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Y Agid

Publications and source records attributed to Y Agid.

At least 55 records · Page 3Linked to original sources
PubMed2001

Caspase-8 is an effector in apoptotic death of dopaminergic neurons in Parkinson's disease, but pathway inhibition results in neuronal necrosis.

Caspase-8 is a proximal effector protein of the tumor necrosis factor receptor family death pathway. In the present human postmortem study, we observed a significantly higher percentage of dopaminergic (DA) substantia nigra pars compacta neurons that displayed caspase-8 activation in Parkinson's disease (PD) patients compared with controls. In an in vivo experimental PD model, namely subchronically 1,2,3,6-tetrahydropyridine-treated mice, we also show that caspase-8 is indeed activated after exposure to this toxin early in the course of cell demise, suggesting that caspase-8 activation precedes and is not the consequence of cell death. However, cotreatment of 1-methyl-4-phenylpyridinium-intoxicated primary DA cultures with broad-spectrum and specific caspase-8 inhibitors did not result in neuroprotection but seemed to trigger a switch from apoptosis to necrosis. We propose that this effect is related to ATP depletion and suggest that the use of caspase inhibitors in pathologies linked to intracellular energy depletion, such as PD, should be cautiously evaluated.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from Founder effects.

A wide variety of mutations in the parkin gene, including exon deletions and duplications, as well as point mutations, result in autosomal recessive early-onset parkinsonism. Interestingly, several of these anomalies were found repeatedly in unrelated patients and may therefore result from recurrent, de novo mutational events or from founder effects. In the present study, haplotype analysis, using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, was performed in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations in the parkin gene, and each mutation was detected in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder.

Age of Onset↗
PubMed2001

The relationship between differentiation and survival in PC12 cells treated with cyclic adenosine monophosphate in the presence of epidermal growth factor or nerve growth factor.

We have asked whether treatment of PC12 cells with cyclic adenosine monophosphate (cAMP) and epidermal growth factor (EGF) results, like treatment with cAMP and nerve growth factor (NGF), in irreversible neuronal differentiation characterized by irreversible neurite extension, loss of serum-dependence, and death by apoptosis after trophic factor withdrawal. Although EGF alone, unlike NGF, did not cause morphological differentiation or prevent cell death, synergy between a cAMP-mediated signal transduction pathway and a pathway activated by the EGF receptor tyrosine kinase resulted in the same irreversible differentiation. EGF/cAMP-differentiated cells required cAMP to survive, but NGF, through a TrkA-dependent mechanism, could substitute for cAMP. The cyclin-dependent kinase inhibitors olomoucine and roscovitine also promoted survival of the irreversibly differentiated cells, by a mechanism that must be determined, since cell death was not associated with nuclear (3)H-thymidine accumulation, an index of mitotic activity.

Animals↗
PubMed2001

14-3-3 protein cerebrospinal fluid detection in human growth hormone-treated Creutzfeldt-Jakob disease patients.

The usefulness of the detection of 14-3-3 protein in the cerebrospinal fluid (CSF) in the diagnosis of Creutzfeldt-Jakob disease transmitted from human growth hormone was evaluated in 20 French patients. The 14-3-3 protein was rarely detectable within the first 3 months of the disease but always positive after 7 months associated with the aggravation of the disease and the occurrence of dementia. 14-3-3 detection was not predictive of the survival time of the patients. The genotype at PRNP codon 129 could influence the timing of appearance of the 14-3-3 protein in the CSF.

14-3-3 Proteins↗
PubMed2001

Caspase-3 activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice.

In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models of Parkinson's disease (PD), dopaminergic (DA) neurons have been shown to die by apoptosis. Moreover, recent postmortem and in vitro results have indicated that apoptotic cell death induced by 1-methyl-4-phenylpyridinium (MPP(+)) may be mediated by caspase-3. To establish whether caspase-3 activation may indeed play a role in an in vivo model of PD, we studied caspase-3 activation in C57Bl/6 mice subchronically intoxicated with MPTP. We show that caspase-3 activation peaks early, at days 1 and 2 after the end of MPTP intoxication. In contrast, pycnotic neurons persist until day 7 postintoxication, indicating that caspase-3 activation is an early and transient phenomenon in apoptotic death of DA neurons. We further demonstrate that loss of tyrosine hydroxylase (TH) immunoreactivity in this model is indeed due to cell loss rather than to loss of TH protein expression. We conclude that mice subchronically intoxicated with MPTP represent a valid PD model to study and manipulate caspase activation in vivo.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Plasticity of afferent fibers to striatal neurons bearing D1 dopamine receptors in Parkinson's disease.

