Riluzole interacts with voltage-activated sodium and potassium currents in cultured rat cortical neurons
Section snippets
Cell culture
Experiments were performed on neocortical neurons removed from 14 day Wistar rat embryos (Morini, Reggio Emilia, Italy) and grown in dissociated cell culture as described previously.6, 7Briefly, the animals were killed by decapitation under ether anaesthesia. Experiments were performed at 21–23°C, on neocortical neurons cultured for 12–16 days in Eagle's minimum essential medium (Gibco) with 5% rat serum, 6 mM of glucose, 2 mM of glutamine, and 100 μg/ml of gentamicine (Gibco). For more details,
Voltage-activated Na+ currents
In a first series of experiments, Ca2+ and K+ currents were pharmacologically blocked by extracellular application of Cd2+ and 4-AP as well as by the addition of Cs+ and TEA in the recording electrode. Under this experimental condition, depolarizing voltage commands from a holding potential of −80 mV elicited a voltage-dependent inward current (Fig. 1A) sensitive to TTX (complete block with 0.5 μM; data not illustrated). This inward Na+ current was maximally activated by a test pulse at −20 mV and
Discussion
Our findings have shown that riluzole induces multiple effects on voltage-activated currents in cultured rat cortical neurons. In fact. this drug causes: (i) a reversible and dose-dependent decrease of the Na+ current; (ii) a negative shift of the steady-state inactivation curve for the Na+ currents; (iii) a reversible and concentration-dependent reduction of the late K+ current. It is also worth mentioning that riluzole does not affect the fast transient outward currents, the voltage-dependent
Conclusions
The reduction of the Na+ current in cortical neurons and the shift of the steady-state inactivation Na+ curve might be related to the clinical effectiveness of riluzole as neuroprotectant. In fact, a depression of the voltage-activated Na+ current certainly reduces an excessive increase in cellular excitability and an enhanced release of excitatory amino acids.[23]These mechanisms might contribute to spare energy consumption and to preserve the ionic milieu during conditions of altered neuronal
Acknowledgements
The authors thank R. Sorge for the help in the statistical analysis and G. Gattoni and M. Federici for their excellent technical assistance.
References (29)
- et al.
2-Amino-6-trifluoromethoxy benzothiazole. A possible antagonist of excitatory amino acid neurotransmission II
Neuropharmacology
(1985) - et al.
Riluzole inhibits the release of glutamate in the caudate nucleus of the cat in vivo
Neurosci. Lett.
(1992) - et al.
Inhibition by riluzole of electrophysiological responses mediated by rat kainate and NMDA receptors expressed in Xenopus oocytes
J. Pharmac.
(1993) Rat cortical neurons in cell culture: culture methods, cell morphology, electrophysiology and synapse formation
Brain Res.
(1978)- et al.
Calcium currents in cultured rat cortical neurons
Brain Res.
(1989) - et al.
Pertussis toxin pretreatment abolishes the inhibitory effect of riluzole and carbachol on d-aspartate release from cultured cerebellar granule cells
Neurosci. Lett.
(1992) - et al.
Ibotenic acid stimulates d-H-aspartate release from cultured cerebellar granule cells
Neurosci. Lett.
(1989) - et al.
The neuroprotective agent riluzole inhibits release of glutamate and aspartate from slices of hippocampal area CA1
Eur. J. Pharmac.
(1993) - et al.
Riluzole prevents hyperexcitability produced by mast cell degranulating peptide and dendrotoxin I in the rat
Eur. J. Pharmac.
(1991) - et al.
Na+ channels as targets for neuroprotective drugs
Trends pharmac. Sci.
(1995)
State-dependent inhibition of Na+ currents by the neuroprotective agent 619C89 in rat hippocampal neurons and in a mammalian cell line expressing rat brain type IIA Na+ channels
Neuroscience
Delayed and fast transient potassium currents in rat neocortical neurons in cell culture
Neurosci. Lett.
Riluzole specifically blocks inactivated Na channels in myelinated nerve fibre
Eur. J. Physiol.
A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group
N. Engl. J. Med.
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