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Biomedical subjects

O Hornykiewicz

Publications and source records attributed to O Hornykiewicz.

At least 37 records · Page 2Linked to original sources
PubMed1995

Striatal dihydroxyphenylalanine decarboxylase and tyrosine hydroxylase protein in idiopathic Parkinson's disease and dominantly inherited olivopontocerebellar atrophy.

We measured the levels of dopamine, tyrosine hydroxylase (TH) protein, and dihydroxyphenylalanine (DOPA) decarboxylase (DDC) protein in the striatum of 10 patients with idiopathic Parkinson's disease (PD) and 23 patients with dominantly inherited olivopontocerebellar atrophy (OPCA). The levels of dopamine were markedly reduced (2% of control) in the striatum of the patients with PD, whereas striatal dopamine in the patients with OPCA ranged from normal (> 60% of control) to moderately reduced (20-60% of control) to severely depleted (< 20% of control). Both TH and DDC protein levels were significantly lower than those of the controls in the striatum of all of the patients with PD and in the subgroup of patients with OPCA having severely depleted dopamine. In contradistinction, TH but not DDC protein levels were reduced in those patients with OPCA having moderately reduced dopamine levels. This suggests that in the early stage of nigrostriatal dopamine neurone degeneration, DDC levels may be less susceptible to neurodegenerative influences than is TH synthesis or, alternatively, DDC synthesis may be more aggressively upregulated. Unexpectedly, from the blot immunolabeling analysis an additional DDC-immunoreactive band of slightly lower apparent molecular mass was detected in two of the patients with PD and in 12 of the patients with OPCA. This additional DDC band, which was not present in any of the control subjects, may reflect posttranslational modification(s) of DDC related to the neurodegenerative process.

Aged↗
PubMed1995

Mechanism of the dopamine-releasing actions of amphetamine and cocaine: plasmalemmal dopamine transporter versus vesicular monoamine transporter.

The effects of amphetamine and cocaine were studied in [3H]-dopamine-loaded and superfused COS-7 cells transfected with either the cDNA of the plasmalemmal dopamine transporter ("DAT cells") or the cDNA of the vesicular amine transporter ("VAT cells"), or with both transporters ("DAT/VAT cells"). Amphetamine (0.01-100 microM, added for 4 min of superfusion) led to a concentration-dependent increase in dopamine release in DAT cells, as well as in DAT/VAT cells. The EC50 of the effect of amphetamine on DAT cells was 1.1 +/- 0.6 microM; the effect on DAT/VAT cells did not reach a plateau in the concentration range tested. With longer exposure to amphetamine, dopamine efflux from DAT cells reached a peak and quickly returned to baseline, in spite of the continued presence of the drug, whereas in DAT/VAT cells and in VAT cells the effect was sustained. Cocaine (up to 100 microM) did not exert any effect of its own in DAT cells or VAT cells but inhibited the amphetamine-induced release of dopamine from DAT cells in a competitive manner. In DAT/VAT cells cocaine and its analogue (-)-2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane caused an efflux of dopamine resembling that caused by amphetamine but quantitatively much smaller. The rank order of potency was the same as in uptake experiments [(-)-2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane > cocaine]. The effect of cocaine was mimicked by the reduction of chloride. The results indicate that there is a plasmalemmal component and a vesicular component in the dopamine-releasing action of amphetamine. The releasing action of cocaine is dependent on the existence of a vesicular pool of the neurotransmitter and seems to be linked to inhibition of the plasmalemmal dopamine transporter.

Amphetamine↗
PubMed1994

The cyclooxygenase and lipoxygenase inhibitor BW755C protects rats against kainic acid-induced seizures and neurotoxicity.