The loss of dopaminergic neurons in the substantia nigra provokes a plasticity of corticostriatal synapses in Parkinson's disease (PD). The corticostriatal pathway nevertheless makes synapses with neurons bearing D1 dopamine receptors (D1R) and/or D2 dopamine receptors. At the ultrastructural level, we analyzed the morphological characteristics of synapses formed by afferent fibers making asymmetric contacts with the dendritic spines of neurons identified by D1R immunoreactivity, in the striatum of control subjects and PD patients. A quantitative analysis of the morphological characteristics of the synapses and of the number of perforated synapses (considered to be very active) was performed. In PD, a 50% increase in the number of perforated synapses making contact with D1R dendritic spines was observed, whereas no change in the number of perforated synapses on non-D1R spines was observed. The change in the number of perforated synapses on D1R dendrites was associated with a slight but nonsignificant increase in the surface area of the corticostriatal afferent fibers and the surface of the mitochondria in these fibers (+29.0% and +34.6%, respectively). This suggests a hyperactivity of corticostriatal fibers in contact with D1R-bearing neurons of the direct pathway in the basal ganglia circuitry. Since stimulation of the direct pathway is thought to alleviate the clinical symptoms of PD, this suggests that the differences observed may be involved in compensatory mechanisms.

Aged↗
PubMed2001

Idazoxan, an alpha-2 antagonist, and L-DOPA-induced dyskinesias in patients with Parkinson's disease.

Dyskinesia is a frequent and disabling side effect in patients with Parkinson's disease treated with chronic dopa-therapy. Preclinical data in the 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) monkey suggest that alpha-2 antagonists may reduce dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. We assessed, in a pilot randomised placebo-controlled study, the effects of single oral doses (10 mg, 20 mg, and 40 mg) of idazoxan, an alpha-2 antagonist, on motor parkinsonian disability and L-DOPA-induced dyskinesia following an acute oral challenge of L-DOPA in 18 patients with Parkinson's disease. The severity of L-DOPA-induced dyskinesia improved after 20 mg idazoxan pretreatment, while there was no concommittant deterioration in the antiparkinsonian response to L-DOPA. These results suggest that blocking alpha-2 receptors in patients with Parkinson's disease might improve L-DOPA-induced dyskinesia without the cost of a return of parkinsonian symptomatology. Further studies are required to assess whether this property could have potential therapeutic applications in the long-term management of dyskinetic patients with Parkinson's disease.

Administration, Oral↗
PubMed2001

LY293558, an AMPA glutamate receptor antagonist, prevents and reverses levodopa-induced motor alterations in Parkinsonian rats.

To evaluate the possible involvement of glutamate AMPA receptor-mediated mechanisms in levodopa-induced motor fluctuations, we investigated the effects of LY293558, a competitive AMPA receptor antagonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of LY293558 was studied to evaluate the possible reversion or prevention of these levodopa effects. In the first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, i.p.) for 22 days and on day 23 LY293558 (5 mg/kg, i.p.) was administered immediately before levodopa. In the second set of experiments, rats were treated daily for 22 days with levodopa and LY293558 (5 mg/kg, twice daily, i.p.). In the third set of experiments, the effect of LY293558 (5 mg/kg, i.p.) administration on selective dopamine D-1 (SKF38393, 1.5 mg/kg, s.c.) and D-2 agonist (quinpirole, 0.1 mg/kg, i.p.)-induced rotational behavior after daily levodopa treatment was studied. The duration of the rotational behavior induced by chronic levodopa decreased by 30% after 22 days. Acute administration of LY293558 on day 23 reversed this effect. The group of animals that were chronically treated with levodopa and LY293558 did not show the decrease in this motor response duration. Chronic levodopa treatment attenuated the rotational response to the D-1 agonist SKF38393 and increased the response to the D-2 agonist quinpirole. LY293558 did not reverse the effect of levodopa on rotational behavior induced by the D-1 agonist but significantly reduced the rotational response to the D-2 agonist in levodopa-treated animals by 40%. Our results demonstrate that an AMPA receptor antagonist reverses and prevents levodopa-induced motor alterations in parkinsonian rats and that this effect on motor fluctuations induced by chronic levodopa is probably due to a modulation of the indirect output pathway of the basal ganglia.

