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

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Abstract

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.

Introduction

Parkinson's disease is due to the progressive death of pigmented nigrostriatal dopaminergic neurones (Ehringer and Hornykiewicz, 1960) in the substantia nigra pars compacta. Palliative treatment of Parkinson's disease with levodopa (Birkmayer and Hornykiewicz, 1961) although efficacious over a variable period of time, inevitably result in drug-related side-effects (e.g., Nutt et al., 1992).

Thus, to develop a neuroprotective drug able to reduce or block nigral neurodegeneration has become a priority. Results of recent studies in rodents (e.g., Turski et al., 1991; Sonsalla et al., 1992; Tabatabaei et al., 1992) and in primates (Zuddas et al., 1992; Lange et al., 1993) suggest that excitatory amino acid antagonists have a neuroprotective effect against pro-parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), toxicity.

Riluzole (2-amino-6-trifluoromethoxy-benzothiazole), a Na+ channel blocker with antiglutamatergic activity, has been shown to display protective activity in various models, using pro-parkinsonian neurotoxins in rodents (Boireau et al., 1994a, Boireau et al., 1994b; Barnéoud et al., 1996). Riluzole has been reported to protect against the MPTP-induced drop in dopamine levels in mice (Boireau et al., 1994a). Clear protection was also found in a model of 1-methyl-4-phenylpyridinium toxicity (Boireau et al., 1994b). In addition, riluzole was shown to alleviate the circling behaviour in 6-hydroxydopamine-treated rats and to reduce the suppression of dopamine metabolism, at both striatal and nigral levels (Barnéoud et al., 1996). Both neuroprotective and palliative effects have also been obtained in an acute model of MPTP intoxication in the monkey (Benazzouz et al., 1995).

We have recently developed a chronic MPTP monkey model that reflects the slow evolution of Parkinson's disease (Bezard et al., 1997c, Bezard et al., 1997d). We now aimed to test the hypothesis that riluzole is able to delay the appearance of parkinsonian motor abnormalities in this dynamic MPTP monkey model.

Section snippets

Animals

Experiments were carried out with nine male cynomolgus monkeys (Macaca fascicularis) weighing 3–4 kg. The monkeys were housed in individual primate cages and their care was supervised by veterinarians skilled in the healthcare and maintenance of primates. Our laboratory operates under the guidelines laid down by the National Institute of Health and is authorized by the French Ministry of the Environment.

Behavioural assessment

The animals' behaviour was evaluated on a parkinsonian monkey rating scale (Kurlan et al.,

Results

The vehicle-treated monkey's motor behaviour remained normal throughout the protocol.

There was a significant difference in the number of MPTP doses necessary to develop parkinsonism between Group I (MPTP) and Group II (MPTP+riluzole) (10.2±1.6 injections and 16.5±2.0 injections, respectively; mean±S.D.) (P<0.05). Monkeys from Group II (Riluzole) thus developed parkinsonian motor abnormalities later than did monkeys of Group I (Fig. 1).

ANOVA comparing the time courses showed a significant

Discussion

The results showed that riluzole delayed the appearance of parkinsonian motor abnormalities in a chronic monkey model of MPTP toxicity, designed to come closer to Parkinson's disease (Bezard et al., 1997d). This added new insight to a previous report of a neuroprotective effect observed in an acute model of MPTP intoxication in monkeys (Benazzouz et al., 1995).

Immunohistochemical determination of tyrosine hydroxylase in surviving dopaminergic neurones (data not shown) showed a sharp cell

Acknowledgements

We should like to thank Dr. J. Pratt for critical reading and helpful discussion and Miss S. Dovero for technical assistance.

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