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E C Hirsch

Publications and source records attributed to E C Hirsch.

At least 109 records · Page 6Linked to original sources
PubMed1995

Alterations of GABAergic neurons in the basal ganglia of patients with progressive supranuclear palsy: an in situ hybridization study of GAD67 messenger RNA.

We analyzed postmortem GABAergic neurons in the basal ganglia of three patients with progressive supranuclear palsy (PSP) and four matched controls by means of glutamic acid decarboxylase (M(r) 67,000 [GAD67]) mRNA in situ hybridization. In PSP, we found a 50 to 60% decrease in the number of neurons expressing GAD67 mRNA in the caudate nucleus, ventral striatum, and the external and internal pallidum. The expression of GAD67 mRNA per neuron was reduced in the caudate nucleus and putamen (-43%), the ventral striatum (-55%), and the external and internal pallidum (-59% and -68%). Our data indicate that striatal and pallidal GABAergic neurotransmission is markedly reduced in PSP and we suggest that this alteration may account for the motor and cognitive symptoms observed in PSP. Furthermore, the destruction of the basal ganglia output systems may explain the lack of responsiveness to L-dopa therapy of PSP patients.

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PubMed1994

Does the calcium binding protein calretinin protect dopaminergic neurons against degeneration in Parkinson's disease?

Parkinson's disease (PD) is characterized by a heterogeneous loss of dopaminergic neurons in the human mesencephalon affecting mainly the substantia nigra pars compacta (SNpc) and to a lesser extent the other dopaminergic cell groups. A rise in intracellular calcium concentrations represents one of the final events leading to nerve cell death. Calbindin D28k, a protein capable of buffering intracellular calcium concentrations is present in the dopaminergic neurons that are selectively preserved in PD but not in those that degenerate. To determine whether other calcium-binding proteins also represent putative protective factors of dopaminergic neurons in PD, we analyzed immunohistochemically the distribution of calretinin-containing (CR+) neurons, in the human mesencephalon of three control subjects and four patients with PD. No significant differences were observed between the number of CR+ neurons in the two subject groups. Sequential double immunostaining for calretinin and tyrosine hydroxylase showed a variable proportion of CR+ neurons among dopaminergic neurons: moderate co-localization was found in catecholaminergic cell group A8 and in the dorsal part of the ventral tegmental area (VTA) and low co-localization in the SNpc, the ventral part of the VTA and the central gray substance. This indicates that calretinin may only protect some dopaminergic neurons against degeneration in PD. Yet, in the SNpc a selective preservation of CR+ dopaminergic neurons was observed, suggesting a neuroprotective role in some dopaminergic cell groups only.

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PubMed1994

Loss of striatal high affinity NGF binding sites in progressive supranuclear palsy but not in Parkinson's disease.

125I-Nerve growth factor (NGF) binding sites were analyzed by autoradiography in the striatum of 3 control subjects, 3 patients with Parkinson's disease and 3 patients with progressive supranuclear palsy. A high level of 125I-NGF binding was observed (0.3-0.4 fmol/mg of tissue equivalent) in the striatum and the nucleus basalis of Meynert of control patients. Pockets of lower 125I-NGF binding corresponding to acetylcholinesterase-poor striosomes were detected in the striatum of control subjects and patients with Parkinson's disease or progressive supranuclear palsy. When compared to controls, the density of 125I-NGF binding sites was reduced by 30% in the striatum of patients with progressive supranuclear palsy but not reduced in that of patients with Parkinson's disease. 125I-NGF binding was not significantly decreased in the nucleus basalis of Meynert in either diseases. Since NGF receptors are thought to be localized on cholinergic neurons in the striatum, the decrease in NGF binding is compatible with the loss of cholinergic neurons reported in the striatum from PSP patients.

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PubMed1994

Monoamine vesicular uptake sites in patients with Parkinson's disease and Alzheimer's disease, as measured by tritiated dihydrotetrabenazine autoradiography.