Adrenergic Agents↗
PubMed2001

The parkin gene and its phenotype. Italian PD Genetics Study Group, French PD Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease.

Mutations of the parkin gene on chromosome 6 cause autosomal recessive, early onset parkinsonism. This is the most frequent form of monogenic parkinsonism so far identified. The associated phenotypical spectrum encompasses early onset, levodopa-responsive parkinsonism (average onset in the early 30s in Europe), and it overlaps with dopa-responsive dystonia in cases with the earliest onset, and with clinically typical Parkinson's disease in cases with later onset. Despite clinical features, Lewy bodies are not found at autopsy in brains of patients with parkin mutations. The parkin protein possesses ubiquitin ligase activity, which is abolished by the pathogenic mutations.

Age of Onset↗
PubMed2001

Use of haplotype information to test involvement of the LRP gene in Alzheimer's disease in the French population.

The low density lipoprotein receptor-related protein gene (LRP) is a good candidate gene for Alzheimer's Disease (AD). Its protein is involved in the physiopathology of AD and has been found in senile plaques; on the other hand, LRP is located in 12q, a region in which genetic linkage to AD was reported. Two common polymorphisms, a tetranucleotide repeat in the 5' untranslated region and a single nucleotide polymorphism at position 766 in exon 3, were found to be associated with AD, but contradictory results were obtained in subsequent association studies. In the absence of clear hypotheses concerning the association of these polymorphisms with AD and their functional role, our objective was to test the association between AD and the two LRP polymorphisms in a large French case-control sample (274 Caucasian AD patients and 290 matched controls) using haplotype analysis. First, the separate study of each polymorphism showed no significant difference in genotype and allele frequencies between AD cases and controls. Second, strong linkage disequilibrium was found between alleles of the two polymorphisms in controls and in cases and the linkage disequilibrium between the 91 bp and C alleles were opposite in cases and in controls. Third, we found that the frequency of the 91-C haplotype was higher in cases than in controls, but the type I error was 0.061, slightly higher than the conventional one of 5%. The haplotype frequencies did not vary significantly as a function of age and APOE epsilon4 status. One interest in this study is the use of the haplotype analysis, which can be used to combine information from several polymorphisms, taking into account their dependence.

Adult↗
PubMed2001

Is Bax a mitochondrial mediator in apoptotic death of dopaminergic neurons in Parkinson's disease?

Bax is a proapoptotic member of the Bcl-2 family of proteins. It is believed to exert its action primarily by facilitating the release of cytochrome c from the mitochondrial intermembrane space into the cytosol, leading to caspase activation and cell death. Because alterations in mitochondrial respiratory function, caspase activation and cell death with morphologic features compatible with apoptosis have been observed post mortem in the brain of patients with Parkinson's disease, we tried to clarify the potential role of Bax in this process in an immunohistochemical study on normal and Parkinson's disease post-mortem brain and primary mesencephalic cell cultures treated with MPP(+). We found that Bax is expressed ubiquitously by dopaminergic (DA) neurons in post-mortem brain of normal and Parkinson's disease subjects as well as in vitro. Using an antibody to Bax inserted into the outer mitochondrial membrane as an index of Bax activation, no significant differences were observed between control and Parkinson's disease subjects, regardless of the mesencephalic subregion analysed. However, in Parkinson's disease subjects, the percentage of Bax-positive melanized SNpc neurons containing Lewy bodies, suggestive of DA neuronal suffering, was significantly higher than the overall percentage of Bax-positive neurons among melanized neurons. Furthermore, all melanized SNpc neurons in Parkinson's disease subjects with activated caspase-3 were also immunoreactive for Bax, suggesting that Bax anchored in the outer mitochondrial membrane of melanized SNpc neurons showing signs of neuronal suffering or apoptosis is increased compared with DA neurons that are apparently unaltered. Surprisingly, MPP(+) treatment of tyrosine hydroxylase (TH)-positive neurons in primary mesencephalic cultures did not cause redistribution of Bax, although cytochrome c was released from the mitochondria and nuclear condensation/fragmentation was induced. Taken together, these findings suggest that in the human pathology, Bax may be a cofactor in caspase activation, but our in vitro data fail to indicate a central role for Bax in apoptotic death of DA neurons in an experimental Parkinson's disease paradigm.

