Neuroprotective effects of riluzole on or veratridine-induced neurotoxicity in rat hippocampal slices

Malgouris, C.; Daniel, Marc; Doble, Adam

doi:10.1016/0304-3940(94)90053-1

Cited by 60 publications

(31 citation statements)

References 17 publications

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“…Riluzole interferes with pre-and postsynaptic glutamate neurotransmission via a complex mechanism of action involving the blockade of voltage-sensitive Na + channels, ionic flux through NMDA channels, and possibly also interaction with G proteins [106][107][108][109][110]. Riluzole inhibits glutamate release, decreases EAA-evoked firing of rat facial motor neurones, and exerts neuroprotective effects in experimental models of acute and chronic neurodegenerative disease [58, [110][111][112][113].…”

Section: Therapeutic Modulation Of Glutamate Neurotransmissionmentioning

confidence: 99%

Glutamate, excitotoxicity and amyotrophic lateral sclerosis

1997

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The "glutamate hypothesis" is one of three major pathophysiological mechanisms of motor neurone injury towards which current research effort into amyotrophic lateral sclerosis (ALS) is directed. There is great structural and functional diversity in the glutamate receptor family which results from combinations of 14 known gene products and their splice variants, with or without additional RNA editing. It is possible that motor neurones express a unique molecular profile of glutamate receptors. Abnormal activation of glutamate receptors is one of five main candidates as a final common pathway to neuronal death. In classical acute excitotoxicity, there is influx of Na+ and CI-, and destabilisation of intracellular Ca2+ homeostasis, which activates a cascade of harmful biochemical events. The concept of secondary excitotoxicity, where cellular injury by glutamate is triggered by disturbances in neuronal energy status, may be particularly relevant to a chronic neurodegenerative disease such as ALS. Data are now beginning to emerge on the fine molecular structure of the glutamate receptors present on human motor neurones, which have a distinct profile of AMPA receptors. Two important molecular features of motor neurones have been identified that may contribute to their vulnerability to neurodegeneration. The low expression of calcium binding proteins and the low expression of the GluR2 AMPA receptor subunit by vulnerable motor neurone groups may render them unduly susceptible to calcium-mediated toxic events following glutamate receptor activation. Eight lines of evidence that indicate a disturbance of glutamatergic neurotransmission in ALS patients are reviewed. The links between abnormal activation of glutamate receptors and other potential mechanisms of neuronal injury, including activation of calcium-mediated second messenger systems and free radical mechanisms, are emphasised. Riluzole, which modulates the glutamate neurotransmitter system, has been shown to prolong survival in patients with ALS. Further research may allow the development of subunit-specific therapeutic targeting of glutamate receptors and modulation of "downstream" events within motor neurones, aimed at protecting vulnerable molecular targets in specific populations of ALS patients.

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Section: Therapeutic Modulation Of Glutamate Neurotransmissionmentioning

confidence: 99%

Glutamate, excitotoxicity and amyotrophic lateral sclerosis

1997

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“…[3][4][5][6] Riluzole (2-amino-6-tri uoromethoxybenzothiazole, Rilutek ® ) is a novel, anti-excitotoxic drug which is indicated for the treatment of patients with ALS. In laboratory tests, riluzole was found to inhibit excitatory neurotransmission, both in vivo and in vitro, [7][8][9][10][11][12] although it has not, as yet, been shown to bind to any known receptor. It has been hypothesized that riluzole may antagonize glutamatergic transmission via an interaction with voltage-dependent sodium channels or with Gproteins.…”

Section: Introductionmentioning

confidence: 96%

The Rilutek ® (riluzole) Global Early Access Programme: An open-label safety evaluation in the treatment of amyotrophic lateral sclerosis

Debove¹,

Zeisser²,

Salzman³

et al. 2001

Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders

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“…1), 2-amino-6-trifluoromethoxybenzothiazole, is an anti-glutamatergic agent, which was found to be protective in several models of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) [1], multiple sclerosis (MS) [2], Parkinson's disease (PD) [3], and ischemia [4]. Riluzole was demonstrated to modulate the anti-glutamatergic activity through glutamate and sodium receptors.…”

Section: Introductionmentioning

confidence: 98%