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E C Hirsch

Publications and source records attributed to E C Hirsch.

At least 55 records · Page 3Linked to original sources
PubMed2000

[Development of dyskinesias induced by treatment for Parkinson's disease: potential role of first exposure to L-DOPA (or phenomenon of priming)].

L-DOPA-induced dyskinesias are one of the main problems encountered in treating patients with Parkinson's disease (PD). They are induced by the antiparkinsonian medications and primarily related to the degree of dopaminergic depletion, as shown by the fact that they tend to appear several years after the onset of the disease. Do the initial therapeutic decisions taken in treating a PD patient influence the point at which dyskinesias first occur? This question is raised in view of the apparent priming phenomenon that occurs in first exposure to L-DOPA. L-DOPA administrated to an MPTP intoxicated monkey rapidly corrects the animals' motor symptoms but generate dyskinesias. In contrast, the administration of dopaminergic agonists with a long half-life has a similar therapeutic effect but without inducing dyskinesias. However, a parkinsonian monkey that had received L-DOPA and developed dyskinesias, which were subsequently abolished when the treatment was withdrawn for several months, proceeded to develop dyskinesias when treatment with dopaminergic agonists with long half-life was introduced. The monkeys' previous exposure to L-DOPA (i.e. priming) thus increased its susceptibility to develop dyskinesias after exposure to drugs which would not otherwise have had this effect. Pulsatile activation of type D2 dopamine receptors is reported to be the principal factor in the triggering of dyskinesias and may well be involved in the priming phenomenon. While the pathophysiological basis of priming is not yet known, the phenomenon would not appear to be related to a hyperexpression of dopamine receptors (types D1 and D2) in the sensorimotor striatum. The results of recent experiments have given rise to several different hypothesis for the mechanisms involved in priming: the role of internalization of dopamine receptors after administration of dopaminergic drugs; change in the distribution of D3 dopamine receptor; changes in the expression of peptides (substance P, enkephalin) in efferent neurons of the striatum; and reorganization of connections at the level of the dopaminergic neurons and their target tissue. While many questions remain unanswered, it may well be that the initial therapeutic decisions taken when treating de novo patient are crucial in trying to delay the onset of dyskinesias.

Animals↗
PubMed2000

Nigrostriatal system plasticity in Parkinson's disease: effect of dopaminergic denervation and treatment.

Clinical studies suggest that the appearance of levodopa-induced dyskinesias may be partly related to changes in the dopaminergic system. This article reviews data on biochemical and morphological changes induced by treatment, the lesion, or both, in dopaminergic neurons themselves, postsynaptic striatal tissue, and afferent fibers to dopaminergic neurons in the substantia nigra. Recent studies on dopaminergic neurons suggest that levodopa therapy can induce sprouting of surviving dopaminergic neurons at their terminals in the striatum. At the postsynaptic level, treatment may trigger induction of D3 dopamine receptors and internalization of D1 receptors. Furthermore, dopaminergic denervation has been shown to be involved in plastic changes in the striatum associated with hyperactivity of glutamatergic fibers making synapses with the head of the spines of gamma-aminobutyric acidergic neurons. At the level of the dendrites of dopaminergic neurons, plasticity of excitatory cholinergic afferent fibers targeting dopaminergic neurons and an involution of noncholinergic afferent fibers have been observed. Taken together, these data suggest that dopaminergic denervation and treatment induce profound plastic changes in the nigrostriatal system. Whether such changes participate in side-effects of treatment and, in particular, the appearance of dyskinesias remains to be determined.

Corpus Striatum↗
PubMed1999

Dopaminergic cell group A8 in the monkey: anatomical organization and projections to the striatum.

