Riluzole neuroprotection in a parkinson's disease model involves suppression of reactive astrocytosis but not GLT-1 regulation

Marica Carbone,Marcus Rattray,Susan Duty

doi:10.1186/1471-2202-13-38

Marica Carbone, Marcus Rattray + Show 1 more

Open Access

https://doi.org/10.1186/1471-2202-13-38

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Journal: BMC neuroscience	Publication Date: Apr 5, 2012
Citations: 82	License type: cc-by

Affiliation: King's College London, University of Reading

Abstract

BackgroundRiluzole is a neuroprotective drug used in the treatment of motor neurone disease. Recent evidence suggests that riluzole can up-regulate the expression and activity of the astrocyte glutamate transporter, GLT-1. Given that regulation of glutamate transport is predicted to be neuroprotective in Parkinson's disease, we tested the effect of riluzole in parkinsonian rats which had received a unilateral 6-hydroxydopamine injection into the median forebrain bundle.ResultsRats were treated with intraperitoneal riluzole (4 mg/kg or 8 mg/kg), 1 hour before the lesion then once daily for seven days. Riluzole produced a modest but significant attenuation of dopamine neurone degeneration, assessed by suppression of amphetamine-induced rotations, preservation of tyrosine hydroxylase positive neuronal cell bodies in the substantia nigra pars compacta and attenuation of striatal tyrosine hydroxylase protein loss. Seven days after 6-hydroxydopamine lesion, reactive astrocytosis was observed in the striatum, as determined by increases in expression of glial fibrillary acidic protein, however the glutamate transporter, GLT-1, which is also expressed in astrocytes was not regulated by the lesion.ConclusionsThe results confirm that riluzole is a neuroprotective agent in a rodent model of parkinson's disease. Riluzole administration did not regulate GLT-1 levels but significantly reduced GFAP levels, in the lesioned striatum. Riluzole suppression of reactive astrocytosis is an intriguing finding which might contribute to the neuroprotective effects of this drug.

Highlights

Riluzole is a neuroprotective drug used in the treatment of motor neurone disease
Since reactive astrocytosis is associated with loss of the protective functions in astrocytes [13], suppression of astrocyte reactivity may be beneficial in disease
Due to the functional deficit of dopamine transmission on the ipsilateral, lesion hemisphere following unilateral 6-OHDA lesion, animals show a high level of ipsiversive rotation when challenged with amphetamine (Figure 1A)

Summary

Introduction

Riluzole is a neuroprotective drug used in the treatment of motor neurone disease. Recent evidence suggests that riluzole can up-regulate the expression and activity of the astrocyte glutamate transporter, GLT-1. Given that regulation of glutamate transport is predicted to be neuroprotective in Parkinson’s disease, we tested the effect of riluzole in parkinsonian rats which had received a unilateral 6-hydroxydopamine injection into the median forebrain bundle. One potential way of regulating glutamate levels, which has been largely overlooked in Parkinson’s disease, is by modulating astrocytes. In animal models of Parkinson’s disease, astrocytes are markedly altered: following dopamine neurone degeneration astrocytes become reactive, as seen by a sustained and progressive increase in the levels of the astrocyte cytoskeletal protein, glial fibrillary acidic protein (GFAP) together with changes in astrocyte morphology [10,11,12]. Since reactive astrocytosis is associated with loss of the protective functions in astrocytes [13], suppression of astrocyte reactivity may be beneficial in disease

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