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Biomedical subjects

Y Agid

Publications and source records attributed to Y Agid.

At least 19 recordsLinked to original sources
PubMed1992

The glutamate antagonist, MK-801, does not prevent dopaminergic cell death induced by the 1-methyl-4-phenylpyridinium ion (MPP+) in rat dissociated mesencephalic cultures.

The neuroprotective effects of MK-801, a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor/channel, were assessed in a culture model which reproduces in vitro the selective degeneration of mesencephalic dopaminergic neurons seen in parkinsonian brains. Dissociated mesencephalic cells derived from rat embryonic brains were subjected for 24 h to intoxication by the 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPP+ at 3 and 10 microM produced selective and dose-dependent damages to dopaminergic neurons as quantified by the loss of the number of TH immunoreactive cells and the loss of [3H]DA uptake whereas other cell types remained unaffected. MK-801 at 3 and 10 microM failed to rescue degenerating dopaminergic neurons in presence of MPP+. At 50 microM, i.e. the highest concentration that is not toxic by itself in this culture system, MK-801 was also found ineffective. Furthermore, degree of dopaminergic cell damage was not reduced when repeated additions of the glutamate antagonist (10 microM/6 h for 24 h) were performed during exposure to MPP+ or when mesencephalic cultures were left after intoxication for up to 2 days in a culture medium still supplemented with MK-801 but free of toxin. In accordance with these results, MK-801 did not affect significantly the uptake of [3H]DA in control cultures, thereby suggesting that this compound cannot prevent intracellular accumulation of MPP+ within dopaminergic neurons. At higher concentrations of MPP+ (100 microM) tested, toxic effects were seen toward dopaminergic neurons and non-dopaminergic cells as quantified by Trypan blue dye accumulation and loss of [3H]GABA uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenylpyridinium↗
PubMed1992

Decreased choline acetyltransferase mRNA expression in the nucleus basalis of Meynert in Alzheimer disease: an in situ hybridization study.

The subnormal choline acetyltransferase (ChoAcTase) activity in the cerebral cortex of patients with Alzheimer disease (AD) is thought to originate from the loss of cholinergic neurons in the nucleus basalis of Meynert (nbM). To examine possible changes in the functional activity of the remaining cholinergic neurons in the nbM of patients with AD, the level of expression of ChoAcTase mRNA was evaluated. A procedure for double-labeling cholinergic neurons to detect ChoAcTase mRNA and the corresponding protein in the same cell was developed, taking advantage of an anti-ChoAcTase antibody and the recently isolated cDNA complementary to a sequence of the human ChoAcTase mRNA. In the study of three controls and four patients with AD, the presence of both ChoAcTase mRNA and protein was observed in the same large neurons in both nbM and putamen. Specificity of in situ hybridization was further supported by the absence of neuronal staining with a sense probe. In AD patients a subnormal level of expression of ChoAcTase mRNA per cholinergic cell was detected in the nbM but not in the putamen. Our data support the hypothesis that expression of ChoAcTase mRNA might be down-regulated in the surviving cholinergic neurons in the nbM of patients with AD, raising the possibility of functional restoration by stimulating ChoAcTase synthesis.

Alzheimer Disease↗
PubMed1992

Effects of a selective partial D1 agonist, CY 208-243, in de novo patients with Parkinson disease.

A selective dopamine D1-receptor agonist, CY 208-243, was administered to 23 de novo patients who had had Parkinson disease (PD) for less than or equal to 3 months. The drug was first used as monotherapy and then in some patients in combination with a dopamine D2-receptor agonist, bromocriptine. Results showed that CY 208-243 exerted a mild antiparkinsonian action, and tremor was the main symptom that consistently improved. The addition of bromocriptine less than or equal to 15 mg to CY 208-243 did not result in additional improvement, but this might be due to the short duration of treatment and the low doses of bromocriptine. The study was prematurely discontinued for safety reasons. We conclude that D1-receptor stimulation may result in improvement of motor disability in PD.

Adult↗
PubMed1992

Corticobasal degeneration: decreased and asymmetrical glucose consumption as studied with PET.

