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Vol. 282, Issue 2, 707-714, 1997
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois
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Abstract |
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 Top
Abstract
Introduction
Methods
Results
Discussion
References
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The effects of riluzole, a neuroprotective drug, on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channels in rat dorsal root ganglion neurons were studied using the whole-cell patch clamp technique. At the resting potential, riluzole preferentially blocked TTX-S sodium channels, whereas at more negative potentials, it blocked both types of sodium channels almost equally. The apparent dissociation constants for riluzole to block TTX-S and TTX-R sodium channels in their resting state were 90 and 143 µM, respectively. Riluzole shifted the voltage dependence of activation of TTX-R sodium channels in the depolarizing direction more than that of TTX-S sodium channels. The voltage dependence of the fast inactivation of both types of sodium channels was shifted in the hyperpolarizing direction in a dose-dependent manner, and the apparent dissociation constants for riluzole to block the inactivated channels were estimated to be 2 and 3 µM for the TTX-S and TTX-R sodium channels, respectively, indicating a much higher affinity for the inactivated channels than for the resting channels. Riluzole was equally effective in blocking both types of sodium channels in their slow inactivated state. Since more TTX-S channels are inactivated than TTX-R channels at the resting potential, riluzole blocks TTX-S sodium channels more potently than TTX-R sodium channels. It was concluded that one of the mechanisms by which riluzole exerts its neuroprotective action is to preferentially block the inactivated sodium channel of damaged or depolarized neurons under ischemic conditions, thereby suppressing excess stimulation of the glutamatergic receptors and massive influx of Ca++.
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Introduction |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Riluzole
is a neuroprotective drug that has antiischemic, sedative and
antiepileptic properties (Malgouris et al., 1989
; Romettino et al., 1991; Pratt et al., 1992; Bryson et
al., 1996), and is effective in slowing the progression of
amyotrophic sclerosis (Bensimon et al., 1994; Couratier
et al., 1994; Bryson et al., 1996). Riluzole is
thought to exert its neuroprotective effects by blocking both
voltage-gated sodium channels and NMDA-receptor-mediated responses
thereby preventing excess calcium influx into neurons (Hubert et
al., 1994; Malgouris et al., 1994). Various other
sodium channel blocking agents such as phenytoin, carbamazepine and
lamotrigine are known to protect neurons from cerebral ischemia,
hypoxia or head trauma (Taylor and Meldrum, 1995). Riluzole inhibits
the glutamate-induced release of aspartate from cerebellar granule cells via a pertussis toxin-sensitive GTP-binding protein, and reduces
the release of glutamate in caudate nucleus and hippocampal slices
(Cheramy et al., 1992; Doble et al., 1992; Martin
et al., 1993). Riluzole does not interact with any of the
known ligand recognition sites on either kainate or NMDA receptor in
radioligand binding studies, but blocks the activity of these
receptor-channels in a noncompetitive manner (Debono et al.,
1993).
The effects of riluzole in blocking sodium channel currents have been
found in frog nodes of Ranvier and cloned rat brain IIA sodium channel
subunits expressed in Xenopus oocytes (Benoit and
Escande, 1991; Hebert et al., 1994). In these preparations, riluzole specifically blocks inactivated sodium channels without affecting the time course of inactivation nor the current-voltage relationship.
Most sodium channels can be blocked by TTX with a
Kd ranging from 1 to 10 nM. The sodium channels
that are resistant to TTX block have been found in various tissues and
in different animal species (see review by Yoshida, 1994). DRG neurons
are endowed with both TTX-S and TTX-R sodium channels (Kostyuk et
al., 1981; Roy and Narahashi, 1992; Elliott and Elliott, 1993;
Ogata and Tatebayashi, 1993). Besides their differences in TTX
sensitivity, they differ in pharmacological profiles. For example,
TTX-R channels are less sensitive to lidocaine, but much more sensitive
to lead, cadmium and pyrethroid insecticides than are TTX-S channels
(Roy and Narahashi, 1992; Tatebayashi and Narahashi, 1994). These two types of sodium channels exhibit different activation and inactivation kinetics as well. Notably, TTX-R sodium channels have slower kinetics of activation and inactivation and activate and inactivate at more
positive potentials than TTX-S sodium channels.