The monoaminergic innervation of the caudate nucleus, putamen and ventral striatum was investigated post mortem, in patients with Parkinson's and Alzheimer's disease as compared to control subjects, by autoradiographic detection of tritiated dihydrotetrabenazine (3H-TBZOH), a specific high affinity ligand of the vesicular monoamine transporter. The binding of 3H-TBZOH was specific and saturable (Kd 5.3 nM). In control striatum, the pattern of distribution of 3H-TBZOH binding was heterogeneous, with higher binding levels in the 'matrix' than in the 'striosome' compartment. Changes in ligand binding levels were observed in the pathological brains compared to controls. In Parkinson's disease (PD), characterized by a severe damage of mesostriatal dopaminergic neurons, the density of 3H-TBZOH binding was reduced. A severe decrease in 3H-TBZOH binding was observed in all parts of the striatum (caudate nucleus: -80%, putamen: -86%, ventral striatum: -94%) in PD brains. The data corroborate the deficiency in striatal dopaminergic transmission and suggest that in PD brains dopaminergic terminals have disappeared and/or no longer contain synaptic vesicles. In Alzheimer's disease (AD), 3H-TBZOH binding was significantly reduced by 57% in the ventral striatum and not in the caudate nucleus and putamen. The specific decrease of monoaminergic transporter levels in the ventral striatum confirm that this nucleus is a target area in AD.

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PubMed1994

Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson's disease.

Activated glial cells observed in the substantia nigra in Parkinson's disease may participate in the mechanism of nerve cell death by providing toxic substances such as cytokines. Among these compounds, tumor necrosis factor-alpha (TNF) is of interest because it can provoke cell death. We detected TNF-immunoreactive glial cells in the substantia nigra of parkinsonian patients but not in those of control subjects. Immunoreactivity for TNF receptors was found in cell bodies and processes of most dopaminergic neurons of control and parkinsonian subjects, suggesting that nigral dopaminergic neurons might be sensitive to TNF produced in Parkinson's disease. These results suggest that TNF may participate in the degenerative processes occurring in Parkinson's disease, at least after a primary insult inducing a reactive gliosis.

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PubMed1994

Decreased tyrosine hydroxylase content in the dopaminergic neurons of MPTP-intoxicated monkeys: effect of levodopa and GM1 ganglioside therapy.

Parkinson's disease is characterized by the degeneration of melanized dopaminergic neurons of the substantia nigra. The functional capacity of the surviving dopaminergic neurons is affected, as suggested by the subnormal levels of tyrosine hydroxylase messenger RNA and protein found in the remaining cells. The reduced expression of tyrosine hydroxylase may be due to either the evolving neurodegenerative process or its downregulation, possibly secondary to chronic levodopa treatment. The cellular content of tyrosine hydroxylase was determined in the mesencephalon from 16 Macaca fascicularis monkeys, using a semiquantitative immunocytochemical method. Thirteen monkeys were rendered parkinsonian by weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 2 (subacute treatment) or 20 (chronic treatment) weeks. Three of the monkeys received levodopa and 3 others received GM1 ganglioside. The loss of dopaminergic neurons in the mesencephalon of the MPTP-intoxicated monkeys was severe in the substantia nigra, intermediate in cell groups A8 and A10, and almost undetectable in the central gray substance. After both subacute and chronic treatment, the cellular content of tyrosine hydroxylase was reduced by 40% in the surviving neurons of the lesioned substantia nigra, but by less in the other mesencephalic dopaminergic regions. Neuronal survival and tyrosine hydroxylase content in monkeys that had received levodopa were not significantly different. The cellular content of tyrosine hydroxylase was increased in the substantia nigra of the monkeys that received GM1 ganglioside injections. The results show that the decreased expression of tyrosine hydroxylase found in nigral dopaminergic neurons after partial degeneration of the mesostriatal dopaminergic system is not influenced by levodopa treatment and is partially reversed by GM1 ganglioside administration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Distribution of manganese-dependent superoxide dismutase in the human brain.

