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Biomedical subjects

F Javoy-Agid

Publications and source records attributed to F Javoy-Agid.

At least 91 records · Page 5Linked to original sources
PubMed1990

Does adrenal graft enhance recovery of dopaminergic neurons in Parkinson's disease?

A 54-year-old man with a 5-year history of Parkinson's disease was treated with and autograft of adrenal medulla into the right caudate nucleus and died 4 months after surgery. Postmortem examination revealed that the graft was necrotic. It consisted mainly of reticulin and collagen fibrosis without catecholaminergic cell bodies identified either by immunohistochemistry or by in situ hybridization with labeled human tyrosine hydroxylase (TH) cDNA probe. Sparse TH-immunoreactive fibers, which did not stain for dopamine-beta-hydroxylase (DBH), ran through the graft. In contrast, intense staining for these catecholaminergic markers was found in the untransplanted adrenal medulla. Densely packed TH-positive, DHB-negative fibers were found in a restricted zone of the host striatum at the periphery of the graft. This effect was selective since the density of other neurons was not modified. The present study describes an additional patient in whom adrenal medulla autotransplantation failed to improve the parkinsonian disability. It suggests, however, that adrenal medulla grafts may stimulate the sprouting of striatal dopaminergic fibers in a limited zone of the grafted striatum.

Adrenal Medulla↗
PubMed1990

Tyrosine hydroxylase gene expression in human ventral mesencephalon: detection of tyrosine hydroxylase messenger RNA in neurites.

The distribution of both tyrosine hydroxylase (TH) antigen and messenger RNA was investigated in the ventral mesencephalon from human brain using a 35S-labeled human TH cDNA probe and a polyclonal TH antibody. A hybridization signal was detected not only in the perikaryon but also in the neurites, most probably dendrites, of immunoreactive neurons. In cell bodies, the level of TH mRNA varies, revealing a regional heterogeneity. In the substantia nigra of patients with Parkinson's disease the number of labeled cells was markedly reduced as compared to controls.

Aged↗
PubMed1990

Glial fibrillary acidic protein and beta A4 protein deposits in temporal lobe of aging brain and senile dementia of the Alzheimer type: relation with the cognitive state and with quantitative studies of senile plaques and neurofibrillary tangles.

The aim of this study was to compare brain glial fibrillary acidic protein (GFAP) levels to the modifications of cognitive functions (Blessed test score [BTS]), the density of the main neuropathological lesions (senile plaques [SP] and neurofibrillary tangles [NFT]), and the density of the two main subtypes of beta A4 deposits (classic plaques and diffuse deposits) in a series of patients with normal aging and senile dementia of the Alzheimer type of various degrees of severity. GFAP levels (enzyme-linked immunosorbent assay [ELISA] technique) and the densities of changes were measured in the temporal lobe of 12 women over 75 years of age. Under these conditions, the ELISA assay could determine GFAP in brain homogenates (aqueous-Triton buffer soluble extract) in a range from 2.5 ng to 600 ng per assay. Least affected patients (with a BTS of 19 and over) all ranged below 60 micrograms/mg protein. Most affected patients (with a BTS under 6) ranged above 150 micrograms/mg protein. However, interindividual variations were wide. A significant correlation between the BTS and the amount of GFAP could be found only when using the non parametric test of Spearman. There was a significant positive correlation between the amount of GFAP and the density of 1) SP, 2) NFT both revealed by Bodian's silver stain, and 3) classic beta A4 plaques shown by immunocytochemistry. On the contrary, no correlation was observed with diffuse beta A4 deposits. One case with very large amounts of diffuse beta A4 deposits without SP or NFT showed no associated GFAP reactivity. This suggests that GFAP production is a critical event in the formation of classic SP.

Aged↗
PubMed1990

Decreased tyrosine hydroxylase messenger RNA in the surviving dopamine neurons of the substantia nigra in Parkinson's disease: an in situ hybridization study.

