Biomedical subjects

E Bezard

Publications and source records attributed to E Bezard.

36 records · Page 2Linked to original sources

PubMed1999

Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter.

MPTP has been shown to induce parkinsonism both in human and in nonhuman primates. The precise mechanism of dopaminergic cell death induced following MPTP treatment is still subject to intense debate. MPP+, which is the oxidation product of MPTP, is actively transported into presynaptic dopaminergic nerve terminals through the plasma membrane dopamine transporter (DAT). In this study, we used mice lacking the DAT by homologous recombination and demonstrated that the MPTP-induced dopaminergic cell loss is dependent on the presence of the DAT. For this we have used tyrosine hydroxylase immunoreactivity (TH-IR) labeling of dopamine cells of the substantia nigra compacta in wild-type, heterozygote, and homozygote mice that were given either saline or MPTP treatments (two ip injections of 30 mg/kg, 10 h apart). Our results show a significant loss of TH-IR in wild type (34.4%), less loss in heterozygotes (22.5%), and no loss in homozygote animals. Thus dopamine cell loss is related to levels of the DAT. These results shed light on the degenerative process of dopamine neurons and suggest that individual differences in developing Parkinson's disease in human may be related to differences of uptake through the DAT of a yet unidentified neurotoxin.

Animals↗

PubMed1999

Effect of the alpha 2 adrenoreceptor antagonist, idazoxan, on motor disabilities in MPTP-treated monkey.

1. The motor effect of the alpha 2 adrenoreceptor antagonist, idazoxan, was compared to that of L-dopa in MPTP-treated monkeys. 2. Idazoxan 2.0 mg/kg improved parkinsonian motor abnormalities which was comparable to the effects of a minimal effective dose of L-dopa. 3. At 2.0 and 5.0 mg/kg, the parkinsonian rigidity was the item most frequently alleviated by idazoxan (respectively 63.6% and 68.2%). 4. These findings provide support for the therapeutic utility of alpha 2 antagonists in the treatment of Parkinson's disease.

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

PubMed1999

From experimentation to the surgical treatment of Parkinson's disease: prelude or suite in basal ganglia research?

Parkinson's disease remains one of the greatest challenges facing those who work in the field of neurological research. Although the development of levodopa treatment revolutionised management of this debilitating diseases, no effective long-term therapy has yet been found. With recent advances in the understanding of basal ganglia physiopathology and the experimental demonstration of the efficacy of certain surgical procedures, there is a renewed interest in the surgical approach. This paper provides a chronological overview of the history of parkinsonian surgery and discusses the principal surgical options at our disposal today. These take three main forms: ablation (thalamotomy, pallidotomy and subthalamotomy); cell graft and gene therapy (mainly in the striatum); and deep brain stimulation (of the thalamus, globus pallidus pars internalis and the subthalamic nucleus). Our knowledge of basal ganglia function and our conception of how motor information is processed by this network have evolved parallel to the development of surgical techniques. Recent results from both clinical and experimental studies underline the complexity of the physiopathological mechanisms which generate parkinsonian symptomatology and lead us to question our assumption that each class of clinical signs (tremor, akinesia, rigidity, levodopa-induced dyskinesias...) is produced by a specific and separate mechanism. In the same way, comparison of the electrophysiological and biochemical effects of the different techniques induced in brain function vary considerably. This complex world of interaction and interconnection is a labyrinth that we are still far from comprehending in its entirety. All the more reason, in consequence, for extending experimental investigation into the impact of any new therapy before proposing its clinical application.

Animals↗

PubMed1999

Involvement of the subthalamic nucleus in glutamatergic compensatory mechanisms.

The purpose of the present study was to investigate whether the subthalamic nucleus (STN) was implicated in the glutamatergic compensatory mechanisms which have been shown to mask the parkinsonian motor abnormalities at the end of the presymptomatic period in experimental parkinsonism. Using multiunit electrophysiological recordings, we follow changes of activity occurring in the STN and in both the pars externalis and the pars internalis of the globus pallidus of monkeys chronically intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), according to a protocol designed to mimic the gradual evolution of dopaminergic neuronal death. STN activity augmented significantly in the course of treatment, even before the first appearance of clinical signs (P < 0.01). This result would indicate that the STN, which increases its level of activity even before the end of the presymptomatic period, is principally responsible for the instigation of glutamatergic compensatory mechanisms which allow the maintenance of the striatal dopaminergic homeostasis.

