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Biomedical subjects

B A Faucheux

Publications and source records attributed to B A Faucheux.

At least 19 recordsLinked to original sources
PubMed2004

Compassionate use of quinacrine in Creutzfeldt-Jakob disease fails to show significant effects.

Quinacrine has been reported as an antiprion agent and proposed as an immediately applicable treatment for Creutzfeldt-Jakob disease (CJD). The authors report the results of an open compassionate procedure to which 32 CJD patients had access. In some genotypic subgroups, a slight but nonsignificant increase in survival was observed, likely due to biased inclusion of long-term surviving patients. There was no pathologic evidence of a beneficial effect of quinacrine treatment.

Brain↗
PubMed2002

FADD: A link between TNF family receptors and caspases in Parkinson's disease.

Fas-associating protein with a death domain (FADD) is a proximal adaptor protein of the tumor necrosis factor (TNF) receptor family death pathway. This human postmortem study showed a significant decrease in the percentage of FADD-immunoreactive dopaminergic (DA) neurons in the substantia nigra pars compacta of patients with PD compared with controls (-24.8%). This decrease correlated with the known selective vulnerability of nigral DA neurons in PD, suggesting that this pathway contributes to the susceptibility of DA neurons in PD to TNF-mediated apoptosis.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Expression of tachykinin NK2 receptor mRNA in human brain.

Tachykinin NK2 receptors have been suggested to play an important role in the central nervous system. This study, using reverse transcription-polymerase chain reaction revealed a detectable expression of NK2 receptor mRNA in various human brain regions, including the caudate nucleus, the putamen, the hippocampus, the substantia nigra and the cerebral cortex. The distribution of NK2 receptor expression in the cortex revealed a major expression in frontal and temporal cortex compared to occipital and parietal areas. These results provide a molecular basis for considering a role of NK2 receptors in human pathophysiology.

Aged↗
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

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

Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease.

Caspase-3 is an effector of apoptosis in experimental models of Parkinson's disease (PD). However, its potential role in the human pathology remains to be demonstrated. Using caspase-3 immunohistochemistry on the postmortem human brain, we observed a positive correlation between the degree of neuronal loss in dopaminergic (DA) cell groups affected in the mesencephalon of PD patients and the percentage of caspase-3-positive neurons in these cell groups in control subjects and a significant decrease of caspase-3-positive pigmented neurons in the substantia nigra pars compacta of PD patients compared with controls that also could be observed in an animal model of PD. This suggests that neurons expressing caspase-3 are more sensitive to the pathological process than those that do not express the protein. In addition, using an antibody raised against activated caspase-3, the percentage of active caspase-3-positive neurons among DA neurons was significantly higher in PD patients than in controls. Finally, electron microscopy analysis in the human brain and in vitro data suggest that caspase-3 activation precedes and is not a consequence of apoptotic cell death in PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

Preservation of midbrain catecholaminergic neurons in very old human subjects.

Parkinson's disease is characterized by a progressive degeneration of dopaminergic neurons in the midbrain, yet the cause of this neuronal loss is still unknown. It has been hypothesized that Parkinson's disease could be the consequence of accelerated ageing. In order to reveal a possible common process during ageing and Parkinson's disease neurodegeneration, catecholaminergic neurons of five anatomical regions of the brainstem (substantia nigra, central grey substance, ventral tegmental area, peri- and retrorubral area, and locus coeruleus) have been quantified using immunohistochemical staining for tyrosine hydroxylase (TH) on regularly spaced sections, between the rostral and caudal poles of the mesencephalon and in the rostral pole of the pons, in post-mortem samples of 21 control subjects who died at ages 44-110 years. No statistically significant loss of TH positive neurons was observed in the older subjects, either in the substantia nigra or in the other midbrain regions that are known to degenerate to a lesser degree in Parkinson's disease. Furthermore, in the later regions no neuronal loss was observed from age 44 to 80 years, indicating that this result is not dependent on the inclusion of 'supernormal' very old people. These results suggest that from age 44 to 110 years, ageing in control adults is not, or is scarcely, accompanied by catecholaminergic cell loss in the midbrain and hence Parkinson's disease is probably not caused by an acceleration of a degenerative process during ageing.

Adult↗
PubMed1998

Iron metabolism and Parkinson's disease.