Our study was undertaken to examine the differential effect of riluzole on TTX-S and TTX-R sodium channels using rat DRG neurons as a model. This preparation was chosen because the differential sensitivity of TTX-S and TTX-R sodium channels to riluzole provided us with an excellent model with which detailed mechanisms of action of riluzole could be elucidated. Riluzole has a much higher affinity for channels in the inactivated state than in the resting state of either TTX-S or TTX-R sodium channels. This difference in affinity accounts for the higher potency of riluzole to block TTX-S sodium channels than TTX-R sodium channels as TTX-S sodium channels are inactivated more at resting membrane potentials than TTX-R sodium channels.
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Material and Methods |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Cell preparations.
DRG neurons were isolated as described
previously (Roy and Narahashi, 1994; Tatebayashi and Narahashi, 1994).
Rats (2-6 days postnatal, either sex) were anesthetized with
methoxyflurane and the spinal column was removed and cut
longitudinally. Ganglia were plucked from between the vertebrae of the
spinal column, and incubated in phosphate-buffered saline solution
(GIBCO BRL, Grand Island, NY) containing trypsin (2.5 mg/ml, type XI,
Sigma Chemical Co., St. Louis, MO) at 37°C for 25 min. After enzyme treatment, ganglia were rinsed with Dulbecco's modified Eagle medium
(GIBCO BRL) supplemented with newborn calf serum (10%, v/v, GIBCO BRL)
and gentamicin (80 µg/ml, Northwestern University Lurie Cancer
Center). Single cells were mechanically dissociated with a
fire-polished Pasteur pipette and plated on
poly-L-lysine-coated glass coverslips. Cells were incubated
for 2 to 7 hr before patch clamp experiments.
Electrophysiological recording.
Currents were recorded using
the whole-cell patch clamp technique (Hamill et al., 1981).
Suction pipettes (0.6-1.2 M
) were made of borosilicate glass
capillary tubes (1.5-1.8 mm inner diameter, Kimble, Vineland, NJ)
using a two-step vertical puller (Narishige, Tokyo, Japan). The pipette
solution contained (in mM): CsF 135, NaCl 10 and HEPES 5. The pH was
adjusted to 7.0 with CsOH and the osmolarity was 275 mOsmol. The
external solution contained (in mM): NaCl 25, tetramethylammonium
chloride 75, tetraethylammonium chloride 20, CsCl 5, CaCl2
1.8, MgCl2 1.0, D-glucose 25, HEPES-acid 5. Lanthanum (LaCl3, 3 µM) was used to block calcium channel
current. The solution was adjusted to pH 7.4 with tetraethylammonium-OH and 290 mOsmol with sucrose. An Ag-AgCl pellet/3M KCl-agar bridge was
used for the reference electrode. Membrane currents were recorded using
an Axopatch 200 amplifier (Axon Instruments, Foster City, CA). Signals
were digitized by a 14-bit analog-to-digital converter, filtered with a
Bessel filter at 5 kHz and stored on a PDP 11/73 computer (Digital
Equipment Corporation, Pittsburgh, PA). Series resistance was
compensated 70 to 75%. Capacitative and leakage currents were
digitally subtracted by using the P + P/4 procedure (Bezanilla and
Armstrong, 1977). The liquid junction potential between internal and
external solution was 
4.7 mV on average. Our data shown in this paper
were compensated for the liquid junction potential. All experiments
were performed at 22 to 24°C.
Data analysis. Results are expressed as means ± S.E.M., and n represents the number of the cells examined. All figures represent typical examples from at least four independent experiments. Analyses of currents were achieved by using REV, a locally developed FORTRAN/IV program on the PDP 11/73 computer and SigmaPlot (Jandel Scientific, San Rafael, CA) on PC.
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Results |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Effects of riluzole on sodium channel currents.
As has been
reported previously, two types of sodium channels were found in rat DRG
neurons (Kostyuk et al., 1981; Roy and Narahashi, 1992;
Elliott and Elliott, 1993; Ogata and Tatebayashi, 1993). TTX-S sodium
currents activated and inactivated quickly and were completely blocked
by 200 nM TTX, whereas the TTX-R sodium currents activated and
inactivated slowly and were not blocked by 200 nM TTX. When the
membrane was held at 80 mV, which was near the resting membrane
potential (Song and Narahashi, 1995), TTX-S sodium currents were more
sensitive to the blocking action of riluzole than TTX-R sodium
currents. At 3 µM, riluzole blocked 50% of the TTX-S sodium current
(fig. 1Aa), whereas it took 30 µM for
riluzole to produce a similar block of the TTX-R sodium currents (fig.