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

PubMed1999

Trichloroethylene and parkinsonism: a human and experimental observation.

This report describes the case of a 47-year-old woman who developed Parkinson's disease after seven years of professional exposure to trichloroethylene. In the light of this clinical report, mice were intoxicated with trichloroethylene and tyrosine hydroxylase immunoreactivity was used to measure neuronal death in the substantia nigra pars compacta. Treated mice presented significant dopaminergic neuronal death in comparison with control mice (50%). The environmental trichlorethylene pollution, as well as other unspecific neurotoxic solvents, could potentially contribute to the genesis of some cases of Parkinson's disease.

Animals↗

PubMed1999

Cortical stimulation and epileptic seizure: a study of the potential risk in primates.

OBJECTIVE: The recent successful development of chronic stimulation of the motor cortex as a treatment for neuropathic and central pain does not exclude the possibility of eventual side effects, such as epileptic seizure or a lowering of the epileptic threshold. This study evaluates the behavioral and electroencephalographic impact of this treatment in three normal monkeys. RESULTS: None of the monkeys presented epileptic behavior or abnormal electroencephalographic activity at parameters of stimulation currently used in clinical series, i.e., frequency and pulse duration of approximately 40 Hz and 90 microseconds, respectively, and an intensity just under the threshold for inducing muscle twitch in painful areas. Higher intensities did, however, induce reversible epileptic seizure. There was, nonetheless, no modification of the epileptic threshold, because even after these seizures, intermittent light stimulation elicited no abnormal electroencephalographic activity. CONCLUSION: It thus seems that motor cortex stimulation does not induce epileptic complications when the classic clinical criteria of stimulation are respected. Nevertheless, it would be wise to subject candidates for implantation to intermittent light stimulation before and after a period of stimulation to ascertain the innocuousness of the cortical stimulation.

Animals↗

PubMed1998

Riluzole delayed appearance of parkinsonian motor abnormalities in a chronic MPTP monkey model.

Preliminary studies have shown that riluzole, a Na+ channel blocker with antiglutamatergic activity, has neuroprotective efficacy in several models of acute dopaminergic neurodegeneration. A chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model which comes closer to the slow evolution of Parkinson's disease has recently been developed in order to allow dynamic studies. The present results show that riluzole delayed the appearance of parkinsonian motor abnormalities in this dynamic model, using from 10.2 +/- 1.6 daily injections for the MPTP-treated monkeys (n = 4) to 16.5 +/- 2.0 daily injections for the MPTP + riluzole-treated monkeys (n = 4). These results strongly suggest that riluzole may be beneficial to slow down the rate of progression of Parkinson's disease.

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

PubMed1998

Effects of L-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey.

We studied the effects of L-DOPA on the firing patterns of pallidal neurons in experimental parkinsonism. After a unilateral injection of MPTP, we observed a decrease in the firing rate of GPe neurons, and a slight increase in their bursting activity. In the GPi, there was a considerable augmentation of both neuronal firing frequency and the number of bursting cells. During l-DOPA treatment (10 mg/kg), GPe neurons.pattern is almost unmodified. The firing frequency of GPi neurons, on the contrary, decreased even lower than the control level. A slight reduction was observed in bursting activity. These unexpected results would show that the normalizing effect of L-DOPA on GPi output is limited.

Animals↗

PubMed1998

Glutamatergic compensatory mechanisms in experimental parkinsonism.

1. Injection cannulae allowing access to the SNc were implanted bilaterally in four monkeys. Once animals had recovered from the operation, daily low-dose treatment with MPTP was started. 2. Group I comprised two monkeys under treatment with MPTP, but still asymptomatic. Group II comprised two monkeys treated with MPTP and presenting clinical symptoms. 3. Both groups received daily intracranial injections of kynurenic acid in order to block the glutamatergic afferents to the SNc. 4. In the first group of asymptomatic monkeys, kynurenic acid induced parkinsonian motor abnormalities. In the second group of symptomatic monkeys, it increased the severity of clinical signs. 5. Glutamatergic inputs to the SNc would therefore appear to be implicated in compensatory phenomena at different stages of experimental parkinsonism.