There are at least three major reasons for thinking that iron participates in the mechanism of nerve cell death in Parkinson's disease (PD): (1) Iron catalyzes the formation of highly toxic hydroxyl radicals through the Fenton reaction. (2) Evidence suggests that oxidative stress participates in the mechanism of nerve cell death in PD. (3) Increased iron concentrations have been observed in the substantia nigra of patients with PD. In this review, we report data suggesting that the vulnerable neurons in PD are particularly sensitive to oxidative stress that may be induced by iron and then discuss the mechanisms by which iron levels may be increased in dopaminergic neurons in PD.

Cell Death↗
PubMed1997

Nuclear translocation of NF-kappaB is increased in dopaminergic neurons of patients with parkinson disease.

Evidence from postmortem studies suggest an involvement of oxidative stress in the degeneration of dopaminergic neurons in Parkinson disease (PD) that have recently been shown to die by apoptosis, but the relationship between oxidative stress and apoptosis has not yet been elucidated. Activation of the transcription factor NF-kappaB is associated with oxidative stress-induced apoptosis in several nonneuronal in vitro models. To investigate whether it may play a role in PD, we looked for the translocation of NF-kappaB from the cytoplasm to the nucleus, evidence of its activation, in melanized neurons in the mesencephalon of postmortem human brain from five patients with idiopathic PD and seven matched control subjects. In PD patients, the proportion of dopaminergic neurons with immunoreactive NF-kappaB in their nuclei was more than 70-fold that in control subjects. A possible relationship between the nuclear localization of NF-kappaB in mesencephalic neurons of PD patients and oxidative stress in such neurons has been shown in vitro with primary cultures of rat mesencephalon, where translocation of NF-kappaB is preceded by a transient production of free radicals during apoptosis induced by activation of the sphingomyelin-dependent signaling pathway with C2-ceramide. The data suggest that this oxidant-mediated apoptogenic transduction pathway may play a role in the mechanism of neuronal death in PD.

Aged↗
PubMed1997

The density of [125I]-transferrin binding sites on perikarya of melanized neurons of the substantia nigra is decreased in Parkinson's disease.

The density of [125I]-diferric-transferrin binding sites was investigated at the cellular level on melanized neurons located in the mesencephalon of patients with Parkinson's disease and control subjects, using quantitative autoradiography of in vitro incubated brain sections. In parkinsonian patients mean densities were reduced, the difference being statistically significant for the ventral tier of the substantia nigra, which is the subregion most affected by neuronal death in the disease. The absence of increase in the number of transferrin receptors on the perikarya within a population of neurons accumulating iron probably reflects the post-transcriptional gene regulation of the number of transferrin receptors that depends upon iron content in eukaryote cells.

Aged↗
PubMed1996

Cellular distribution of the iron-binding protein lactotransferrin in the mesencephalon of Parkinson's disease cases.

Changes in the distribution of the iron-binding protein lactotransferrin have recently been described in the central nervous system during a variety of neurodegenerative disorders. To investigate whether lactotransferrin is associated with the neuropathological changes that characterize Parkinson's disease, we analyzed the distribution of this protein in the mesencephalon of neurologically normal individuals and patients affected with Parkinson's disease using quantitative immunohistochemical methods. High levels of lactotransferrin were observed in a large population of neurons in the substantia nigra of control cases. Lactotransferrin-positive neurons were severely affected by the neurodegenerative process that occurs in Parkinson's disease as indicated by a severe decrease in the number of immunolabeled neurons in all of these cases. Quantitative analysis also demonstrated higher immunolabeling levels of lactotransferrin in the surviving neurons in the substantia nigra and ventral tegmental area of Parkinson's disease cases compared to control cases. These results suggest that lactotransferrin may participate actively in the mechanism of neuronal degeneration in Parkinson's disease.

Aged↗
PubMed1995

Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease.

The degeneration of nigral dopaminergic neurons in Parkinson disease is believed to be associated with oxidative stress. Since iron levels are increased in the substantia nigra of parkinsonian patients and this metal catalyzes the formation of free radicals, it may be involved in the mechanisms of nerve cell death. The cause of nigral iron increase is not understood. Iron acquisition by neurons may occur from iron-transferrin complexes with a direct interaction with specific membrane receptors, but recent results have shown a low density of transferrin receptors in the substantia nigra. To investigate whether neuronal death in Parkinson disease may be associated with changes in a pathway supplementary to that of transferrin, lactoferrin (lactotransferrin) receptor expression was studied in the mesencephalon. In this report we present evidence from immunohistochemical staining of postmortem human brain tissue that lactoferrin receptors are localized on neurons (perikarya, dendrites, axons), cerebral microvasculature, and, in some cases, glial cells. In parkinsonian patients, lactoferrin receptor immunoreactivity on neurons and microvessels was increased and more pronounced in those regions of the mesencephalon where the loss of dopaminergic neurons is severe. Moreover, in the substantia nigra, the intensity of immunoreactivity on neurons and microvessels was higher for patients with higher nigral dopaminergic loss. These data suggest that lactoferrin receptors on vulnerable neurons may increase intraneuronal iron levels and contribute to the degeneration of nigral dopaminergic neurons in Parkinson disease.