Cerebral energy metabolism was studied by positron emission tomography and [18F]fluorodeoxyglucose in five patients with clinical diagnoses of probable corticobasal degeneration. A reduction in glucose consumption was observed in most cortical and subcortical structures compared to age-matched controls. The reduction was greatest on the side of the brain contralateral to the most affected limbs, as shown by the significantly lower ratios of contralateral to homolateral metabolic rates, in the temporal and sensorimotor cortex of patients compared to controls. A distinct asymmetry between the two hemispheres could be observed in a patient who was examined twice in the course of his illness. Detection of this asymmetrical decrease in brain cortical and subcortical glucose metabolism may prove useful as additional evidence supporting clinical diagnoses of the disease.

Aged↗
PubMed1992

Brain muscarinic cholinergic receptors in Huntington's disease.

Muscarinic cholinergic receptors and choline acetyltransferase (ChAT) activity were studied in postmortem brain tissue from patients with Huntington's disease and matched control subjects. In comparison with controls, reductions in ChAT activity were found in the hippocampus, but not in the temporal cortex in Huntington's disease. Patients with Huntington's disease showed reduced densities of the total number of muscarinic receptors and of M-2 receptors in the hippocampus while the density of M-1 receptors was unaltered. Muscarinic receptor binding was unchanged in the temporal cortex. These results indicate a degeneration in Huntington's disease of the septo-hippocampal cholinergic pathway, but no impairment of the innominato-cortical cholinergic system.

Brain Chemistry↗
PubMed1992

Alzheimer's disease: is the decrease of the cholinergic innervation of the hippocampus related to intrinsic hippocampal pathology?

Consistent findings in the hippocampi of patients with Alzheimer's disease are the presence of neurofibrillary tangles in pyramidal neurons and the loss of choline acetyltransferase activity due to degeneration of hippocampal cholinergic terminals. The present study sought to clarify, in the brains of five patients with Alzheimer's disease and four controls, whether the loss of cholinergic terminals in the hippocampal stratum pyramidale in Alzheimer's disease is related to degenerative changes in hippocampal pyramidal cells. A polyclonal antibody to human choline acetyltransferase was employed to visualize immunohistochemically cholinergic terminals. Hippocampal neurons were stained with Cresyl Violet, neurofibrillary tangles with thioflavin S and a monoclonal antibody against phosphorylated neurofilament (RT97). Quantification of the stained structures was performed in CA4, CA1 and the subiculum, on five sections selected from the entire anteroposterior extent of each hippocampus. In the group of Alzheimer patients, the densities of cholinergic terminals were homogeneously diminished in the three hippocampal subregions in comparison with the controls (32-33%). In contrast, a significant loss of pyramidal neurons was found only in CA1, and the density of neurofibrillary tangles was markedly increased only in CA1 and the subiculum in Alzheimer's disease. These findings suggest that there is no relationship between the loss of cholinergic terminals and the degeneration of pyramidal cells in the hippocampus of patients with Alzheimer's disease.

Aged↗
PubMed1992

Cardiomyopathy in Friedreich's ataxia: a Doppler-echocardiographic study.

Heart involvement is frequent in Friedreich's ataxia (FA), the most prevalent of the spino-cerebellar degenerative diseases, which is inherited with an autosomal recessive pattern. However, the pathophysiological link between cardiac and neurological disorders is not yet clearly established. We compared a group of 10 patients with FA to a control group (C) of 16 normal subjects, using Doppler-echocardiography. To see whether cardiac involvement was specific to FA, the data of patients with FA were also compared to those of patients with autosomal dominant olivo-ponto-cerebellar atrophia (OPCA), another spino-cerebellar degenerative disease. There was an increase in left ventricular mass index in FA (154 +/- 9 g.m-2 vs 99 +/- 7 g. m-2 in C, P < 0.001), systolic function was normal, the ejection fraction (EF) slope and E/A ratio were decreased (85 +/- 9 mm.s-1 vs 130 +/- 7 mm.s-1 in C, P < 0.001 and 1.5 +/- 0.1 vs 1.7 +/- 0.1 in C, P < 0.01, respectively), while the isovolumic relaxation period was increased (96 +/- 3 ms vs 92 +/- 2 ms in C, P < 0.01). Deceleration time and time-velocity integrals of A wave to total mitral flow were not modified. In OPCA only the E/A ratio was decreased (1.5 +/- 0.1 vs 1.7 +/- 0.1 in C, P < 0.05). These data show the presence of cardiomyopathy in FA with left ventricular hypertrophy and suggest the presence of diastolic function abnormalities. The cardiomyopathy seems specifically associated with FA and not to spino-cerebellar degenerative disease in general.