Parkinson's disease is associated with a massive loss in melanized dopaminergic neurons in the substantia nigra resulting in a severe striatal dopaminergic denervation. The hyperactivity which develops in the remaining striatal dopaminergic terminals may be related to an increased rate of tyrosine hydroxylation. This could be related to changes in the level of expression of the gene coding for tyrosine hydroxylase. Thus, the detection of tyrosine hydroxylase messenger RNA was looked for at cellular levels by in situ hybridization histochemistry. Image analysis shows that the hybridization signal was significantly reduced in the surviving neurons when compared to control. The subnormal tyrosine hydroxylase messenger RNA content may express a change in level of tyrosine hydroxylase gene transcription, possibly in relation to sustained suffering of the neurons still present at late stages of the disease.

Aged↗
PubMed1990

Microtopography of D1 dopaminergic binding sites in the human substantia nigra: an autoradiographic study.

The autoradiographic distribution of D1 dopaminergic binding sites was studied in the human ventral mesencephalon using the D1 antagonist [3H]SCH 23390. [3H]SCH 23390 binding was characterized by a single class of sites with a Kd of 2.5 nM and a Bmax of 31 fmol/mg of tissue. The density of [3H]SCH 23390 binding sites was high in the substantia nigra, moderate in the ventral tegmental area and low in the peri- and retrorubral field (catecholaminergic region A8). Binding densities were similar in pars compacta and pars reticulata of the substantia nigra, except for a peak value of high [3H]SCH 23390 in the pars reticulata, at a level just ventral to a zone of hyperdensity of melanized dopaminergic neurons in the pars compacta. The anatomical organization of the human ventral mesencephalon was analysed on adjacent sections stained for acetylcholinesterase histochemistry and tyrosine hydroxylase, substance P, dynorphin B, somatostatin and methionine-enkephalin immunohistochemistry, respectively. The similarity in distribution of [3H]SCH 23390 binding sites and substance P or dynorphin B immunoreactivity suggests that D1 binding sites are mainly located on the striatonigral projections. In accordance with these results: (1) the density of [3H]SCH 23390 binding sites was reduced in the substantia nigra of a patient with Huntington's chorea, a disease associated with a degeneration of striatonigral neurons; (2) the density of [3H]SCH 23390 binding sites was unaffected in the substantia nigra of a patient with Parkinson's disease, a disorder characterized by a marked loss in nigral tyrosine hydroxylase-positive neurons. [3H]SCH 23390 binding sites showed a characteristic, heterogeneous distribution within the human ventral mesencephalon, confirming data obtained in other species. The preferential localization of D1 dopamine receptors on striatonigral projections in human brain suggests that pharmacological manipulation of these receptors modulates the activity of striatonigral pathways, thereby affecting the various outputs of the nigral complex.

Acetylcholinesterase↗
PubMed1989

Localization of copper-zinc superoxide dismutase mRNA in human hippocampus by in situ hybridization.

The cellular localization of copper-zinc superoxide dismutase (CuZn SOD) mRNA was determined in the human hippocampus by in situ hybridization with a 35S-labelled DNA probe complementary to human CuZn SOD mRNA. A positive hybridization signal was detected in pyramidal cell layers CA1-CA4 of Ammon's horn (CA), pyramidal cells of subiculum and in the granule cells of the dentate gyrus. The fact that CuZn SOD gene expression is important in neurones which are preferentially vulnerable in neurodegenerative processes such as Alzheimer's disease, suggests a role played by oxygen free radicals in the mechanism of nerve cell death.

Aged↗
PubMed1989

Striatal dopamine deficiency in Parkinson's disease: role of aging.

The striatal dopaminergic innervation was investigated postmortem in 49 control and 57 parkinsonian brains by assessing the binding of tritiated alpha-dihydrotetrabenazine ([3H]TBZOH), a specific ligand of the vesicular monoamine transporter. The density of [3H]TBZOH binding sites in the caudate nucleus of control subjects decreased significantly with age, suggesting an age-dependent reduction in striatal dopamine innervation. In contrast, an increase with the age at time of death was observed in patients with Parkinson's disease, although the density of [3H]TBZOH binding sites was subnormal. Mean values represented 26.5% and 12.7% of control values in the caudate nucleus and in the putamen, respectively. The binding of [3H]TBZOH in the caudate nucleus decreased exponentially with the duration of Parkinson's disease. The rate of [3H]TBZOH binding decrease, an index of the rate of striatal dopaminergic denervation, was about twice as high in parkinsonian patients as in controls and was not related to the age at onset of the disease. The data suggest that (1) parkinsonian symptoms appear above a threshold degeneration state corresponding to 50% of the normal innervation at the age of 60, and (2) aging does not play a major role in the process of nigrostriatal neuron degeneration in Parkinson's disease.

