Kainate-induced currents in rat cortical neurons in culture are modulated by riluzole.
The action of the neuroprotective and anticonvulsant agent riluzole on kainate-induced currents was studied in rat cortical neurons in primary culture by using the whole-cell configuration of the patch-clamp technique. Kainate elicited macroscopic, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-sensitive inward currents in all the patched cells and the amplitude of the current was concentration-dependent (EC50= 106 microM). Riluzole decreased the inward currents induced by 100 microM kainate at all holding potentials and the reduction was dose-dependent (IC50= 101 microM). The maximal response to kainate decreased in the presence of 50 microM riluzole, without changing its EC50, indicating a noncompetitive mechanism of inhibition. The amplitude of the responses induced by kainate under control conditions and during riluzole was a linear function of the membrane potential and the reversal potential of the currents was not significantly different in the two experimental conditions. Instead, the total conductance of the cell membrane for the currents induced by 100 microM kainate was significantly reduced in the presence of 50 microM riluzole (P < 0.05). The analysis of the kainate membrane current noise performed under control conditions and during perfusion of 100 microM riluzole revealed that riluzole reduced the probability of kainate-activated ionic channels to be in the open state. Conversely, the unitary conductance of channels, as well as their characteristic time constant, seemed to be unchanged. These results reveal an additional mechanism by which riluzole can interact with glutamatergic neurotransmission and provides further support for the idea that riluzole may prove beneficial in the treatment of central nervous system injuries involving the excitotoxic actions of glutamate.
Zona
Cristina
C
Fisiologia Umana, Università degli Studi di Roma "Tor Vergata," 00133 Rome, Italy. zona@med.uniroma2.it
Cavalcanti
Silvio
S
De Sarro
Giovanbattista
G
Siniscalchi
Antonio
A
Marchetti
Caterina
C
Gaetti
Chiara
C
Costa
Nicola
N
Mercuri
Nicola
N
Bernardi
Giorgio
G
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005333:Fetus; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects* / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000187:drug effects* / Q000378:metabolism; D019782:Riluzole / Q000494:pharmacology*
D018690:Excitatory Amino Acid Agonists; D007473:Ion Channels; D007608:Kainic Acid; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D019782:Riluzole