Adolescent↗
PubMed1992

Is the vulnerability of neurons in the substantia nigra of patients with Parkinson's disease related to their neuromelanin content?

The contribution of neuromelanin (NM) to the pathogenesis of Parkinson's disease (PD) has long been suspected. In particular, a correlation has been reported between the estimated cell loss in the mesencephalic dopaminergic cell groups and the percentage of NM-pigmented neurons in these cell groups. To test whether the amount of pigment per cell is a critical factor or whether the presence of NM within a neuron is sufficient to account for the degeneration of dopaminergic neurons, the NM content was measured in each neuron from representative sections throughout the ventral mesencephalon of four controls subjects and four patients with PD. Intraneuronal NM was quantified by a densitometric method, using known amounts of synthetic melanin as standards. In control brains, the distribution of melanized neurons in the nigral complex showed a high proportion of lightly melanized neurons in the ventral tegmental area and the pars alpha and gamma of the substantia nigra (SN), whereas heavily melanized neurons were mostly located in the pars beta and lateralis of the SN. An inverse relationship was observed between the percentage of surviving neurons in PD compared with controls and the amount of NM they contain, suggesting that the vulnerability of the dopaminergic neurons is related to their NM content. Factors other than NM may be involved in the differential vulnerability of catecholaminergic neurons in PD. In particular, the constant topography of the cell loss suggests that cell position within the nigral complex is a key factor.

Aged↗
PubMed1992

Toxic effects of iron for cultured mesencephalic dopaminergic neurons derived from rat embryonic brains.

Iron, a transition metal possibly involved in the pathogenesis of Parkinson's disease, was tested for its toxic effects toward cultures of dissociated rat mesencephalic cells. When cultures were switched for 24 h to serum-free conditions, the effective concentrations of ferrous iron (Fe2+) producing a loss of 50% of dopaminergic neurons, as quantified by tyrosine hydroxylase (TH) immunocytochemistry, TH mRNA in situ hybridization, and measurement of TH activity, were on the order of 200 microM. High-affinity dopamine (DA) uptake, which reflects integrity and function of dopaminergic nerve terminals, was impaired at significantly lower concentrations (EC50 = 67 microM). Toxic effects were not restricted to dopaminergic neurons inasmuch as trypan blue dye exclusion index and gamma-aminobutyric acid uptake, two parameters used to assess survival of other types of cells present in these cultures, were also affected. Protection against iron cytotoxicity was afforded by desferrioxamine and apotransferrin, two ferric iron-chelating agents. Normal supplementation of the culture medium by serum proteins during treatment was also effective, presumably via nonspecific sequestration. Potential interactions with DA were also investigated. Fe2+ at subtoxic concentrations and desferrioxamine in the absence of exogenous iron added to the cultures failed to potentiate or reduce DA cytotoxicity for mesencephalic cells, respectively. Transferrin, the glycoprotein responsible for intracellular delivery of iron, was ineffective in initiating selective cytotoxic effects toward dopaminergic neurons preloaded with DA. Altogether, these results suggest (a) that ferrous iron is a potent neurotoxin for dopaminergic neurons as well as for other cell types in dissociated mesencephalic cultures, acting likely via autoxidation into its ferric form, and (b) that the presence of intra- and extracellular DA is not required for the observed toxic effects.

Animals↗
PubMed1992

Duplication within chromosome 17p11.2 in 12 families of French ancestry with Charcot-Marie-Tooth disease type 1a. The French CMT Research Group.