Aged↗
PubMed1989

Comparison of [3H] phencyclidine ([3H] PCP) and [3H] N-[1-(2-thienyl) cyclohexyl] piperidine ([3H] TCP) binding properties to rat and human brain membranes.

The investigation of [3H] PCP and [3H] TCP binding properties to rat cerebrum and cerebellum resulted in the demonstration of multiple binding sites for the two drugs. In the two tissue preparations PCP had a lower affinity than TCP. In membranes from the cerebrum an equal number of high affinity binding sites were present for [3H] PCP and [3H] TCP. However, low affinity binding sites were two times more numerous for [3H] PCP than for [3H] TCP. In the cerebellum, the number of high and low affinity sites labeled by the two radioligands was identical, but the number of high affinity sites was about 7 fold lower than in the cerebrum. Taken together these results may indicate that in the cerebrum [3H] PCP labels other sites than NMDA/PCP receptor(s), maybe sigma receptors and/or the dopamine uptake complex. In human cerebral cortex samples [3H] TCP also bound to two different sites. The number of high and low affinity sites were 12 and 3 times, respectively, less abundant than in the rat cerebrum. Low affinity sites were of higher affinity (5 times) than corresponding sites in the rat brain. In the human cerebellum [3H] TCP binding parameters were identical to those measured in the same region in the rat.

Animals↗
PubMed1989

Distribution of monoaminergic, cholinergic, and GABAergic markers in the human cerebral cortex.

Mapping of a number of biochemical markers for noradrenergic, dopaminergic, serotoninergic, cholinergic and GABAergic systems was undertaken in 93 samples removed from the human cerebral cortex. The right hemisphere of brains from two subjects with no known history of neurological and psychiatric diseases was examined. Neurotransmitter markers were present in all cortical samples analysed, suggesting a widespread distribution of the corresponding neurons throughout the cerebral cortex. Each marker distributed heterogeneously in a distinct pattern. Noradrenaline concentrations were highest in the frontoparietal region and lowest in prefrontal and occipital areas. Markers for dopaminergic neurons (dopamine levels, dopamine/noradrenaline ratio and homovanillic acid levels) seemed denser in the prefrontal and temporal regions. 5-Hydroxyindolacetic acid levels were particularly high in the occipital area and decreased along the caudorostral axis. Choline acetyltransferase activity was highest in temporal and frontal lobes, at variance with muscarinic receptor distribution, which was highest in occipital cortex. Glutamate decarboxylase activity, an index of GABAergic innervation, did not vary markedly among the different areas of the cerebral cortex. The different biochemical markers investigated were detected in all cerebral cortical regions; their distribution was not homogeneous. A mismatch was observed between the distribution of cholinergic neuronal systems and receptors.

Aged↗
PubMed1989

Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease.

Polyunsaturated fatty acid (PUFA) levels (an index of the amount of substrate available for lipid peroxidation) were measured in several brain regions from patients who died with Parkinson's disease and age-matched control human postmortem brains. PUFA levels were reduced in parkinsonian substantia nigra compared to other brain regions and to control tissue. However, basal malondialdehyde (MDA; an intermediate in the lipid peroxidation process) levels were increased in parkinsonian nigra compared with other parkinsonian brain regions and control tissue. Expressing basal MDA levels in terms of PUFA content, the difference between parkinsonian and control substantia nigra was even more pronounced. Stimulating MDA production by incubating tissue with FeSO4 plus ascorbic acid, FeSO4 plus H2O2, or air alone produced lower MDA levels in the parkinsonian substantia nigra, probably reflecting the lower PUFA content. These results may indicate that an increased level of lipid peroxidation continues to occur in the parkinsonian nigra up to the time of death, perhaps because of continued exposure to excess free radicals derived from some endogenous or exogenous neurotoxic species.

