Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes)
Section snippets
Materials
Fura-2-acetoxymethyl ester and DiSC3(5) were obtained from Molecular Probes (Eugene, OR, USA). Percoll was obtained from Pharmacia. Riluzole was obtained from Tocris Cookson (Bristol, USA). Glutamate dehydrogenase and all other reagents were obtained from Sigma (Poole, UK) or Merck (Poole, UK).
Synaptosomal preparation
Synaptosomes were purified as described previously (Sihra, 1997). Briefly, the cerebral cortex from 2-month-old male Sprague–Dawley rats was isolated and homogenised in a medium containing 320 mM sucrose,
Results
Glutamate release from purified cerebrocortical synaptosomes was monitored on-line continuously using an assay employing exogenous GDH and NADP+ to couple the oxidative deamination of released glutamate to the generation of NADPH, which is detected fluorometrically (Nicholls et al., 1987). Under synaptosomes incubated in the presence of 1 mM CaCl2, the release of glutamate evoked by 3 mM 4AP, a potassium channel blocker that opens voltage-gated Ca2+ channels and induces the release of vesicular
Discussion
Riluzole is primarily used clinically in the treatment of ALS, where glutamate damage is considered as a major pathogenetic factor. Thus, it prompted us to focus on this neurotransmitter in the present study. The results of the present study demonstrate that riluzole inhibits glutamate release from rat cerebrocortical nerve terminals possibly by reducing Ca2+ influx through P/Q-type Ca2+ channels, and that the activation of a pertussis toxin-sensitive G protein is involved in this effect.
Acknowledgements
This work was supported by the National Science Council of Taiwan, Republic of China (NSC 92-2320-B-030-005).
References (53)
- et al.
Inhibition of N-, P/Q- and other types of calcium channels in rat hippocampal nerve terminals by the adenosine A1 receptors
Eur J Pharmacol
(1997) - et al.
Riluzole inhibits the release of glutamate in the caudate nucleus of the cat in vivo
Neurosci Lett
(1992) Glutamate neurotoxicity and diseases of the nervous system
Neuron
(1988)- et al.
Pertussis toxin pretreatment abolishes the inhibitory effect of riluzole and carbachol on d-[3H]aspartate release from cultured cerebellar granule cells
Neurosci Lett
(1992) - et al.
A new generation of Ca2+ indicators with greatly improved fluorescence properties
J Biol Chem
(1985) - et al.
Presynaptic Ca-antagonist omega-conotoxin irreversibly blocks N-type Ca-channels in chick sensory neurons
Neurosci Res
(1987) - et al.
Therapeutic advances in amyotrophic lateral sclerosis
Trends Pharmacol Sci
(1997) - et al.
Neuroprotective effects of riluzole on N-methyl-d-aspartate- or veratridine-induced neurotoxicity in rat hippocampal slices
Neurosci Lett
(1994) - et al.
Involvement of class A calcium channels in the KCl induced Ca2+ influx in hippocampal synaptosomes
Brain Res
(1995) - et al.
The neuroprotective agent riluzole inhibits release of glutamate and aspartate from slices of hippocampal area CA1
Eur J Pharmacol
(1993)
P-type calcium channels in rat central and peripheral neurons
Neuron
Selective depression of low-release probability excitatory synapses by sodium channel blockers
Neuron
Lymphocyte membrane potential assessed with fluorescent probes
Biochim Biophys Acta
Presynaptic potassium channels
Curr Opin Neurobiol
Definition of the readily releasable pool of vesicles at hippocampal synapses
Neuron
Presynaptic inhibition of miniature excitatory synaptic currents by baclofen and adenosine in the hippocampus
Neuron
Localized Ca2+ entry preferentially effects protein dephosphorylation, phosphorylation, and glutamate release
J Biol Chem
Differential inhibition by riluzole, lamotrigine, and phenytoin of sodium and calcium currents in cortical neuronsImplications for neuroprotective strategies
Exp Neurol
Pharmacological characterization of presynaptic calcium channels using subsecond biochemical measurements of synaptosomal neurosecretion
Neuropharmacology
Cannabinoid CB1 receptor-mediated inhibition of glutamate release from rat hippocampal synaptosomes
Eur J Pharmacol
Riluzole
Lancet
Modulation of calcium uptake and d-aspartate release by BABAB receptors in culture cerebellar granule cells
Eur J Pharmacol
Riluzole interacts with voltage-activated sodium and potassium currents in cultured rat cortical neurons
Neuroscience
Ionic dependence of membrane potential and glutamate receptor-linked responses in synaptoneurosomes as measured with a cyanine dye, DiS-C2-(5)
J Neurochem
A controlled trial of riluzole in amyotrophic lateral sclerosisAls/riluzole study group
N Engl J Med
A synaptic model of memoryLong-term potentiation in the hippocampus
Nature
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