The first part of the study was a quantitative analysis of the distribution of A8 neurons compared with that of A9 and A10 neurons by means of tyrosine hydroxylase and calbindin-D(28K) immunohistochemistry and image analysis in monkeys. Then the striatal projection of A8 neurons was studied using retrograde and anterograde tracing methods. It was compared with that originating in cell groups A9 and A10 by performing injections of the retrograde tracer wheat germ agglutinin conjugated to horseradish peroxidase into different regions of the striatum. Ten percent of all mesencephalic dopaminergic neurons are located in cell group A8. This cell group, along with A10 and the dorsal part of A9, constitutes the dorsal tier, which accounts for 28% of mesencephalic dopaminergic neurons. Double-staining experiments showed that the neurons located in the dorsal tier were calbindin positive, whereas those from the ventral tier were not. In terms of anatomical projection, the dorsal tier mainly projects to the ventral part of the associative striatum, with preferential projections of A8 neurons to the ventrocaudal putamen, of A10 neurons to the nucleus accumbens, and of dorsal A9 neurons to both. Conversely, the main targets of the ventral tier of mesencephalic neurons (ventral part of A9) are the sensorimotor putamen and the associative caudate nucleus. In conclusion, each mesencephalic cell group projects primarily to one specific striatal region but also participates, albeit to a lesser extent, in the innervation of all the remaining striatal parts.

Animals↗
PubMed1999

FcepsilonRII/CD23 is expressed in Parkinson's disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells.

Oxidative stress is thought to be involved in the mechanism of nerve cell death in Parkinson's disease (PD). Among several toxic oxidative species, nitric oxide (NO) has been proposed as a key element on the basis of the increased density of glial cells expressing inducible nitric oxide synthase (iNOS) in the substantia nigra (SN) of patients with PD. However, the mechanism of iNOS induction in the CNS is poorly understood, especially under pathological conditions. Because cytokines and FcepsilonRII/CD23 antigen have been implicated in the induction of iNOS in the immune system, we investigated their role in glial cells in vitro and in the SN of patients with PD and matched control subjects. We show that, in vitro, interferon-gamma (IFN-gamma) together with interleukin-1beta (Il-1beta) and tumor necrosis factor-alpha (TNF-alpha) can induce the expression of CD23 in glial cells. Ligation of CD23 with specific antibodies resulted in the induction of iNOS and the subsequent release of NO. The activation of CD23 also led to an upregulation of TNF-alpha production, which was dependent on NO release. In the SN of PD patients, a significant increase in the density of glial cells expressing TNF-alpha, Il-1beta, and IFN-gamma was observed. Furthermore, although CD23 was not detectable in the SN of control subjects, it was found in both astroglial and microglial cells in parkinsonian patients. Altogether, these data demonstrate the existence of a cytokine/CD23-dependent activation pathway of iNOS and of proinflammatory mediators in glial cells and their involvement in the pathophysiology of PD.

Aged↗
PubMed1999

Levodopa induces a cytoplasmic localization of D1 dopamine receptors in striatal neurons in Parkinson's disease.

Parkinson's disease is characterized by a massive loss of nigral dopamine neurons that results in a reduction of dopamine concentrations in the striatum. The most commonly used treatment for this disease is levodopa therapy to restore striatal dopamine. This treatment is mediated by dopamine receptors, but the effect of treatment and the disease on receptor distribution is unknown. In this study, the distribution of D1 dopamine receptors was analyzed at the cellular and subcellular level in the striatum of 5 patients with Parkinson's disease (all treated with levodopa) and 4 control subjects. In the control brains, D1 dopamine receptors were mostly detected on the plasma membrane of medium-sized spiny neurons. The quantitative analysis performed at the ultrastructural level in patients with Parkinson's disease revealed an increase in immunostaining in the cytoplasm of medium-sized neurons. This effect was likely the result of the treatment rather than the dopaminergic denervation, as such changes were not observed in the striatum of rats with a unilateral 6-hydroxydopamine nigrostriatal lesion, but were present in normal or lesioned rats treated with a D1 dopamine agonist. Altered localization of D1 dopamine receptors may participate in the occurrence of side effects of levodopa therapy such as dyskinesia and fluctuations in motor performances.

