine ([3H]flunitrazepam) binding density (Bmax) and affinity in cerebellar cortex of the Huntington's disease patients were not significantly different from control values. Similarly, maximal GABA stimulation of benzodiazepine binding was normal in the Huntington's disease cerebellum. In addition, no significant changes were observed in the concentrations of GABA, glutamate, and taurine in cerebellar cortex, nor of GABA in the dentate nucleus.

Amino Acids↗