Biomedical subjects

S Palfi

Publications and source records attributed to S Palfi.

25 records · Page 2Linked to original sources

PubMed1997

Riluzole reduces incidence of abnormal movements but not striatal cell death in a primate model of progressive striatal degeneration.

Riluzole has been shown recently to increase life expectancy in patients with amyotrophic lateral sclerosis. A number of experimental studies also suggest that this compound may be a neuroprotectant. We have investigated in baboons whether riluzole would protect striatal neurons from a prolonged 3-nitropropionic acid (3NP) treatment and ameliorate the associated motor symptoms. In animals receiving 3NP and the solvent of riluzole, 12 weeks of high-dose 3NP treatment resulted in the appearance of persistent leg dystonia and significant increases in the incidence of three categories of abnormal movements and in the dyskinesia index in the apomorphine test (0.5 mg/kg i.m.). Quantitative assessment of these behavioral deficits using a video movement analysis system demonstrated a significant decrease in locomotor activity and peak tangential velocity in 3NP-treated animals compared to controls. Histological analysis showed the presence of severe, bilateral, striatal lesions, localized in both caudate and putamen. Cotreatment with riluzole (4 mg/kg i.p., twice daily) significantly reduced the dyskinesia index (-35%, P < 0.02) in the apomorphine test. In the quantitative behavioral analysis, riluzole significantly ameliorated the decrease in peak tangential velocity (P < 0.02) but not the decrease in locomotor activity observed after 3NP. Comparative histological analysis of the two groups of treated animals did not demonstrate a clear neuroprotective effect of riluzole. The present study suggests that one potential therapeutic interest for riluzole in neurodegenerative disorders may reside in the reduction of motor symptoms associated with striatal lesions.

Acetylcholinesterase↗

PubMed1997

Quantifiable bradykinesia, gait abnormalities and Huntington's disease-like striatal lesions in rats chronically treated with 3-nitropropionic acid.

Impairment in energy metabolism is thought to be involved in the aetiology of Huntington's disease. In line with this hypothesis, chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid to rats and monkeys produces selective striatal lesions similar to Huntington's disease. The present study examined whether rats treated with varying regimen of 3-nitropropionic acid could present motor abnormalities reminiscent of Huntington's disease symptomatology, correlated with Huntington's disease specific striatal symptomatology. Subacute 3-nitropropionic acid treatment (15 mg/kg per day intraperitoneally for 10 days) produced dramatic motor symptoms associated with extensive neuronal loss and gliosis in the lateral striatum as well as severe hippocampal degeneration in 50% of the cases. In contrast, chronic 3-nitropropionic acid treatment (10 mg/kg per day subcutaneously for one month) led to more subtle excitotoxic-like lesions, selective for the dorsolateral striatum and more closely resembling Huntington's disease striatal pathology. Animals with these Huntington's disease-like lesions showed spontaneous motor symptoms including mild dystonia, bradykinesia and gait abnormalities, which were barely detectable on visual inspection but could be readily identified and quantified by computerized video analysis. In these chronic animals, the degree of striatal neuronal loss was significantly correlated with the severity of spontaneous motor abnormalities, as is the case in Huntington's disease. The present study demonstrates that chronic low-dose 3-nitropropionic acid treatment in rats results in a valuable model of both the histological features and motor deficits which occur in Huntington's disease. Despite the interanimal variability in terms of response to 3-nitropropionic acid treatment, this rat model may be particularly useful for evaluating the functional benefits of new therapeutic strategies for Huntington's disease, particularly those aiming to reduce the severity of motor symptoms.

Analysis of Variance↗

PubMed1997

Riluzole protects from motor deficits and striatal degeneration produced by systemic 3-nitropropionic acid intoxication in rats.

The putative neuroprotective effect of riluzole was investigated in a rat model of progressive striatal neurodegeneration induced by prolonged treatment (three weeks, intraperitoneal) with 3-nitropropionic acid, an irreversible inhibitor of succinate dehydrogenase. Quantitative analysis of motor behaviour indicated a significant protective effect (60%) of riluzole (8 mg/kg/day) on 3-nitropropionic acid-induced motor deficits as assessed using two independent motor tests. Furthermore, quantitative analysis of 3-nitropropionic acid-induced lesions indicated a significant 84% decrease in the volume of striatal damage produced by 3-nitropropionic acid, the neuroprotective effect apparently being more pronounced in the posterior striatum and pallidum. In addition, it was checked that this neuroprotective effect of riluzole against systemic 3-nitropropionic acid did not result from a decreased bioavailability of the neurotoxin or a direct action of riluzole on 3-nitropropionic acid-induced inhibition of succinate dehydrogenase. We found that riluzole significantly decreased by 48% the size of striatal lesions produced by stereotaxic intrastriatal injection of malonate, a reversible succinate dehydrogenase inhibitor. Furthermore, the inhibition of cortical and striatal succinate dehydrogenase activity induced by systemic 3-nitropropionic acid was left unchanged by riluzole administration. The present results, consistent with a beneficial effect of riluzole in amyotrophic lateral sclerosis, suggest that this compound may be useful in the treatment of chronic neurodegenerative diseases.