In this study the effect of the anti-inflammatory drugs indomethacin, ibuprofen, ebselen (PZ 51, 2-phenyl-1,2-benzoisoselenazol-3(2H)-one), and BW755C (3-amino-1-(m-(trifluoromethyl-phenyl)-2-pyrazoline) on kainic acid (KA)-induced behavioral and neurochemical changes in rats was investigated. Rats injected with KA (10 mg/kg s.c.) developed seizure activity with a 20% mortality within the first 4 h and neuronal degeneration in the limbic system after 3 days. Pretreatment with the cyclooxygenase inhibitor indomethacin (10 mg/kg i.p.) augmented KA-induced epileptic activity and increased the mortality in status epilepticus to 80%. Another cyclooxygenase inhibitor, ibuprofen (20 mg/kg i.p.), and the lipoxygenase inhibitor ebselen (20 mg/kg i.p.) showed no effect on KA-induced symptoms and neurochemical changes. Application of the cyclooxygenase/lipoxygenase inhibitor BW755C (40 mg/kg i.p.) reduced the severity of seizures and protected significantly from irreversible brain lesions induced by KA. The marked reduction of glutamate decarboxylase (GAD; 53.3 +/- 12.2% of control) and choline acetyltransferase (ChAT; 60.9 +/- 9.1% of control) activities in amygdala/pyriform cortex and GAD activity in hippocampus (69.4 +/- 5.6% of control) observed 3 days after KA injection was abolished by BW755C treatment. Histopathological analyses of brain tissue showed that treatment with BW755C prevented the KA-induced nerve cell degeneration, edema, hemorrhages, and tissue necrosis in amygdala/pyriform cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1994

Noradrenaline, dopamine and serotonin levels and metabolism in the human hypothalamus: observations in Parkinson's disease and normal subjects.

In order to determine whether, besides the severe striatal dopamine (DA) loss, other brain neurotransmitter changes may be a constant biochemical feature of idiopathic Parkinson's disease (iPD), we measured the concentration of the three major brain monoamines noradrenaline (NA), DA, and serotonin (5-HT) and their metabolites in five rostro-caudal subdivisions of the hypothalamus of eight control patients and nine patients with morphologically confirmed iPD. In the whole hypothalamus of the iPD patients we found a mild to moderate mean reduction of NA (-52%, P < 0.05), DA (-25%), and 5-HT (-26%). At the subregional level, the most consistently affected area was the intermediate subdivision of the hypothalamus proper where all three monoamines were statistically significantly reduced. Evaluation of individual patient values indicated that, in contrast to the constant and severe DA reduction present in putamen of each of the iPD patients (DA loss ranging from 96% to 99%), several of these patients had whole (and subregional) hypothalamic monoamine values well within the range of controls. We conclude that, although possibly involved in autonomic and/or endocrine disturbances in some patients with iPD, none of the observed monoamine changes in the hypothalamus is an obligatory feature of iPD. Our study demonstrates the need for evaluation of individual patient values rather than mean differences in order to permit valid conclusions to be drawn as to whether an observed neurochemical change can be regarded as specific to a given brain disorder.

Aged↗
PubMed1994

Dopa-responsive dystonia: pathological and biochemical observations in a case.

We report the first neuropathological and neurochemical study of a patient with dopa-responsive dystonia. She had onset of foot dystonia at age 5 years and by age 8 years it was generalized with prominent right leg and arm involvement. On levodopa 750 mg daily she had complete symptomatic improvement that was sustained for 11 years until death. Pathological studies revealed normal numbers of hypopigmented substantia nigra neurons, normal tyrosine hydroxylase (TH) immunoreactivity and TH protein in the SN, no inclusion bodies or gliosis, and no evidence of a degenerative process in the striatum. Biochemical studies revealed reduced dopamine in the substantia nigra and striatum (8% in the putamen and 18% of control in the caudate) with a similar but not identical subregional distribution as in idiopathic Parkinson's disease. In the striatum, TH protein and TH activity was reduced, with the loss more pronounced in the putamen than the caudate. The GBR 12935 binding to DA transporter was normal in the caudate and at the lower end of the range of control values in the putamen. We conclude that disturbed dopamine synthetic capacity or a reduced arborization of striatal dopamine terminals may be the major disturbance in dopa-responsive dystonia.

Adult↗
PubMed1994

Brain monoamines in progressive supranuclear palsy--comparison with idiopathic Parkinson's disease.

Like idiopathic Parkinson's disease (iPD), Progressive Supranuclear Palsy (PSP) is characterized, inter alia, by a pronounced non-overlapping loss of dopamine (DA) in caudate, putamen and substantia nigra. Unlike iPD, in PSP the striatal DA loss is more severe in the caudate than in the putamen; this may contribute to the higher frequency of cognitive deficits in PSP. In contrast to iPD, in patients with PSP the serotonin (5-HT) levels in the basal ganglia are not significantly reduced, thus resulting in a relative predominance of the inhibitory serotonergic influences on the motor behaviour in these patients. It is suggested that combination of levodopa with a 5-HT receptor blocker may substantially improve the (poor) responsiveness of patients with PSP to DA substitution therapy.