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

PubMed1998

Compensatory mechanisms in experimental and human parkinsonism: towards a dynamic approach.

This paper provides an overview of the compensatory mechanisms which come into action during experimental and human parkinsonism. The intrinsic properties of the dopaminergic neurones of the substantia nigra pars compacta (SNc) which degenerate during Parkinson's disease are described in detail. It is generally considered that the nigrostriatal pathway is principally responsible for the compensatory preservation of dopaminergic function. It is also becoming clear that the morphological characteristics of dopaminergic neurones and the dual character, synaptic and asynaptic, of striatal dopaminergic innervation engender two modes of transmission, wiring and volume, and that both these modes play a role in the preservation of dopaminergic function. The plasticity of the dopamine neurones, extrinsic or intrinsic to the striatum, can thus be regarded as another compensatory mechanism. Recent anatomical and electrophysiological studies have shown that the SNc receives both glutamatergic and cholinergic inputs. The dynamic role this innervation plays in compensatory mechanisms in the course of the disease is explained and discussed. Recent developments in the field of compensatory mechanisms speak for the urgence to develop a valid chronic model of Parkinson's disease, integrating all the clinical features, even resting tremor, and illustrating the gradual evolution of nigral degeneration observed in human Parkinson's disease. Only a dynamic approach to the physiopathological study of compensatory mechanisms in the basal ganglia will be capable of elucidating these complex questions.

Adaptation, Physiological↗

PubMed1998

Experimental models of Parkinson's disease: from the static to the dynamic.

The experimental models of Parkinson's disease (PD) available today can be divided into two categories according to the mode of action of the compound used: transient pharmacological impairment of dopaminergic transmission along the nigrostriatal pathway or selective destruction by a neurotoxic agent of the dopaminergic neurons of the substantia nigra pars compacta. The present article looks at the relative merits of each model, the clinical symptoms and neuronal impairment it induces, and the contribution it could make to the development of a truly dynamic model. It is becoming more and more clear that there is an urgent need for a chronic model integrating all the clinical features of PD including resting tremor, and reproducing the gradual but continuous nigral degeneration observed in the human pathology. Discrepancies have been reported several times between results obtained in classic animal models and those described in PD, and it would seem probable that such contradictions can be ascribed to the fact that animal models do not, as yet, reproduce the continuous evolution of the human disease. Dynamic experimental models which come closer to the progressive neurodegeneration and gradual intensification of motor disability so characteristic of human PD will enable us to investigate crucial aspects of the disease, such as compensatory mechanisms and dyskinesia.

Animals↗

PubMed1997

Kinetics of nigral degeneration in a chronic model of MPTP-treated mice.

The chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model we have developed in monkey reproduces all the cardinal features of Parkinson's disease, and, in particular the characteristic slow evolution of clinical signs. We still know little, however, of the kinetics of the nigral degeneration induced. This present study charts the progressive destruction of tyrosine hydroxylase-immunoreactive neurones in mice treated daily with low doses of MPTP for 20 days. Our results show that the neuronal death rate is initially high, subsequently decreases, and stabilizes. This new protocol thus mirrors closely the pattern of evolution assumed to be that of Parkinson's disease and should prove useful for studies on neuroprotection and compensatory mechanisms.

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

PubMed1997

A chronic MPTP model reproducing the slow evolution of Parkinson's disease: evolution of motor symptoms in the monkey.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism both in man and non-human primates. Several models have now been developed, but acute MPTP administration does not consistently reproduce all the clinical features of the disease. To mirror the slow evolution observed in human pathology, a chronic model of intoxication is necessary. The present study describes a chronic MPTP protocol in the monkey. Six monkeys received daily injections of MPTP (0.2 mg/kg i.v.) until they reached a score over 8 on the clinical rating scale (15.5 days +/- 1.1). Full parkinsonism was first obtained on the 22nd day. Levodopa testing (20 mg/kg per os) alleviated motor abnormalities (51%), proving the parkinsonian nature of these disturbances. Histological lesions reproduced those observed in Parkinson's disease with a decrease in tyrosine hydroxylase immunoreactivity of 90%. This model so could be of great interest for the study of the dynamic physiopathological changes which occur in Parkinson's disease and consequently for research on new neuroprotective therapies.