1Ab). Both types of sodium currents were blocked within 3 min after
bath application of the drug and the currents recovered within a few
minutes after washout with drug-free external solution. When the peak
current amplitude in the presence of riluzole was normalized to the
control value, the activation and inactivation kinetics were not
changed by riluzole in TTX-S sodium current (fig. 1Ba), whereas the
time course of inactivation of TTX-R sodium current was greatly
accelerated by riluzole (fig. 1Bb).
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;
Tatebayashi and Narahashi, 1994). Because the steady-state inactivation
for TTX-S sodium channels occurs at more negative potentials than that
for TTX-R sodium channels, and because riluzole is known to have a
higher affinity for the inactivated state than for the resting state of
TTX-S sodium channels in other preparations (Benoit and Escande, 1991;
Hebert et al., 1994), the apparent difference in the potency
of riluzole block of TTX-S and TTX-R sodium channels in DRG neurons
could be due to their different inactivation characteristics.
To examine this hypothesis, the membrane was held at large negative
potentials, i.e., 120 mV for TTX-S and 100 mV for TTX-R channels. Under these conditions, riluzole blocked both types of sodium
channels to almost the same degree (figs.
2A and 3A). Riluzole had no effect on the time course of TTX-S sodium currents evoked at 0 mV, as evidenced from superimposed currents in the presence
and absence of drug (fig. 2Bb). These results suggest that riluzole
does not alter either activation or inactivation of TTX-S sodium
channel currents at 0 mV (fig. 2Bb). However, it slightly accelerated
the inactivation time course of TTX-S sodium currents at 20 mV (fig.
2Ba). The time course of TTX-R sodium currents was greatly accelerated
by riluzole at all membrane potentials tested; this effect was more
pronounced at negative potentials than at positive potentials (fig.
3Ba, b and c). The small outward currents seen in riluzole (fig. 3, a
and b) may de due to an artifact of the P+P/4 procedure since the
potassium channel was blocked by internal cesium.
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Effect of riluzole on the time constant of inactivation.
The
decay of sodium currents was fitted to a single exponential function
and the time constants are plotted as a function of membrane potential
in figure 4. In TTX-S sodium channels,
riluzole reduced the time constant of inactivation at potentials more
negative than 25 mV but had little or no effect at potentials more
positive than 25 mV (fig. 4A).
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Effects of riluzole on the kinetics of sodium channel
activation.
Effects of riluzole on the current-voltage
relationship and the conductance-voltage curve are illustrated in
figure 5 for TTX-S sodium channels and
figure 6 for TTX-R sodium channels. As can be seen from the
current-voltage curve, riluzole blocked TTX-S sodium currents to the
same degree in the entire membrane potential range (fig. 5A). The
membrane potential corresponding to half-maximum conductance
(Vg0.5) was 27.9 ± 1.4 mV
(n = 4) for TTX-S channels. Riluzole at 30 and 100 µM
shifted Vg0.5 of TTX-S channels by 1.3 ± 1.5 and 5.0 ± 1.8 mV (n = 4), respectively, in
the depolarizing direction (fig 5B; table
1). The slope factor (kg) for
the conductance-voltage curve was increased by riluzole or the slope
became less steep after application of riluzole (table 1).
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16.6 ± 1.3 mV (n = 4). Riluzole at 30 and 100 µM shifted Vg0.5 by 8.7 ± 0.1 and
18.5 ± 0.1 mV (n = 4), respectively, in the
depolarizing direction (fig. 6B, table 1). The slope factor (kg) for the conductance-voltage curve was also affected by
riluzole, becoming larger (table 1).
The apparent dissociation constant for riluzole block of sodium
channels in the resting state.
To estimate the apparent
dissociation constant for riluzole to block sodium channels in the
resting state (KR), the membrane was held at
120 mV for TTX-S sodium channels and 100 mV for TTX-R sodium
channels. At these potentials sodium channel inactivation was
completely removed. To minimize errors due to the shift in conductance-voltage curve by riluzole, currents were elicited by
depolarizing steps to +50 mV for both types of sodium channels to
elicit the maximum conductance. The percentage of current inhibition is
plotted as a function of riluzole concentration in figure
7. The dose-response data were fitted to
the Hill equation with KR values of 90 and 143 µM, and Hill coefficients of 1.12 and 1.15, for the TTX-S and TTX-R
sodium channels, respectively.
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Effects of riluzole on the fast sodium channel inactivation.