Hereditary motor and sensory neuropathy type I (HMSN I), also designated Charcot-Marie-Tooth disease type 1 (CMT1), is a peripheral neuropathy frequently inherited as an autosomal dominant trait, characterised by progressive distal muscular atrophy and sensory loss with markedly decreased nerve conduction velocity. A duplication within chromosome 17p11.2, cosegregating with the disease, has recently been reported in several CMT1a families. In order to estimate the frequency of this anomaly and determine the location of a duplication in this region, 12 CMT1 families were analysed with polymorphic DNA markers located within 17p11.2-12. Duplications were found in all families including loci D17S61 (EW401), D17S122 (VAW409R3a and RM11-GT), and D17S125 (VAW412R3). The duplications were completely linked and associated with the disease (lod score of 20.77 at zero recombination). Screening for the RM11-GT microsatellite showed that most of the duplicated haplotypes were heterozygous, supporting the hypothesis that the duplication resulted from an unequal crossing over. There was no significant haplotype association within the duplicated region suggesting that the duplication resulted de novo as an independent event in each family. In one family, recombination within the duplicated region was observed, indicating that genetic instability in 17p11.2 might be related to a high recombination rate. Since most cases of CMT1a seem to result from this segmental trisomy, it can be used as a basis for DNA diagnosis of the disease.

Base Sequence↗
PubMed1992

In-vivo SPECT imaging of D2 receptor with iodine-iodolisuride: results in supranuclear palsy.

We assessed the potential use of [123I]iodolisuride (ILIS), a new iodine ergolene derivative, to study human striatal D2 dopamine receptors with SPECT. In normal subjects, we found that the tracer accumulated preferentially in striatum. This was prevented by high doses of haloperidol. The striatal accumulation was maximal between 60 and 180 min after injection. The striatum-to-cerebellum radioactivity concentration ratio as an index of specific binding, measured 60 min after injection, was 1.52 +/- 0.19 (mean +/- s.d.) in controls and 1.36 +/- 0.11 in patients with supranuclear palsy (p less than 0.03). Our results show that ILIS may be used to study D2 receptors with SPECT. In-vivo changes of D2 receptors in human brain may be detected with this method.

Adult↗
PubMed1992

Does loss of nerve growth factor receptors precede loss of cholinergic neurons in Alzheimer's disease? An autoradiographic study in the human striatum and basal forebrain.

The mechanism by which cholinergic neurons degenerate in Alzheimer's disease is not known. Some of these neurons depend, however, on trophic support from NGF via a membrane receptor. We have analyzed the state of these receptors by autoradiography, with 125I-NGF as the ligand, in the caudate nucleus, putamen, ventral striatum, nucleus basalis of Meynert, and nucleus tegmenti pedunculopontinus of six patients with Alzheimer's disease and five controls, matched for age and postmortem delay. The binding characteristics were similar in the striatum (including caudate nucleus, putamen, and ventral striatum) and basal forebrain of control subjects and patients with Alzheimer's disease (Kd = 2.5-4 x 10(-11) M). In control brains, high levels of 125I-NGF binding were observed in the basal forebrain and striatum (0.32-0.49 fmol/mg tissue equivalent), but no specific binding was detected in the nucleus tegmenti pedunculopontinus. NGF binding sites were distributed heterogeneously in the striatum with patches of low density, corresponding to AChE-poor striosomes, surrounded by a matrix in which receptor density was significantly greater. In Alzheimer's disease, the density of NGF receptors was markedly decreased in the caudate nucleus, putamen, ventral striatum, and nucleus basalis of Meynert. In contrast, AChE staining decreased less in the nucleus basalis of Meynert in all Alzheimer's disease patients, and in the ventral striatum of those most severely affected. These results indicate that if NGF receptors are located on cholinergic neurons, receptor loss and the consequent decrease in trophic support may precede cell degeneration in Alzheimer's disease. The relationship between the loss of these receptors and the pathogenesis of the disease remains to be determined.

Acetylcholinesterase↗
PubMed1991

[3H]MK-801 binding to NMDA glutamatergic receptors in Parkinson's disease and progressive supranuclear palsy.

The interactions existing between glutamatergic and dopaminergic systems, notably in the basal ganglia, suggest that glutamatergic antagonists may have therapeutic interest in extrapyramidal disorders characterized by impaired dopaminergic transmission. The binding of [3H]dizocilpine maleate (MK-801) to glutamate receptors of the N-methyl-D-aspartate (NMDA)-subtype was characterized in temporal and frontal cortex, in hippocampus and in subcortical areas (caudate nucleus and putamen) from controls and patients with Parkinson's disease or progressive supranuclear palsy. The binding affinity (KD) and the maximal specific binding capacity (Bmax) of [3H]MK-801 were unchanged in all the cerebral regions studied in both diseases. This indicates the existence of preserved NMDA glutamate receptors, which is required for potential therapeutic efficacy of specific antagonists.

Aged↗