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Biomedical subjects

O Hornykiewicz

Publications and source records attributed to O Hornykiewicz.

At least 109 records · Page 6Linked to original sources
PubMed1982

Reversible drug-induced parkinsonism. Clinicopathologic study of two cases.

Parkinsonism developed in two patients who were received neuroleptic drugs. In each case the clinical manifestations remitted completely when the offending drug or drugs were discontinued. Histologic examination in each patient disclosed abnormalities characteristic of idiopathic paralysis agitans (IPA). Levels of homovanillic acid were low in both cases, and dopamine (DA) levels were measurably reduced in the striatum in one case. It is postulated that before administration of neuroleptic drugs, both patients had preclinical IPA, which predisposed them to parkinsonism when challenged with DA antagonists. Our observations suggest that some patients with irreversible drug-induced parkinsonism may suffer from IPA and that the reversibility of clinical features does not exclude the presence of subclinical IPA.

Aged↗
PubMed1981

Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch-Nyhan syndrome.

Different brain regions were removed post mortem from three patients with the Lesch-Nyhan syndrome and were examined for alterations in hypoxanthine-guanine phosphoribosyl transferase (HGPRT), adenine phosphoribosyl transferase, and biochemical indexes of norepinephrine, dopamine, serotonin, gamma-aminobutyric acid (GABA), and acetylcholine neuron function, as compared with age-matched controls. The level of HGPRT activity in the material from patients with the Lesch-Nyhan syndrome was less than 1 per cent of control levels, whereas adenyl phosphoribosyl transferase was not significantly altered. All biochemical aspects of the function of dopamine-neuron terminals in the striatum (except dihydroxyphenylacetic acid levels) were decreased to 10 to 30 per cent of the control values. Serotonin and 5-hydroxyindoleacetic acid levels were increased, striatal choline acetyltransferase levels were low, and striatal glutamic acid decarboxylase and guanylate cyclase activities were unaltered. The disruption of the balance between the functions of GABA, dopamine, and acetylcholine neurons in the extrapyramidal system probably accounts for some of the symptoms observed in the Lesch-Nyhan syndrome (e.g., choreoathetosis).

Acetylcholine↗
PubMed1981

Kainic acid-induced changes of serotonin and dopamine metabolism in the striatum and substantia nigra of the rat.

Levels of the putative neurotransmitters serotonin (5-HT) and dopamine (DA) and their respective metabolites 5-hydroxyindoleacetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC) was determined in the rat striatum after unilateral intrastriatal injection of the convulsive neurotoxin kainic acid. Two days after intrastriatal kainic acid injection, levels of the 5-HT metabolite 5-HIAA were increased by abut 200% in the injected striatum and by about 150% in the contralateral striatum. An elevated striatal 5-HIAA content was still detectable 10 days after the kainate lesion, but approached normal values 10 weeks after the injection of the neurotoxin. Two days after the lesion, but not at the other time intervals, a moderate increase of 5-HIAA also occurred bilaterally in other brain areas such as the substantia nigra, frontal cortex and hypothalamus. Levels of 5-HT were decreased significantly in the injected striatum 2 days after the intrastriatal application of kainic acid and increased by about 40% after 10 weeks. The 5-HT concentration in the contralateral striatum or in the three other brain areas examined was unchanged at all time intervals. Levels of the DA metabolite DOPAC and DA turnover were increased in the lesioned striatum 2 days after kainic acid injection; concomitantly the DOPAC level was increased in the substantia nigra of the contralateral side. DOPAC levels of the contralateral striatum were unchanged or slightly reduced 2 days after the injection. Ten days as well as 10 weeks after the lesion there was a slightly increased DOPAC concentration in both striata. The levels of DA were not altered at any time interval after the injection of kainic acid.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1981

The pallido-subthalamic projection in rat: anatomical and biochemical studies.