Biogenic Monoamines↗
PubMed1993

Cerebral cortex Gs alpha protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder.

Experimental animal and peripheral blood cell studies point to guanine nucleotide regulatory (G) protein disturbances in bipolar affective disorder. We have previously reported elevated prefrontal cortex Gs alpha protein in bipolar affective disorder and have now extended these preliminary observations in a larger number of subjects, assessing the brain regional specificity of these changes in greater detail, determining the functional biochemical correlates of such changes, and evaluating their diagnostic specificity. Membrane G protein (Gs alpha, Gi alpha, Go alpha, and G beta) immunoreactivities were estimated by western blotting in postmortem brain regions obtained from 10 patients with a DSMIII-R diagnosis of bipolar affective disorder and 10 nonpsychiatric controls matched on the basis of age, postmortem delay, and brain pH. To examine whether there were functional correlates to the observed elevated Gs alpha levels, basal and GTP gamma S- and forskolin-stimulated cyclic AMP production was determined in the same brain regions. Compared with controls, Gs alpha (52-kDa species) immunoreactivity was significantly (p < 0.05) elevated in prefrontal (+36%), temporal (+65%), and occipital (+96%) cortex but not in hippocampus (+28%), thalamus (-23%), or cerebellum (+21%). In contrast, no significant differences were found in the other G protein subunits (Gi alpha, Go alpha, G beta) measured in these regions. Forskolin-stimulated cyclic AMP production was significantly increased in temporal (+31%) and occipital (+96%) cortex but not in other regions. No significant differences were apparent in basal or GTP gamma S-stimulated cyclic AMP production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1993

Role of glucocorticoids in the cholinergic degeneration in rat hippocampus induced by ethylcholine aziridinium (AF64A).

Glucocorticoids potentiate hippocampal damage induced by various noxious insults in vivo and in vitro and are implicated in age-related loss of neurons in the hippocampus of various species. The cholinergic innervation of the hippocampus appears to be especially prone to the endangering effect of glucocorticoids, since corticosterone, like acute stress or ACTH, induces a rapid activation of the cholinergic septo-hippocampal pathway. We now report the influence of glucocorticoids on the degeneration of this pathway induced by the cholinergic neurotoxin ethylcholine aziridinium (AF64A). The toxic effect of a submaximal dose of AF64A on cholinergic neurons was evaluated in rats during exposure to glucocorticoids or vehicle as well as in adrenalectomized or sham-operated rats. Daily treatment with either corticosterone or dexamethasone, starting 7 d before the bilateral intracerebroventricular injection of AF64A (1 nmol/ventricle), significantly increased the AF64A-induced loss of ChAT activity in the whole hippocampus, whereas bilateral adrenalectomy 7 d prior to AF64A-injection attenuated the effect of AF64A. Short-term exposure to corticosterone starting 24 hr before AF64A was as effective as the 7 d pretreatment. Dexamethasone exacerbated the AF64A-induced cholinergic lesion in the hippocampal subregions CA1, CA3, and dentate gyrus, and adrenalectomy protected all subregions against the action of AF64A. Along the longitudinal axis of the hippocampus a comparable influence was seen in the dorsal and ventral parts. The subregional pattern in the response to glucocorticoid suggests the involvement of mineralocorticoid type I receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

Functional sensitization of striatal dopamine D1 receptors in the 6-hydroxydopamine-lesioned rat.