Aged↗
PubMed1999

Mechanism and consequences of nerve cell death in Parkinson's disease.

The etiology of Parkinson's disease remains unknown, making it difficult to develop therapeutical approaches to stop the progression of the disease. The best known treatment to date is based on the use of L-DOPA or dopaminergic agonists. These are merely substitutive therapies and have limitations because of their side effects. Thus, the development of new therapeutical strategies will require a far better knowledge of the mechanism and the consequences of nerve cell death in Parkinson's disease. Parkinson's disease is characterized by a selective vulnerability of sub-populations of dopaminergic neurons in the mesencephalon. The fact that the neurons which degenerate in Parkinson's disease are already sensitive to oxidative stress in control subjects and the reported increased production of oxygen free radicals in Parkinson's disease suggest that oxidative stress may be involved in the mechanism of nerve cell death. Furthermore, oxygen free radicals are also involved in an oxygen-dependent pro-apoptotic pathway stimulated by the inflammatory reaction observed in Parkinson's disease. These data suggest that anti-oxidant or anti-inflammatory treatments may slow down the progression of the disease. On the other hand, new substitutive therapies may be developed by trying to restore the activity of the neurons located downstream from the nigrostriatal pathway. Indeed, the nigrostriatal denervation induces a hyper-activity of the output structures of the basal ganglia (internal segment of the globus pallidus and substantia nigra pars reticulata), as demonstrated in various animal models of the disease. These changes in the activity of the output structures of the basal ganglia seem to be directly induced by the hyperactivity of the glutamatergic afferent fibers from the subthalamic nucleus. The fact that L-DOPA treatment or a reduction in the activity of the subthalamic nucleus alleviate the symptoms of the disease and restore the activity of the output structures of the basal ganglia in parkinsonism suggests that these structures play a key role in the pathophysiology of the disease and could represent a potential therapeutic target.

Animals↗
PubMed1999

Systemic administration of NMDA and AMPA receptor antagonists reverses the neurochemical changes induced by nigrostriatal denervation in basal ganglia.

In Parkinson's disease, nigrostriatal denervation leads to an overactivity of the subthalamic nucleus and its target areas, which is responsible of the clinical manifestations of the disease. Because the subthalamic nucleus uses glutamate as neurotransmitter and is innervated by glutamatergic fibers, pharmacological blockade of glutamate transmission might be expected to restore the cascade of neurochemical changes induced by a dopaminergic denervation within the basal ganglia. To test this hypothesis, two types of glutamate antagonists, the NMDA receptor antagonist MK-801 and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist LY293558, were administered systemically, either alone or in combination with L-DOPA, in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. The effect of treatment was assessed neurochemically by analyzing at the cellular level the functional activity of basal ganglia output structures and the subthalamic nucleus using the expression levels of the mRNAs coding for glutamic acid decarboxylase and cytochrome oxidase, respectively, as molecular markers of neuronal activity. The present study shows that treatment with glutamate antagonists, and particularly with AMPA antagonists, alone or in combination with L-DOPA, reverses the overactivity of the subthalamic nucleus and its target areas induced by nigrostriatal denervation. These results furnish the neurochemical basis for the potential use of glutamate antagonists as therapeutic agents in Parkinson's disease.

Animals↗
PubMed1999

The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28K) immunohistochemistry.