Animals↗

PubMed1996

Chronic 3-nitropropionic acid treatment in baboons replicates the cognitive and motor deficits of Huntington's disease.

We showed recently that chronic administration of the mitochondrial inhibitor 3-nitropropionic acid (3NP) in primates produces various dyskinetic movements and dystonic postures associated with selective striatal lesions displaying many similarities with the pathological features of Huntington's disease (HD). In the present study, we examined whether such a toxic treatment could also induce frontal-type deficits similar to those observed in HD patients. Cognitive performances of 3NP-treated and control baboons were compared using the object retrieval detour task (ORDT), a test designed to assess the functional integrity of the frontostriatal pathway in human and nonhuman primates. During the same time, the motor function of each animal was assessed under spontaneous "no drug" conditions, and time-sampled neurological observations were used after apomorphine administration. A significant impairment in the ORDT was observed in the 3NP animals after 3-6 weeks of treatment, occurring in the absence of spontaneous abnormal movements by in the presence of apomorphine-inducible dyskinesias. Prolonged 3NP treatment resulted in the progressive appearance of spontaneous abnormal movements. Histological evaluation of these animals showed selective bilateral caudate-putamen lesions with sparing of the cerebral cortex, notably the prefrontal cortex. The present study demonstrates that chronic 3NP treatment replicates in primates the basic pathophysiological triad of HD, including spontaneous abnormal movements, progressive striatal degeneration, and a frontostriatal syndrome of cognitive impairment.

Animals↗

PubMed1996

Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7-Nitroindazole (7-NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS) that blocks MPTP neurotoxicity in mice. We now show that 7-NI protects against profound striatal dopamine depletions and loss of tyrosine hydroxylase-positive neurons in the substantia nigra in MPTP-treated baboons. Furthermore, 7-NI protected against MPTP-induced motor and frontal-type cognitive deficits. These results strongly implicate a role of nitric oxide in MPTP neurotoxicity and suggest that inhibitors of neuronal NOS might be useful in treating Parkinson's disease.

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

PubMed1996

[Microsurgical vascular decompression in the treatment of facial hemispasm. A retrospective study of a series of 65 cases and review of the literature].

The results of a series of 65 consecutive patients operated on to relieve hemifacial spasm (HFS) at Pierre Wertheimer Hospital in Lyon and at Henri Mondor Hospital in Creteil, using the same microvascular decompression (MVD) method, are reported. MDV was performed through a retromastoid keyhole approach. A neurovascular conflict (NVC) was found in 62 cases (i.e., 95.5%). The conflicting vessel was the posterior inferior cerebellar artery (PICA) in 23 cases (35.4%), the anterior inferior cerebellar artery (AICA) in 22 cases (33.8%), the vertebro-basilar artery (VBA) with PICA and/or AICA in 13 cases (20%), and VBA alone in 4 cases (3.1%). The conflicting artery was maintained apart from the REZ of VII nerve by interposing a ball made of Teflon fibers and/or a plaque of Dacron. Forty-five patients (69.2%) were totally cured, 16 patients (24.6%) had only a partial (more than 50%) improvement, and in 4 patients (6.2%) surgery failed. Follow-up ranged from 1 month to 13 years (mean: 4 years and 8 months). Important was that in 9 patients, total relief of spasm occurred only secondarily with a delay sometimes as long as one year. Post-operative complications were dominated by: 1) facial nerve deficits in 16 cases (24.6%), of which 14 were transient and 2 were permanent; 2) hearing decrease in 10 cases (15.4%), of which 5 were transient and 5 were permanent. These complications were encountered at the start of the experience and at a time when monitoring of intraoperative brainstem auditory evoked potentials (BAEP) was not routinely done. Our data proved to be consistent with those published in the literature.

Adult↗

PubMed1993

[Hemifacial spasm treated with botulinum toxin].

Botulinum toxin produces a transient presynaptic focal block at the neuromuscular junction. Thus it induces muscle weakness which has a significant beneficial effect on hemifacial spasm. Fifty-four patients were treated and received at least 2 and at the most 22 consecutive injections over a 5-year period. Injections were repeated every 9 weeks on average. The interval between injections corresponded to the time elapsed between the last injection and the re-emergence of spasms. Nineteen patients abandoned the treatment for various reasons. The most frequent side-effect was a ptosis which was observed in 1 out of 6 injections. Ptosis is due to diffusion of the botulinum toxin over a territory larger than expected. The results obtained in 42 patients were analyzed: there was no effect in 7 patients (17%); 11 patients improved by less than 50%; 13 by 50 to 70% and 11 more than 75%.

Adult↗