1-Methyl-4-phenylpyridinium↗
PubMed2000

Improvement of sleep architecture in PD with subthalamic nucleus stimulation.

High-frequency stimulation of the subthalamic nucleus (STN) was used to investigate the relationship of sleep disorders with motor handicap in PD. In 10 insomniac patients with PD, stimulation reduced nighttime akinesia by 60% and completely suppressed axial and early morning dystonia, but did not alleviate periodic leg movements (n = 3) or REM sleep behavior disorders (n = 5). Total sleep time increased by 47%; wakefulness after sleep onset decreased by 51 minutes. Insomnia in patients with PD may predominantly result from nighttime motor disability.

Adult↗
PubMed2000

Mitochondrial free calcium levels (Rhod-2 fluorescence) and ultrastructural alterations in neuronally differentiated PC12 cells during ceramide-dependent cell death.

Mitochondrial free calcium levels measured by Rhod-2 fluorescence and ultrastructure were examined during cell death in nerve growth factor (NGF)-differentiated PC12 cells that were 1) exposed to C2-ceramide, 2) deprived of serum to induce endogenous ceramide production, or 3) treated with calcium ionophore A23187. Rhod-2 fluorescence in mitochondria and also in the nucleolus increased to a maximum within 3 hours after C2-ceramide treatment or serum withdrawal. In A23187-treated cells, Rhod-2 fluorescence remained at baseline levels. In all three models, enlargement of the endoplasmic reticulum was the first ultrastructural alteration, followed by mitochondrial shrinkage in ionophore-treated cells, but by mitochondrial swelling in the ceramide-dependent models, in which rupture of the outer mitochondrial membrane and unfolding of the inner membrane were frequently seen. Dihydro-C2-ceramide, which did not cause cell death, had no effect on cellular ultrastructure. NGF, which inhibits ceramide-dependent cell death, prevented the effects of serum deprivation on mitochondrial ultrastructure but not on endoplasmic reticulum morphology or Rhod-2 fluorescence. Nuclear shrinkage with loss of nuclear membrane integrity, characterized by nuclear pores, free or surrounded by electron-dense filaments, was a late event in ceramide-dependent cell death. Chromatin condensation and other morphological features associated with apoptosis were seen in only a few atypical cells. Ceramide-mediated cell death, therefore, did not involve classical apoptosis but was mediated by a reproducible series of events beginning in the endoplasmic reticulum, followed by the mitochondria, and then the nucleus. NGF-dependent cell death inhibition intervenes at the mitochondrial level, not by blocking the increase in Rhod-2 fluorescence but by preventing the ultrastructural changes that follow.

Animals↗
PubMed2000

Ipsilateral and contralateral subthalamic activity after unilateral dopaminergic lesion.

Unilateral lesions of the dopaminergic nigral neurons in rats are currently used as a model of Parkinson's disease. However, several neurochemical studies have questioned the possible influence of the lesioned side on the contralateral non-lesioned side. To address this question, electrophysiological recordings in the ipsilateral and contralateral subthalamic nucleus was performed on anaesthetized rats, 3, 7 and 14 days after induction of a unilateral dopaminergic lesion. At these three times, the mean discharge rate of the subthalamic neurons recorded ipsilateral to the lesion was increased by 85, 176 and 127%, respectively, whereas this rate was decreased by 16, 27 and 43%, respectively, in the opposite subthalamic nucleus. This result emphasizes the importance of interhemispheric regulation of this structure, contrasting with the unilateralized current model of the functional organization of the basal ganglia.

Action Potentials↗
PubMed2000

Failure of long-term pallidal stimulation corrected by subthalamic stimulation in PD.

Bilateral high-frequency continuous stimulation of the internal globus pallidus or subthalamic nucleus constitutes a new therapeutic approach for the treatment of patients with severe PD. The authors report two patients in whom stimulation of the globus pallidus failed to give long-term relief and was successfully replaced by bilateral subthalamic stimulation. The results emphasize the reversibility of deep brain stimulation therapy and suggest that the subthalamic target is preferable to the pallidal target.

Electric Stimulation↗