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

PubMed1997

Subthalamic stimulation elicits hemiballismus in normal monkey.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) reduces parkinsonian symptoms in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey and in human patients. The effects of stimulation on normal waking primates have never been evaluated. While low frequency stimulation has no effect, HFS induces dyskinesias contralateral to the stimulated STN resembling human hemiballismus and those obtained in primates after neurotoxic lesion or pharmacological blockade of the STN. In the normal monkey, HFS appears reversibly to incapacitate the STN and allow the emergence of involuntary proximal displacements, due to disinhibition of the thalamo-cortical pathway. In the MPTP-treated monkey HFS buffers STN overactivity and alleviates akinesia and rigidity by reducing inputs to the internal segment of the globus pallidus.

Animals↗

PubMed1997

Presymptomatic revelation of experimental parkinsonism.

Parkinson's disease results from a progressive loss of dopaminergic neurones of the substantia nigra (SNc). Clinical symptoms only appear, however, when neuronal death exceeds 50-60%: their late appearance is due to compensatory mechanisms. The possibility exists that glutamatergic inputs to the SNc may be implicated in this 'masking' of the disease. To test this hypothesis, we evaluated the effects of reversible pharmacological blockage of these inputs in asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. The result was the appearance of motor disturbances. This finding supports the idea that SNc glutamatergic inputs are largely involved in compensatory mechanisms during presymptomatic period. Blockade of these inputs could lead to presymptomatic diagnosis of Parkinson's disease.

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

PubMed1997

Effects of different schedules of MPTP administration on dopaminergic neurodegeneration in mice.

Although a valuable 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of human Parkinson's disease has been developed, our knowledge of the course of nigral degeneration remains fragmentary. Experimental factors which could possibly influence the destructive process must be taken into account. To evaluate the impact of experimental design, we compared the effects of different schedules of injection of the same cumulative dose of MPTP, in mice, by measuring tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta. Massive injection of the total dose over 1 day (4 injections of 20 mg/kg) destroyed more dopaminergic neurons than did the long-term daily injections of a lower dose of MPTP (20 injections of 4 mg/kg). This suggests that different schedules of administration of MPTP might induce different mechanisms of neuronal death. These mechanisms need to be better understood if chronic models of intoxication that replicate the evolution of human Parkinson's disease more precisely are to be developed.

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

PubMed1997

Compensatory effects of glutamatergic inputs to the substantia nigra pars compacta in experimental parkinsonism.

The effect of transitory blockage of substantia nigra pars compacta glutamatergic inputs by intracranial injections of kynurenic acid were evaluated in two monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The MPTP protocol was designed to mimic the gradual evolution of human Parkinson's disease. No effects were observed before MPTP treatment or in the first stage of treatment. Once clinical signs appeared, however, motor abnormalities were significantly aggravated by blockage of these inputs (P < 0.001). Conversely, after full Parkinsonism was established, blockage no longer had any behavioural effect. These results confirm the postulated compensatory role of the glutamatergic pathways feeding the substantia nigra pars compacta. This added insight into the physiopathology of the basal ganglia, when compared with previous data on the presymptomatic revelation of experimental Parkinsonism, should help elucidation of the time pattern of evolution of Parkinson's disease.

Animals↗

PubMed1996

High frequency stimulation of the internal Globus Pallidus (GPi) simultaneously improves parkinsonian symptoms and reduces the firing frequency of GPi neurons in the MPTP-treated monkey.

The firing pattern of the neurons of the internal Globus Pallidus (GPi) is greatly disturbed in Parkinson's disease. Surgical lesion or high frequency stimulation (HFS) of the GPi reduces parkinsonian rigidity and akinesia. We evaluated in this study the effects of HFS of the GPi on the firing pattern of its neurons. Extracellular recordings were carried out under three types of experimental conditions in rhesus monkeys, normal state, after MPTP treatment and during HFS of the GPi. After intracarotidian MPTP injection, the firing rate of GPi cells increased significantly. During HFS, MPTP-induced parkinsonian motor symptoms clearly improved correlatively with a significant decrease in the firing rate of GPi cells in the stimulated area. HFS restored a firing frequency similar to that in normal animals and, unexpectedly, did not completely block neuronal activity.

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