Parkinson's disease is characterized by massive degeneration of dopamine-containing neurons in the midbrain. However, the vulnerability of these neurons is heterogeneous both across different midbrain dopamine-containing cell groups and within the substantia nigra, the brain structure most affected in this disease. To determine the exact pattern of cell loss and to map the cellular distribution of candidate pathogenic molecules, it is necessary to have landmarks independent of the degenerative process by which to subdivide the substantia nigra. We have developed a protocol for this purpose based on immunostaining for calbindin D(28K), a protein present in striatonigral afferent fibres. We used it to examine post-mortem brain samples from seven subjects who had had no history of neurological or psychiatric disease. We found intense immunostaining for calbindin D(28K) associated with the neuropil of the ventral midbrain. Within the calbindin-positive region, there were conspicuous calbindin-poor zones. Analysed in serial sections, many of the calbindin-poor zones seen in individual sections were continuous with one another, forming elements of larger, branched three-dimensional structures. Sixty per cent of all dopamine-containing neurons in the substantia nigra pars compacta were located within the calbindin-rich zone, which we named the nigral matrix, and 40% were packed together within the calbindin-poor zones, which we named nigrosomes. We identified five different nigrosomes. This organization was consistent from one control brain to another. We propose that subdivision of the human substantia nigra based on patterns of calbindin immunostaining provides a key tool for analysing the organization of the substantia nigra and offers a new approach to analysing molecular expression patterns in the substantia nigra and the specific patterns of nigral cell degeneration in Parkinson's disease.

Aged↗
PubMed1999

The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease.

To achieve accuracy in studying the patterns of loss of midbrain dopamine-containing neurons in Parkinson's disease, we used compartmental patterns of calbindin D(28K) immunostaining to subdivide the substantia nigra with landmarks independent of the degenerative process. Within the substantia nigra pars compacta, we identified dopamine-containing neurons in the calbindin-rich regions ('matrix') and in five calbindin-poor pockets ('nigrosomes') defined by analysis of the three-dimensional networks formed by the calbindin-poor zones. These zones were recognizable in all of the brains, despite severe loss of dopamine-containing neurons. The degree of loss of dopamine-containing neurons in the substantia nigra pars compacta was related to the duration of the disease, and the cell loss followed a strict order. The degree of neuronal loss was significantly higher in the nigrosomes than in the matrix. Depletion was maximum (98%) in the main pocket (nigrosome 1), located in the caudal and mediolateral part of the substantia nigra pars compacta. Progressively less cell loss was detectable in more medial and more rostral nigrosomes, following the stereotyped order of nigrosome 1 > nigrosome 2 > nigrosome 4 > nigrosome 3 > nigrosome 5. A parallel, but lesser, caudorostral gradient of cell loss was observed for dopamine-containing neurons included in the matrix. This pattern of neuronal loss was consistent from one parkinsonian substantia nigra pars compacta to another. The spatiotemporal progression of neuronal loss related to disease duration can thus be drawn in the substantia nigra pars compacta for each Parkinson's disease patient: depletion begins in the main pocket (nigrosome 1) and then spreads to other nigrosomes and the matrix along rostral, medial and dorsal axes of progression.

Aged↗
PubMed1998

Neuronal distribution of intranuclear inclusions in Huntington's disease with adult onset.

Neuronal intranuclear inclusions were recently found in the brain of patients with inherited neurodegenerative disorders characterized by the expansion of a polyglutamine stretch in the mutated protein. These inclusions are ubiquitinated and, for some of these diseases, the presence of the mutated protein could be also identified. Using immunohistochemistry, we show here that ubiquitinated intranuclear inclusions are also observed postmortem in the brain of patients suffering from Huntington's disease characterized by small polyglutamine expansions and adult onset. We were, however, unable to detect the mutated form of huntingtin in these inclusions. These intranuclear inclusions were detected only in the affected cerebral regions, suggesting that their presence is probably linked to the neurodegenerative process.

Adult↗
PubMed1998

Glial cells and inflammation in Parkinson's disease: a role in neurodegeneration?

The data reviewed here show that, in Parkinson's disease (PD), some dopaminergic neurons are more vulnerable than others to the pathologic process. The glial cells surrounding dopaminergic neurons may be involved in this selective vulnerability. One subpopulation of glial cells, in particular, may play a neuroprotective role by metabolizing dopamine and scavenging oxygen free radicals that are associated with dopamine metabolism. Another subpopulation of glial cells may be deleterious to dopaminergic neurons. This effect may be mediated by the production of nitric oxide and cytokines, which may in turn account for the oxidative stress observed in the substantia nigra of patients with PD. Finally, this inflammatory reaction may result in the induction of apoptosis.