Horseradish peroxidase injected into the rat globus pallidus was transported retrogradely to subthalamic nucleus neuronal cell bodies and anterogradely to axon terminals in the subthalamic nucleus. Electron microscopic observations revealed that the labeled axon terminals made symmetrical axosomatic and axo-dendritic synaptic contacts with labeled subthalamic nucleus perikarya and dendrites. Injection of kainic acid in the globus pallidus several days prior to the horseradish peroxidase injection abolished the anterograde but not the retrograde transport of the tracer. This suggested the anterograde labeling observed in the subthalamic nucleus originated from neuronal cell bodies in the globus pallidus. Kainic acid lesions identical to those employed in the above anatomical studies resulted in a loss of neuronal cell bodies throughout the globus pallidus and caused a drop in glutamic acid decarboxsylase and choline acetyltransferase levels in the globus pallidus. Levels of these two enzymes were not changed in the subthalamic nucleus after the globus pallidus kainic acid lesions, but both showed small, statistically significant decreases in the substantia nigra. It was concluded that there is a massive pathway from the globus pallidus to the subthalamic nucleus, which terminates on subthalamic nucleus neurons projecting back to the globus pallidus. Neither gamma-aminobutyric acid nor acetylcholine is the major neurotransmitter in the massive pallido-subthalamic pathway.

Animals↗
PubMed1981

Striatal ganglioside levels in the rat following kainic acid lesions: comparison with Huntington's disease.

Ganglioside and DNA levels were estimated in the striatum of rats 10 days and 6 weeks after lesioning by intrastriatal injection of kainic acid. There was a moderate, 21-24% decrease of the ganglioside concentration per unit protein on the side of the lesion, which can be ascribed to the loss of the intrinsic striatal neurons following the injection of kainic acid. On the other hand, there was a 131 and 60% increase of DNA per unit protein in the kainate injected side 10 days and 6 weeks after the lesions, respectively; these changes apparently reflected the gliotic reaction brought about by the neurotoxin. Qualitatively similar findings--a decrease of ganglioside and an increase of DNA levels per unit protein--were also found in the brain of patients with Huntington's disease; however, as compared with the corresponding control material, the decrease of the ganglioside concentration was more pronounced in the striatum of Huntington's disease (by 38% in the caudate nucleus and by 46% in the putamen) than in the kainate lesioned rat striatum. This difference could be due to the different proportions of the intrinsic and extrinsic neuronal plasma membranes in the striatum of the two species; however, the possibility of a more generalized affection of neuronal plasma membranes in Huntington's disease may also be envisaged.

Animals↗
PubMed1981

Evidence for neuronal localization of histamine-N-methyltransferase in rat brain.

There is evidence that histamine may be a neurotransmitter in mammalian brain. Histamine in neurons of the central nervous system is easily released and rapidly turned over. The cellular localization of histamine-N-methyltransferase, the proposed histamine-inactivating enzyme, was investigated by measuring its activity in rat striatum after applying neurochemical or electrolytic lesions. The results indicate a major neuronal localization of the enzyme in this area.

Animals↗
PubMed1980

Kinetics of L-DOPA metabolism in the caudate nucleus of cats with ventrotegmental lesions.

Sixteen days after a unilateral lesion of the ventromedial tegmentum (VMT) of the midbrain, adult cats received an intravenous dose of L-DOPA (20 mg/kg), and the caudate nucleus from each hemisphere was removed at various time intervals thereafter. In the caudate nucleus contralateral, to the VMT lesions, DA levels reached 200% of control values within 15 min, and maintained this elevation for at least 2 hours. DA levels in the caudate nucleus ipsilateral to the VMT lesion were much lower than contralateral values; however, they were much higher than those of non-DOPA treated animals with comparable lesions. DA levels in the caudate nucleus of the lesioned hemisphere were directly related to the remaining DOPA decarboxylase activity. The striatal serotonin concentrations were unchanged after L-DOPA, but an increase in 5-hydroxyindoleacetic acid levels was observed. From these results, we conclude that, (i) in cats with nigrostriatal tract lesions after low doses of L-DOPA comparable to those given to patients with Parkinson's disease, the bulk of the newly formed DA in the caudate nucleus is contained in nigrostriatal neurons, and (ii) there exists an inverse relationship between the ability of the caudate to synthesize DA and the severity of the nigrostriatal tract lesion.

Animals↗
PubMed1980

A sensitive and reliable assay for dopamine beta-hydroxylase in tissue.