The distribution of manganese-dependent superoxide dismutase, an enzyme that transforms superoxide radicals into hydrogen peroxide, was studied in the human brain post mortem using a sheep polyclonal antiserum raised against the enzyme from liver mitochondria. One band, corresponding to a protein of 22,000 mol. wt was detected in the human brain by western blot analysis. At the light-microscopy level, a punctate immunostaining was observed in the neuropil and in some but not all, glial and neuronal cell bodies. Electron-microscopy revealed that the staining was exclusively confined to the inner mitochondrial membrane. A heterogeneous distribution of manganese-dependent superoxide dismutase was observed in the human brain. In the forebrain, numerous immunostained neurons were detected in the striatum, thalamus, pallidal complex and the nucleus basalis of Meynert. In the cerebellum, only granular and Purkinje cells were immunostained. Various nuclei from the brainstem displayed superoxide dismutase immunoreactivity, including the cranial nerve nuclei, the nucleus supratrochlearis, the red nucleus, the substantia nigra, the nucleus cuneiformis and subcuneiformis, the nucleus parabigeminal, the nucleus centralis superior, the nucleus supraspinalis, the nucleus of the medullae oblongata and the gigantocellularis nucleus. Large pyramidal neurons containing superoxide dismutase were detected in the CA subsectors, the hilus of the hippocampus and the cerebral cortex. Smaller immunostained neurons were also observed in layers I, IV and VI of all cortical regions studied. The distribution of immunostained glial cells was more limited, and restricted to the internal and external capsules, the hypothalamus, the red nucleus, the pyramidal white matter and surrounding areas, the cerebral cortex and the sub-ependymal layer, the alveus and the stratum oriens of the hippocampus. This heterogeneous but not ubiquitous distribution of cells expressing manganese-dependent superoxide dismutase suggests that not all cells in the human brain are protected to the same extent against the deleterious effects of superoxide.

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PubMed1994

Immunohistochemical study of catechol-O-methyltransferase in the human mesostriatal system.

The cellular localization of catechol-O-methyltransferase was analysed in the mesostriatal system of human brain post mortem by means of immunohistochemistry. In the human nigral complex, catechol-O-methyltransferase immunostaining was not detected in melanized dopaminergic neurons, except in the ventral tegmental area and substantia nigra pars lateralis, where few neurons displayed intense immunolabelling. In the striatum, catechol-O-methyltransferase immunostaining was found in numerous cell bodies and in the neuropile. Observations at the electron microscope level revealed that catechol-O-methyltransferase immunoreactivity was present in the cell bodies of neurons and their processes, including the dendritic spines. No catechol-O-methyltransferase immunolabelling was observed in striatal nerve terminals in contact with dendritic spines, indicating that dopaminergic nerve terminals do not exhibit catechol-O-methyltransferase immunoreactivity. Catechol-O-methyltransferase-immunoreactive cell bodies and processes of glial cells were also detected in the striatum. The data suggest that catechol-O-methyltransferase is either not expressed or only slightly expressed by the dopaminergic nigrostriatal neurons, whereas it is clearly present in striatal neurons and glial cells. Thus, the catabolic degradation of striatal released dopamine by its O-methylation may involve postsynaptic neurons rather than dopaminergic presynaptic neurons. The presence of catechol-O-methyltransferase in some dopaminergic neurons of the ventral tegmental area and substantia nigra pars lateralis suggests that methylation of dopamine may occur in these neurons, which may consequently be better protected against dopamine auto-oxidation than those of the substantia nigra pars compacta.

Animals↗
PubMed1994

High affinity neurotrophin receptors in cholinergic neurons in the human brain.

Tyrosine protein kinases TrkA and TrkC are signal-transducing receptors for nerve growth factor (NGF) and neurotrophin-3 (NT-3), respectively. In the human brain postmortem, using sequential immunohistochemistry, we detected the presence of TrkA and TrkC on 99% and 95% of cholinergic neurons from the basal forebrain and on some cholinergic neurons (22% and 16%, respectively) from the striatum, but not on those from the mesencephalon. These results suggest that some cholinergic neurons, particularly those of the nucleus basalis of Meynert, may be sensitive to both NGF and NT-3 in the human brain. The sensitivity of cholinergic neurons to these two neurotrophins may have a special interest in therapeutic strategies for Alzheimer's disease.

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PubMed1993

Low affinity nerve growth factor receptor, adrenal transplant and Parkinson's disease.