The effects of riluzole on the fast steady-state inactivation curves of
both TTX-S and TTX-R sodium channels are shown in figure
8. Prepulses of 150-msec duration were
used. Riluzole greatly shifted the inactivation curves of both types of
sodium channels in the hyperpolarizing direction. In control
experiments, the half-maximum inactivation potential
(Vh0.5) was estimated to be 61.2 ± 2.2 mV for TTX-S channels and 27.3 ± 1.0 mV for TTX-R channels
(n = 4). Riluzole shifted the curve in the
hyperpolarizing direction, with a greater shift occurring in TTX-S
channels than TTX-R channels at the same concentration of riluzole.
However, riluzole did not change the slope factor, kh, in
either type of sodium channels. The riluzole-induced changes in
parameters of sodium channel inactivation are given in table
2.
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The apparent dissociation constant for riluzole block of sodium
channels in the inactivated state.
The apparent dissociation
constant for riluzole to block sodium channels in the inactivated
state, KI, was estimated from KR and the shift in
Vh0.5. As shown in figure
9, the shift in Vh0.5 is plotted as a function of riluzole
concentration. The data are plotted along with three lines with
different parameters according to the equation,
Vh0.5 = khln{(1 + [RZ]/KR)/(1 + [RZ]/KI)} (Bean et al., 1983).
Curves were best fitted when KI values for TTX-S
and TTX-R sodium channels are 2.0 and 3.0 µM, respectively. Thus,
compared to the resting state, riluzole has a much higher affinity for
the inactivated state of both types of sodium channels.
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Effect of riluzole on the slow steady-state inactivation of sodium
channels.
To examine whether different inactivation states of
sodium channels affects the riluzole's effect, long pre-pulse duration (20 sec) was given to measure the slow inactivation. In the absence of
riluzole, Vh0.5 was estimated to be 77.0 ± 1.8 mV (n = 6) and 47.6 ± 1.3 mV
(n = 5) for TTX-S and TTX-R sodium channels, respectively. These values were 16 and 20 mV more negative for TTX-S
and TTX-R channels, respectively, than those of fast inactivation using
150 msec prepulse. Vh0.5 was shifted by
8.5 ± 1.0 mV (n = 6) by 3 µM riluzole in
TTX-S channels and 15.6 ± 0.7 mV by 30 µM riluzole in TTX-R
channels (fig. 10; table 2). Both
shifts were comparable to those obtained for fast inactivation curve.
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Discussion |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Our study demonstrated that riluzole at low concentrations preferentially blocked both TTX-S and TTX-R sodium channels of rat DRG neurons in their inactivated state although it had much less effect on the channels in the resting state. Riluzole blocked both TTX-S and TTX-R sodium channels to nearly the same extent under the experimental conditions where the inactivation of two types of channels was minimal.
The apparent dissociation constants for riluzole to block sodium
channels in their resting states were estimated to be 90 and 143 µM
for the TTX-S and TTX-R sodium channels, respectively. These values are
in the same order of magnitude as those previously reported. In frog
nodes of Ranvier and rat brain IIA sodium channel -subunits
expressed in Xenopus oocytes, KR
values were estimated to be 90, and 30 µM, respectively (Benoit and
Escande, 1991; Hebert et al., 1994).
Riluzole shifted the steady-state inactivation curves to the same
extent with either 150 msec or 20 sec prepulse. Therefore, riluzole
does not distinguish between the fast and slow inactivated states of
sodium channels, and blocks both inactivated states almost equally. The
apparent dissociation constants for riluzole to block the sodium
channels in the fast inactivated state were estimated from the
concentration-dependent shift in the steady-state inactivation curve.
The KI values were 2 and 3 µM for the TTX-S and TTX-R sodium channels, respectively. These values are considerably smaller than those for blocking the resting channels. However, our
estimates of the KI values are almost 10 times
larger than those previously reported in other preparations (Benoit and
Escande, 1991; Hebert et al., 1994).