A new assay procedure for dopamine beta-hydroxylase (DBH) in tissue extracts is described. Solubilized DBH was adsorbed from crude extracts on Concanavalin A-Sepharose (Con A-Sepharose), resulting in enrichment of the enzyme as well as removal of endogenous catecholamines and inhibitory substances. The enzymatic assay was carried out with DBH still adsorbed to Con A-Sepharose. The adsorption of the DBH to Con A-Sepharose offers three advantages over previous assay procedures. (1) Because of removal of the endogenous inhibitory substances, a single Cu2+ concentration can be used for the determination of DBH activity, regardless of the tissue dilution or inhibitor content of the analysed sample. Using this procedure, the optimal Cu2+ concentration for DBH of bovine adrenal gland extracts was 3 microM and for rat brain 10 microM. (2) Because of removal of endogenous catecholamines, dopamine, the main physiological substrate of DBH in noradrenergic neurons, can be used for the assay. The enzymatic reaction product, noradrenaline, was determined by high performance liquid chromatography and electrochemical detection (hplc-ec). This procedure resulted in an approx. 10-fold increase in sensitivity of the assay compared with other procedures, e.g., the radioenzymatic assay. (3) Direct determination of the immediate product of the enzymatic reaction (noradrenaline) permits kinetic analysis. It was found that the Michaelis constants for the substrate (dopamine) and co-factor (ascorbic acid) (2 mM and 0.65 mM, respectively) determined in bovine adrenal tissue extracts by the described procedure were identical with the values for the purified DBH preparation.

Adrenal Glands↗
PubMed1980

Brain monoamines in the rhesus monkey during long-term neuroleptic administration.

1. In this study, rhesus monkeys were given daly high doses of chlorpromazine (up to 40 mg/kg orally) or haloperidol (up to 1 mg/kg orally) for up to 17 months. After sacrifice the brains were analyzed for regional concentrations of DA, HVA, 5-HT, 5-HIAA, and NE. 2. The most prominent effects of this long-term administration of neuroleptics were (a) a widespread elevation of NE levels in the forebrain, including the hypothalamus, thalamus, olfactory area, and nucleus accumbens; (b) a decrease of 5-HT turnover (calculated from the ratio "5-HT/5-HIAA") in several limbic forebrain areas, including the amygdaloid nucleus, septum, and nucleus accumbens as well as thalamus; and (c) a mild but consistent increase of HVA concentration in all DA-containing forebrain regions; in the striatum, this effect was found in the CPZ but not the HAL group. 3. The possible involvement of these neurochemical changes in the clinical actions of neuroleptics characteristically requiring long-term medication, such as the production of persistent (tardive) dyskinesias as well as the antipsychotic effect, is discussed.

Animals↗
PubMed1980

[Brain dopamine and brain disorders - and what we have learned from these studies (author's transl)].

1. Two examples are given to illustrate the role of dopamine in brain disorders: a) In Parkinson's disease there is a marked deficiency of dopamine in several subcortical brain regions, particularly the striatum (caudate nucleus and putamen) and substantia nigra. This extensive dopaminergic denervation of the basal ganglia results in compensatory pre- and postsynaptic changes, i.e. increase in neuronal activity in the remaining dopamine neurons, and increase in the number of the postsynaptic dopamine receptor sites. These changes are of great functional significance, inter alia for the therapeutic efficacy of L-dopa as an antiparkinson medication. - b) Recently, increased number of dopamine receptors has been measured in the striatum and nucleus accumbens of patents dying with schizophrenic symptomatology. This observation, taken together with the fact that all antipsychotically effective neuroleptics are potent blockers of brain dopamine receptors, has lead to the hypothesis that dopaminergic brain mechanisms are involved in the pathophysiology of the schizophrenic disorder(s). 2. The possible involvement of brain dopamine receptors in brain disorders raises the more basic question as to the physiological role of the diverse dopamine (and other monoamine) receptors in brain function. Since in the brain the majority of the monoamine-containing nerve terminals are devoid of synaptic contacts, a nonsynaptic role for dopamine (and other brain amines) is envisaged, e.g. modulation of neuronal impulse activity characterized by long lasting changes in reactivity of the neuronal elements and circuits.

Animals↗