Immunohistochemistry of low-affinity nerve growth factor receptor (LNGFR) was performed postmortem in the striatum and the adrenal gland of a parkinsonian patient with an adrenal to brain transplantation. Few LNGFR-positive fibers were observed in the necrotic graft. By contrast numerous immunostained fibers were detected in a restricted zone of the host striatum adjacent to the graft, corresponding to a selective zone of sprouting of tyrosine hydroxylase-positive fibers. This suggests that nerve growth factor or related growth factors may promote sprouting of catecholaminergic fibers in the host striatum.

Adrenal Medulla↗
PubMed1993

Autoradiographic study of [125I]epidermal growth factor-binding sites in the mesencephalon of control and parkinsonian brains post-mortem.

Epidermal growth factor (EGF) is assumed to act as a neurotrophic factor on dopaminergic nigrostriatal neurons in cell cultures and animal brain. This led us to consider its possible role in the pathophysiology of Parkinson's disease. An autoradiographic study of the distribution of EGF-binding sites was performed in the mesencephalon of controls and patients with Parkinson's disease, a neurodegenerative disease associated with dramatic damage to the mesostriatal dopaminergic neurons. Scatchard analysis revealed a single type of binding sites with a high affinity constant, in the various mesencephalic dopaminergic areas examined. The characteristics and density of [125I]EGF-binding sites were similar in controls and parkinsonian patients. This suggests that EGF receptors in the mesencephalon are unaffected in Parkinson's disease and may therefore contribute to the increased activity and survival of the remaining dopaminergic neurons.

Autoradiography↗
PubMed1993

Differential vulnerability to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine of dopaminergic and cholinergic neurons in the monkey mesopontine tegmentum.

Parkinson's disease is characterized by a loss of dopaminergic neurons in the substantia nigra and, in the most severe cases, by degeneration of mesopontine cholinergic neurons. In a monkey model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine we report that, despite a severe loss of dopaminergic neurons, in the mesopontine tegmentum cholinergic neurons are preserved in the same region. This suggests that the loss of mesopontine cholinergic neurons in parkinsonian patients may represent an end-stage degenerative process, the cause of which may be independent of the mechanism of dopaminergic cell death.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

In situ hybridization of GAD mRNA in monkey and human brain: quantification at both regional and cellular levels.

GAD mRNA was detected in human and monkey brain postmortem by in situ hybridization with an [35S]-labelled copy RNA corresponding to a 2.7-kb fragment of the coding region of human GAD mRNA. A characteristic and reproducible pattern of hybridization was obtained with the anti-sense, but not the sense probe in both monkey and human brain. Microscopic examination of tissue sections showed that only neuronal perikarya, not glial cells, were labelled. The data confirm the heterogeneity of GAD mRNA distribution reported in rodent brain and non-human primate brain.

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PubMed1993

Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer's disease.

Cholinergic neurons were studied by immunohistochemistry, with an antiserum against choline acetyltransferase (ChAT), in the basal forebrain (Ch1 to Ch4) of four patients with Alzheimer's disease (AD) and four control subjects. ChAT-positive cell bodies were mapped and counted in Ch1 (medial septal nucleus), Ch2 (vertical nucleus of the diagonal band), Ch3 (horizontal nucleus of the diagonal band) and Ch4 (nucleus basalis of Meynert). Compared to controls, the number of cholinergic neurons in AD patients was reduced by 50% on average. The interindividual variations in cholinergic cell loss were high, neuronal loss ranging from moderate (27%) to severe (63%). Despite the small number of brains studied, a significant correlation was found between the cholinergic cell loss and the degree of intellectual impairment. To determine the selectivity of cholinergic neuronal loss in the basal forebrain of AD patients, NPY-immunoreactive neurons were also investigated. The number of NPY-positive cell bodies was the same in controls and AD patients. The results (1) confirm cholinergic neuron degeneration in the basal forebrain in AD and the relative sparing of these neurons in some patients, (2) indicate that degeneration of cholinergic neurons in the basal forebrain contributes to intellectual decline, and (3) show that, in AD, such cholinergic cell loss is selective, since NPY-positive neurons are preserved in the basal forebrain.