Dopamine↗
PubMed1998

[125I]EGF binding in basal ganglia of patients with Parkinson's disease and progressive supranuclear palsy and in MPTP-treated monkeys.

Since EGF is known to protect and stimulate the activity of dopaminergic neurons, an autoradiographic study of [125I]EGF binding sites was performed in the striatum and pallidal complex in parkinsonian syndromes. The analysis was performed on postmortem brain tissues of three control subjects, three patients with Parkinson's disease, and three patients with progressive supranuclear palsy, another parkinsonian syndrome in which dopaminergic neurons also degenerate. Since all six patients had been treated with L-Dopa, we also analyzed the effects of this drug in an animal model of Parkinson's disease. Quantitative analysis of [125I]EGF binding was performed on the brains of three control monkeys, nine monkeys rendered parkinsonian by MPTP intoxication, three of which were treated with L-Dopa. An increased density of [125I]EGF binding was observed at anterior levels in the dorsal striatum, but not in the pallidum, of patients with Parkinson's disease and progressive supranuclear palsy. [125I]EGF binding was unchanged in parkinsonian monkeys whether or not they had been treated with L-Dopa. The data suggest an increased expression of EGFRs in the striatum in chronic parkinsonian syndromes but not in acute models of the disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

trkB messenger RNA expression in normal human brain and in the substantia nigra of parkinsonian patients: an in situ hybridization study.

trkB is a high-affinity receptor for brain-derived neurotrophic factor, a neurotrophin acting on numerous cells, including dopaminergic neurons. Yet, little is known of its expression in the human brain. We report an in situ hybridization analysis of trkB messenger RNA, encoding the catalytic form of the receptor, in the human brain post mortem. Its expression was found to be widespread but heterogeneous among all the cerebral structures studied, the highest level being found in the cerebral cortex and the cerebellum. A strong but less intense staining was observed in the striatum, nucleus basalis of Meynert, hippocampus, tegmental pedonculopontinus nucleus and substantia nigra pars compacta. Combined immunohistochemistry for tyrosine hydroxylase and in situ hybridization for trkB messenger RNA showed that within the substantia nigra pars compacta a major proportion of dopaminergic neurons expressed trkB messenger RNA. Furthermore, we compared trkB messenger RNA expression in the mesencephalon of six control subjects and five patients with Parkinson's disease, a neurodegenerative disorder characterized by a severe loss of dopaminergic neurons. Despite the fact that the number of trkB messenger RNA-containing neurons was dramatically reduced in the substantia nigra pars compacta and ventral tegmental area of patients with Parkinson's disease, the level of trkB messenger RNA was unchanged in the remaining neurons in diseased brains. These results suggests that trkB is not involved in the process of neuronal death in Parkinson's disease. Furthermore, expression of brain-derived neurotrophic factor high-affinity receptor in patients could allow this neurotrophin to be used to prevent degeneration of surviving neurons at early stages of the disease.

Autoradiography↗
PubMed1998

Striatal expression of glutamic acid decarboxylase gene in Alzheimer's disease.

To examine potential alteration of GABAergic striatal neurons in Alzheimer's disease, we used quantitative in situ hybridization to analyze the messenger RNA coding for Mr 67,000 glutamic acid decarboxylase (GAD67 mRNA) in the striatum of five patients with Alzheimer's disease (AD) and nine matched control subjects. We found a 51-57% increase in the optical density of hybridization signal in the caudate nucleus and putamen, corresponding to a 30-42% increase in the number of neurons expressing a detectable amount of GAD67 mRNA. By contrast, no alteration was observed in the ventral striatum. The expression of GAD67 mRNA per neuron was similar in AD and control subjects both in the dorsal and ventral striatum. Taken together, our data indicate that, in AD, GABAergic neurotransmission is increased in the dorsal striatum but not in the ventral striatum. We suggest that this increased GABAergic neurotransmission may explain extrapyramidal signs often observed in AD.

Aged↗