Inasmuch as riluzole does not exhibit much difference in blocking TTX-S
and TTX-R sodium channels at either resting or inactivated state, how
can one explain the differential block of TTX-S and TTX-R channels by
riluzole near the resting membrane potential? When the membrane is held
at 80 mV, 61% of TTX-S channels and 95% of TTX-R channels are
available for activation (fig. 10). More TTX-S channels are in the
inactivated state than the TTX-R channels. Thus, riluzole
preferentially blocks the TTX-S sodium channels. Because the resting
membrane potential of DRG neurons with either type of sodium channels
is around 80 mV (Song and Narahashi, 1995), it is expected that TTX-S
sodium channels experience more block than TTX-R sodium channels by the
same concentration of riluzole. The percentage of riluzole block of
sodium channels at a given membrane potential can be estimated from the
following equation (Hebert et al., 1994):
![[1-(I<SUB>RZ</SUB>/I<SUB>control</SUB>)]<IT>×100</IT>](/content/vol282/issue2/fulltext/707/img001.gif)
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![<IT>=100/</IT>{<IT>1+</IT>(<IT>h<SUB>∞</SUB>×</IT>[RZ]<IT>/K</IT><SUB><IT>R</IT></SUB>)<IT>+</IT>[(<IT>1−</IT>h<SUB><IT>∞</IT></SUB>)<IT>×</IT>[RZ]<IT>/K</IT><SUB><IT>I</IT></SUB>]}](/content/vol282/issue2/fulltext/707/img002.gif)
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is the availability of sodium channels for
activation at a given membrane potential, and [RZ] is the
concentration of riluzole. At the resting membrane potential of 80
mV, riluzole at 10 and 30 µM blocks 67 and 86% of TTX-S sodium
channels, respectively, although the same concentrations of riluzole
block only 19 and 41% of TTX-R sodium channels, respectively.
Riluzole greatly accelerated the time course of inactivation of sodium
channels in rat DRG neurons especially in TTX-R sodium channels. This
is a unique phenomenon because it is not observed in the TTX-S sodium
channels in DRG neurons, frog nodes of Ranvier, or rat brain IIA sodium
channel subunit expressed in Xenopus oocytes (Benoit and
Escande, 1991; Hebert et al., 1994). The voltage dependence
of inactivation time constant of TTX-R sodium channels appears to be
shifted in the hyperpolarizing direction by riluzole. However, the
difference between the effects on the two types of channels may arise
from the differences in the inherent voltage dependence of the
channels.
Another difference between two types of sodium channels was found with
respect to the riluzole effect on the sodium channel activation.
Riluzole shifted the conductance-voltage curves for both TTX-S and
TTX-R sodium channels in the depolarizing direction. However, the
degree of shift was far greater for TTX-R sodium channels than for
TTX-S sodium channels. Also the conductance curves became less steep
after riluzole treatment and the effect was more pronounced in TTX-R
sodium channels. The effects of riluzole on the sodium channel
activation kinetics were not observed in other preparations (Benoit and
Escande, 1991; Hebert et al., 1994).
Ischemic conditions will cause gradual depolarization of neuronal
membranes evoking repetitive discharges and glutamate release from
nerve terminals that in turn stimulate the NMDA receptors. Massive
calcium influx will ensue through the open NMDA receptor channels
causing cell death. Because riluzole blocks the sodium channels much
more potently in the inactivated state than in the resting state, it
will effectively suppress the sodium channel activity and action
potentials in the ischemic conditions, preventing cell death. Riluzole
block of high voltage-gated N-type and P/Q-type calcium channels (Huang
et al., 1996, submitted for publication) and the NMDA
receptor (Debono et al., 1993) also contributes to neuroprotective activity. It should be noted that the plasma
concentration of riluzole in healthy human volunteers is estimated to
be 1.62 µM 1 hr after administration of 100 mg riluzole, a usual dose (Bryson et al., 1996). This plasma concentration is in the
same order of magnitude as the apparent dissociation constants of
riluzole to block the TTX-S and TTX-R sodium channels in their
inactivated state that are estimated to be 2 and 3 µM, respectively.
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Acknowledgments |
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The authors thank Julia Irizarry for secretarial assistance.
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Footnotes |
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Accepted for publication April 16, 1997.
Received for publication October 14, 1996.
1 This study was supported by National Institutes of Health Grant NS-14144.
Send reprint requests to: Dr. Toshio Narahashi, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611-3008.
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Abbreviations |
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TTX-S, tetrodotoxin-sensitive;
TTX-R
tetrodotoxin-resistant, NMDA, N-methyl-D-asparate;
DRG, dorsal root ganglion;
HEPES, N-2-hydroxyethylpiperazine-N
-2-ethanesulfonic acid;
DMSO, dimethylsulfoxide;
RZ, riluzole;
GTP, guanosine 5-triphosphate.
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References |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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subunit by the neuroprotective drug riluzole.
Mol. Pharmacol.
45: 1055-1060, 1994[Abstract].-tocopherol (vitamin E).
J. Pharmacol. Exp. Ther.
275: 1402-1411, 1995This article has been cited by other articles:
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) and presence of 30 µM (
) or 100 µM (
) riluzole are
plotted as a function of test potentials. A, TTX-S sodium channels.
Currents were evoked by 10-msec step depolarizations to various levels (ranging from 
). Currents were
evoked by 10-msec depolarizing steps to various levels from a holding potential of 