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PubMed1993

Tyrosine hydroxylase protein and messenger RNA in the dopaminergic nigral neurons of patients with Parkinson's disease.

To analyze the roles of transcriptional and post-transcriptional regulatory mechanisms of tyrosine hydroxylase (TH) gene expression during dopaminergic denervation in Parkinson's disease (PD), the cellular content of TH messenger RNA (mRNA) and TH protein in the substantia nigra were compared in control subjects and patients with PD. The average amounts of TH mRNA as well as those of TH protein per neuron were variable among controls but correlated to each other. In PD patients, both TH mRNA and TH protein content in nigral neurons were reduced relative to controls, however, the ratio between TH protein and TH mRNA levels was unaffected. The data suggest that, in PD: (1) TH protein content is decreased in the surviving nigral dopaminergic neurons, most likely as a result of a lowered TH mRNA cellular content. Thus the surviving neurons at end stages of the disease may be in a premorbid state. (2) The TH mRNA translation rate is not modified to compensate for dopamine deficiency.

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PubMed1993

GM-1 ganglioside promotes the recovery of surviving midbrain dopaminergic neurons in MPTP-treated monkeys.

We have examined the influence of chronic GM-1 treatment (20 mg/kg i.m. for 16 consecutive days) on the extent of dopaminergic damage induced by acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in cynomolgus monkeys using immunohistochemical and neurochemical analysis. The total number of tyrosine hydroxylase-immunoreactive neurons was reduced in different catecholaminergic mesencephalic regions of MPTP-treated monkeys such as substantia nigra pars compacta, mainly in the ventral portion of the nucleus (39% reduction), substantia nigra pars lateralis (31%), peri- and retrorubral catecholaminergic cell group and ventral tegmental area (A8 and A10 respectively, 20% reduction). A similar degree of neuronal loss was observed in the MPTP+GM-1-treated animals, suggesting that GM-1 ganglioside does not exert a protective effect against MPTP-induced dopaminergic cell loss. Moreover, no neurochemical recovery from the striatal dopaminergic depletion induced by MPTP was found after GM-1 treatment. However, the optical density of tyrosine hydroxylase fibers and the cellular tyrosine hydroxylase content were increased in the substantia nigra pars compacta and ventral tegmental area of the MPTP-treated monkeys which received GM-1 ganglioside, compared with animals treated only with the neurotoxin. These results indicate that GM-1 does not protect against cell death but exerts a neurotrophic effect on surviving dopaminergic neurons in the midbrain of MPTP-lesioned monkeys, suggesting that GM-1 ganglioside may be potentially useful for the treatment of neurodegenerative disorders such as Parkinson's disease.

Animals↗
PubMed1993

Glutathione peroxidase, glial cells and Parkinson's disease.

Hyperoxidation phenomena are suspected to be involved in dopaminergic cell death in Parkinson's disease, which affects preferentially the neuromelanin-containing dopaminergic neurons of the substantia nigra. Glutathione peroxidase is the major protective enzyme against hydrogen peroxide toxicity. The distribution of glutathione peroxidase-containing cells was investigated by immunohistochemistry in the midbrain of four control subjects and four patients with Parkinson's disease. (1) Glutathione peroxidase-like immunoreactivity was detected exclusively in glial cells. (2) In control brains, the density of glutathione peroxidase-positive cells was higher in the vicinity of the dopaminergic cell groups known to be resistant to the pathological process of Parkinson's disease. (3) In Parkinson's disease, an increased density of glutathione peroxidase-immunostained cells was observed, surrounding the surviving dopaminergic neurons. The increase in glutathione peroxidase-containing cells was correlated with the severity in dopaminergic cell loss in the respective cell groups. The data suggest that in control brains, a low density of glutathione peroxidase-positive cells surround the dopaminergic neurons the most vulnerable to Parkinson's disease, and that in parkinsonian brains, the increased number of glutathione peroxidase-positive cells may contribute to protect neurons against pathological death. Thus, the amount of glutathione peroxidase protein-containing cells may be critical for a protective effect against oxidative stress, although it cannot be excluded that the level of the enzyme activity remains the crucial factor.

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