Dopamine-stimulated adenylyl cyclase activity was measured in striatal homogenates of rats in which the nigrostriatal pathway was lesioned by 6-hydroxydopamine 20-24 months before the experiments. In the intact (contralateral) striatum the potency and the efficacy of dopamine in stimulating adenylyl cyclase was lower in the presence of high NaCl concentrations (120 mM) compared with the effects of dopamine in an NaCl-poor assay medium (20 mM). The same effect of NaCl was observed in the striatum on the side of a weak, behaviourally ineffective 6-hydroxydopamine lesion resulting in a loss of 57% of striatal dopamine. This effect of NaCl was absent in the strongly denervated striatum, i.e. in rats having a 99.8% dopamine loss and rotating when challenged with a low dose of apomorphine. Thus, in denervated vs intact striatum, in the presence of a physiological concentration of NaCl, dopamine-stimulated adenylyl cyclase showed a sensitization which was absent in assays with 20 mM NaCl. The inhibition of adenylyl cyclase by dopamine via D2 receptors, which was seen in the presence of 120 mM NaCl and the D1 antagonist SCH 23390, was not affected by denervation. We suggest that chronic dopaminergic denervation of the striatum results in a stabilized, i.e. NaCl-insensitive, high affinity state of D1 receptors. This may be the basis for a sensitization of the coupling mechanism of the denervated D1 receptors to adenylyl cyclase.

Adenylyl Cyclases↗
PubMed1992

Cholinergic markers in ALS spinal cord.

We analyzed binding sites for quinuclidinyl benzilate (QNB) and hemicholinium-3 (HC-3) by quantitative slice autoradiography and the activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in spinal cord of 5-7 patients with amyotrophic lateral sclerosis (ALS). In the ventral horn, QNB binding sites were markedly reduced (38% of controls; P less than 0.001), whereas HC-3 binding sites were only moderately affected (76%, P less than 0.01). Losses in cholinergic marker enzymes were inconsistent. The loss of muscarinic binding sites in the ventral horn was the most reliable cholinergic disease marker in ALS.

Acetylcholinesterase↗
PubMed1992

Mechanisms of neuronal loss in Parkinson's disease: a neuroanatomical-biochemical perspective.

It is shown that the specific inter- and subregional patterns of striatal dopamine loss in idiopathic Parkinson's disease can serve as a criterion for the evaluation of neurotoxic processes suggested to play an etiological role in this disorder. Based on this premise, the possibility is examined that dopamine-based free radicals (oxidative stress), or a MPTP-like mechanism may be the primary cause of the substantia nigra cell death in idiopathic Parkinson's disease. It is concluded that the most likely determinant of the specific patterns of nigral cell loss and striatal dopamine deficit might be the peculiar topomorphological arrangement of the melanin-containing neurones in the human substantia nigra.

Animals↗
PubMed1992

Aging produces a specific pattern of striatal dopamine loss: implications for the etiology of idiopathic Parkinson's disease.

To examine the possible causal contribution of normal or accelerated aging to the neurodegenerative process of Parkinson's disease, we measured the influence of aging on subregional striatal dopamine and homovanillic acid levels in postmortem brain of 23 neurologically and psychiatrically normal human subjects 14-92 years old. We observed a significant decline in striatal dopamine levels and increase in the homovanillic acid/dopamine molar ratios with increasing age. The dopamine loss, on average, was of the same magnitude in the caudate nucleus and the putamen (-60% in the 84-year-old group as compared with the 22-year-old group), with the caudal component of both nuclei being more affected than the rostral subdivisions. The level of subregional dopamine metabolism, as measured by the homovanillic acid/dopamine ratio, in our young individuals (mean age, 22 years) was found to be inversely correlated to the degree of subregional dopamine loss suffered by the individuals in the older age groups. We conclude the following: (a) Striatal subdivisions with physiologically higher dopamine metabolism are not at a greater risk of suffering dopamine neuronal damage with advancing age, as would seem to be implied by the oxidative stress hypothesis; thus, formation of dopamine-derived oxy radicals in the human striatum appears unlikely to be a primary factor responsible for the age-related striatal dopamine loss. (b) The regional and subregional pattern of striatal dopamine loss in normal aging differs substantially from the pattern typically observed in idiopathic Parkinson's disease; therefore, the cause of idiopathic Parkinson's disease cannot be primarily an age-dependent neurodegenerative process.

Adolescent↗
PubMed1992

Sensitization of dopamine-stimulated adenylyl cyclase in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys and patients with idiopathic Parkinson's disease.