Aged↗
PubMed1995

Regional distribution of monoamine vesicular uptake sites in the mesencephalon of control subjects and patients with Parkinson's disease: a postmortem study using tritiated tetrabenazine.

The distribution of the vesicular monoamine transporter was investigated post mortem in the human ventral mesencephalon of control subjects (n = 7) and patients with Parkinson's disease (n = 4) using tritiated dihydrotetrabenzine binding and autoradiography. Tritiated dihydrotetrabenazine binding was characterized by a single class of sites with a Kd of 7 nM and a Bmax of 180 fmol/mg of protein in the substantia nigra. Tritiated dihydrotetrabenazine binding sites were heterogeneously distributed in the mesencephalon of control subjects: the density of tritiated dihydrotetrabenazine binding sites was high in the substantia nigra pars compacta, locus coeruleus and nucleus raphe dorsalis, moderate in the ventral tegmental area and low in the substantia nigra pars reticulata and catecholaminergic cell group A8. Within the substantia nigra, a zone with maximal density of tritiated dihydrotetrabenazine binding, two times higher than the mean estimate for the whole substantia nigra pars compacta, was detected in the medial part of the structure. The anatomical organization of the human ventral mesencephalon was analyzed on adjacent sections stained for acetylcholinesterase histochemistry and tyrosine hydroxylase immunohistochemistry. Tritiated dihydrotetrabenazine binding displayed the same characteristic regional pattern of distribution as that observed with tyrosine hydroxylase immunohistochemistry except in the nucleus raphe dorsalis, where no tyrosine hydroxylase immunoreactivity was detected. In parkinsonian brains, the level of tritiated dihydrotetrabenazine binding was dramatically decreased in all regions of the ventral mesencephalon analyzed except in the substantia nigra pars reticulata. In the substantia nigra pars compacta, the reduction was by 55% for the whole structure and by 65% in its medial zone, where binding site density was maximal. In most nigral subsectors analyzed, the decrease in density of tritiated dihydrotetrabenazine binding sites reached the level expected given the loss of tyrosine hydroxylase-positive cells observed. By contrast, the ratio of [3H]dihydrotetrabenazine binding to the number of tyrosine hydroxylase positive neurons was significantly increased in the zone of high [3H]dihydrotetrabenazine binding sites. This relative sparing of tritiated dihydrotetrabenazine binding sites may be due either to the contribution of other monoaminergic neurons such as serotoninergic neurons or more likely to hyperactivity of the still surviving dopaminergic neurons.

Acetylcholinesterase↗
PubMed1995

Autoradiographic localization and density of [125I]ferrotransferrin binding sites in the basal ganglia of control subjects, patients with Parkinson's disease and MPTP-lesioned monkeys.

Degeneration of the nigro-striatal dopaminergic neurons occurring in Parkinson's disease is associated with an increase in iron concentrations in the substantia nigra. As this metal catalyzes the production of free radicals, and oxidative stress may participate in the cascade of events ending in cell death, this increase in iron content may be involved in dopaminergic neuronal death. The localization and number of receptors for transferrin were investigated postmortem by quantitative autoradiography of iodinated-ferrotransferrin binding in the basal ganglia from controls, parkinsonian patients and MPTP-lesioned monkeys. In human controls, specific [125i] ferrotransferrin binding-site density was highest in the putamen and the caudate nucleus, and lowest in the globus pallidus. In parkinsonian patients, it was increased in the putamen and caudate nucleus, while in MPTP-intoxicated monkeys, there was a tendency for levels to decrease in these two regions. An inverse relationship between binding density and iron content reported in the studied regions supports the assumption of a possible capture of iron at the level of dopaminergic terminals and, in parkinsonian patients, on other cellular elements as well. These results suggest an involvement of transferrin receptors in iron uptake in the striatum of patients with Parkinson's disease, with differences between the 'acute' nigro-striatal MPTP-induced degeneration syndrome and the chronic long lasting human disease.

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