Aged↗
PubMed1988

[3H]GBR 12935 binding to dopamine uptake sites: subcellular localization and reduction in Parkinson's disease and progressive supranuclear palsy.

[3H]GBR 12935 bound with high affinity to dopamine uptake sites in rat striatum where a close parallelism was observed between the subcellular localization profiles for [3H]dopamine uptake and [3H]GBR 12935 specific binding. Using the same ligand, we characterized the dopamine uptake sites in human striatum: the mean KD value was 3.2 nM and the specific binding was inhibited by several dopamine uptake blockers but with slightly lower affinities than those observed in the rat. The subcellular localization profile revealed a synaptosomal enrichment of the specific binding in human striatum. [3H]GBR 12935 binding was decreased in the putamen and caudate nucleus of subjects with Parkinson's disease (33 and 46% of control values, respectively) and progressive supranuclear palsy (38 and 57% of control values, respectively). It is very unlikely that the remaining binding sites in both diseases correspond to piperazine acceptor sites that are not involved in dopamine uptake. However, we cannot exclude the possibility that some of these remaining dopamine transporter sites are not functional, since the reduction in [3H]GBR 12935 specific binding was less marked than the decrease in the dopamine content of the same areas.

Animals↗
PubMed1988

Benzodiazepine receptors in normal human brain, in Parkinson's disease and in progressive supranuclear palsy.

Benzodiazepine receptors have been characterized in human brain. They have been localized mainly in the cerebral cortex and a synaptosomal enrichment was observed after brain fractionation by differential centrifugation. Benzodiazepine receptors were studied in Parkinson's disease and in progressive supranuclear palsy (PSP). In both diseases, the [3H]flunitrazepam specific binding was unchanged when compared to control groups (Bmax and KD values) except in the caudate nucleus of parkinsonian patients where an increase of the specific binding was observed. The subcellular distribution profile of benzodiazepine receptors in Parkinson's disease was similar to that of controls. gamma-Aminobutyric acid (GABA) still enhanced the [3H]flunitrazepam-specific binding (increase of binding affinity), indicating that the functional link between GABA and benzodiazepine receptors remained intact in Parkinson's disease. The present results suggest that benzodiazepine receptors in human striatum are localized on neuronal elements which do not degenerate in Parkinson's disease and PSP.

Aged↗
PubMed1988

Decrease of serotonin-S2 receptors in temporal cortex of patients with Parkinson's disease and progressive supranuclear palsy.

The number of serotonin-S2 receptors was decreased in the temporal cortex of patients with Parkinson's disease and progressive supranuclear palsy (PSP). There was no significant modification of these receptors in the frontal cortex or in the hippocampus and putamen in both diseases. The decrease in number of receptors in PSP was unexpected, because the cerebral cortex is thought to be spared in this disease. There was no correlation between the decrease in number of serotonin-S2 receptors and the degree of dementia in Parkinson's disease, suggesting that these receptors are not directly involved in the deterioration of cognitive functions.

Aged↗
PubMed1988

D1 and D2-type dopamine receptors in patients with Parkinson's disease and progressive supranuclear palsy.

The densities of D1- and D2-type dopamine receptors were measured with [3H]SCH23390 and [3H]spiperone, in the caudate nucleus and putamen of a large series of patients with Parkinson's disease or progressive supranuclear palsy, in relation to markers of dopaminergic and cholinergic innervation of the striatum ([3H]dihydrotetrabenazine binding and choline acetyltransferase activity). Correlations were sought between these parameters and clinical characteristics of the patients (abnormal involuntary movements, dementia, confusional syndrome or treatment). In Parkinson's disease, the densities of both types of receptors were unchanged, whereas in PSP, the density of D2, but not D1-type dopamine receptors, was decreased in the caudate nucleus and the putamen. No correlations between the biochemical and clinical data were found.

Adenylyl Cyclases↗