Dopamine-stimulated adenylyl cyclase activity was measured in striatal homogenates of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys and humans with idiopathic Parkinson's disease and compared with the activity in control tissue. No differences between parkinsonian and control tissue were found in the presence of 20 mM NaCl. However, when 120 mM NaCl was included in the assay medium, a significantly higher increase in the Vmax of dopamine-stimulated adenylyl cyclase activity was observed in the caudate of MPTP-parkinsonian rhesus monkeys and the putamen of patients with idiopathic Parkinson's disease. No such sensitization was seen in the MPTP-treated rhesus putamen or human Parkinson's disease caudate tissue. A role of D2 receptors in this sensitization could be ruled out by the concomitant use of the D2 antagonist l-sulpiride and by [3H]spiperone saturation analysis of the D2 receptor density, which was found at control level in the caudate tissue of MPTP-treated rhesus monkeys. Similarly, on the basis of saturation binding with the D1 selective ligand 125I-SCH 23982, there was no difference in caudate nucleus D1 receptor densities between control and MPTP-treated monkeys. Our results point to a region-specific functional sensitization of D1 receptors as a consequence of severe dopaminergic denervation of the striatum and suggest the possibility of a therapeutic potential of a D1 agonist with full intrinsic activity in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Brain neurotransmitter changes in human narcolepsy.

We measured the concentrations of the three major monoamine neurotransmitters noradrenaline, dopamine, and serotonin, their metabolites, and receptor binding sites in autopsied brain of three patients with narcolepsy. As compared with the controls, concentrations of the noradrenaline and serotonin metabolites MHPG and 5-HIAA, respectively, were markedly elevated in cerebral cortical subdivisions of the narcolepsy patients together with a trend for above-normal neurotransmitter/metabolite "turnover" ratio. A moderately reduced number of alpha 1-adrenoceptors, as judged by the reduced levels of 3H-prazosin binding, was observed in cerebral cortex of two of the three patients with narcolepsy. Mean striatal levels of dopamine and its metabolite homovanillic acid were normal, whereas the concentration of dopamine's second metabolite, dihydroxyphenylacetic acid, was markedly reduced by 50% or greater. This was accompanied by a marked increase (+125%) in mean 3H-spiperone binding to the D2 dopamine receptor in both caudate and putamen; in contrast, the levels of 3H-SCH 23390 binding to the striatal D1 dopamine receptor were in the normal range. Our data provide evidence for altered brain monoaminergic neurotransmitter function in human narcolepsy.

Adult↗
PubMed1991

Amyotrophic lateral sclerosis: changes of noradrenergic and serotonergic transmitter systems in the spinal cord.

Noradrenaline (NA), dopamine (DA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in discrete subdivisions of cervical, thoracic and lumbar spinal cord segments obtained at autopsy of 4 subjects with amyotrophic lateral sclerosis (ALS) and 7 control patients. NA concentrations in thoracic and lumbar spinal cord of ALS patients were 2- to 4-fold higher compared with values obtained in control patients. 5-HT levels were unchanged at the cervical and thoracic level and slightly above normal in lumbar spinal cord, while the concentration of 5-HIAA was lowered in cervical and thoracic, but within the control range, in lumbar spinal cord. As a result, the molar ratios of 5-HT/5-HIAA were increased at all spinal levels in ALS. No difference in spinal DA concentration was found between ALS and control patients. The changes in the noradrenergic and serotonergic transmitter systems reported here most probably reflect a decreased release of these transmitter substances in ALS spinal cord. Since lack of the facilitatory monoaminergic influence would necessitate an increase in the excitatory, potentially neurotoxic glutamatergic input onto the motoneurones, we hypothesize that this could contribute to the progressive loss of spinal motoneurones in amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis↗
PubMed1991

Lower efficacy of the dopamine D1 agonist, SKF 38393, to stimulate adenylyl cyclase activity in primate than in rodent striatum.

The selective D1 agonist, SKF 38393, stimulated adenylyl cyclase by about 40% of basal activity in rat striatum but by only about 10% in the striatum of rhesus monkeys. In contrast, dopamine stimulated striatal adenylyl cyclase in both species with equal efficiency (70-80%). SKF 38393 30 microM inhibited the effect of 30 microM dopamine by about 45% in rat and by about 75% in primate tissue. This difference may be due to a lower D1 receptor reserve in primate than in rodent tissue and suggests that only selective D1 agonists with full efficacy at D1 receptors can be expected to have beneficial effects in patients with Parkinson's disease.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