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NEUROPHARMACOLOGY
CNS/CV Biological Research, Schering-Plough Research Institute, Kenilworth, New Jersey
Received for publication
February 28, 2003
Accepted
April 22, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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3-fold increase
in vinpocetine potency when whole-cell NaV1.8 conductances were
elicited from relatively depolarized potentials (–35 mV; IC50
= 3.5 µM) compared with hyperpolarized holding potentials (–90 mV;
IC50 = 10.4 µM). Vinpocetine also produced an 22 mV
leftward shift in the voltage dependence of NaV1.8 channel
inactivation but did not affect the voltage range of channel activation. These
properties are reminiscent of several other known sodium channel blockers and
suggested that vinpocetine may exhibit frequency-dependent block. Accordingly,
tonic block of NaV1.8 channels by vinpocetine (3 µM) increased
proportionally with increasing depolarizing commands over the frequency range
0.1 to 1Hz. In summary, the present data demonstrate that vinpocetine is
capable of blocking NaV1.8 sodium channel activity and suggest a
potential additional utility in various sensory abnormalities arising from
abnormal peripheral nerve activity.
). This somewhat promiscuous pharmacology has led to the
justifiable classification of vinpocetine as a "nootropic", an
aptly vague terminology given the lack of a clear mechanism of action.
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Despite the somewhat nonselective pharmacological profile, vinpocetine is
claimed to be remarkably devoid of major side effects at clinically used
dosages (Anonymous, 2002). A
number of studies have indicated, clearly, that vinpocetine achieves good
brain exposure after systemic administration
(Bonoczk et al., 2002;
Gulyas et al., 2002), and it
is reasonable to assume that all of the above-mentioned actions may contribute
to a therapeutic neuroprotective effect. The significance of the ion channel
blocking effect of vinpocetine, particularly in respect to a sodium channel
action, is supported by an anticonvulsant action in rodent seizure models
(Schmidt, 1990) and from a
comparative study using the established anticonvulsant drug phenytoin
(Molnar and Erdo, 1995). In
addition to their clinical utility in the prevention of epileptiform seizures,
anticonvulsants have found favor as a therapeutic approach to the management
of certain pain states (Hunter and
Loughhead, 1999; Dickenson et
al., 2002). There is mounting evidence
(Hunter and Loughhead, 1999;
Devor, 2001) to support a
fundamental role for ectopic, epileptiform-like burst firing in peripheral
nerves as a substrate for paroxysmal pains often described as
"stabbing" or "electric-shock-like." Peripheral nerve
axons express a mixed complement of sodium channel isoforms, one of which is a
TTX-insensitive conductance mediated by NaV1.8
(Hunter and Loughhead, 1999).
Although there is an ongoing debate over the relevant roles of various sodium
channel activities in generating and sustaining chronic pain states, several
studies have indicated a prominent role for NaV1.8
(Lai et al., 2000;
Lai et al., 2002;
Gold et al., 2003). This study
was designed to address the effects of vinpocetine on recombinant rat
NaV1.8 sodium channels expressed in a clonal cell line (ND7/23,
derived from a dorsal root ganglion progenitor;
Wood et al., 1990), the data
suggest a potential additional utility of the drug as an antinociceptive for
use in neuropathic pain states.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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).
The oligonucleotide sequences were as follows: 5'-ATGGAGCTCCCCTTTGCGTCC
and 5'-TCACTGAGGTCCAGGGCTGTT. Clones were sequence verified on an
ABI3700 DNA sequencer with Big Dye Terminators version 2.0 (Applied
Biosystems, Foster City, CA). The full-length coding sequence was inserted
into the retroviral expression vector pMX for cloning. For all whole-cell voltage-clamp experiments, a transient expression strategy was adopted that involved the cotransfection of rNaV1.8 and green fluorescent protein (GFP) cDNAs, the latter was used as a marker gene to identify successfully transfected cells within a given population. ND7/23 cells were bulk cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum and 1% penicillin and 1% streptomycin. Transfections were performed weekly, cells were seeded into six-well culture plates at a density of 500 K/well and allowed 24 h to attach. A transfection mixture (100 µl) containing FuGENE-6 (3 ml in 100 ml of serum-free DMEM; Invitrogen) and cDNA vectors (pcDNA3.1) containing coding sequences for GFP (0.5 µg) and rNaV1.8 (0.5 µg), was added to each well. After 24-h incubation, the cells were resuspended in fresh DMEM and seeded, at a density of 50 K, on poly-L-lysine-coated coverslips for subsequent electrophysiological recordings.
Whole-Cell Voltage-Clamp Recordings. All whole-cell patch-clamp recordings were carried out 48 to 72 h post-transfection; experiments were conducted at room temperature (19–21°C). At the time of the experiment, an individual coverslip was removed from the culture plate and placed into a perfusion chamber mounted on the stage of an inverted phase-contrast microscope equipped with fluorescence optics. The cells were continuously perfused with a salt solution of the following composition: 129 mM NaCl, 3.2 5 mM KCl, 2 mM CaCl2, 2 mM MgCl2, 10 mM HEPES, 11 mM D-glucose, and 20 mM tetraethylammonium-Cl, pH 7.4, 345 mOsM. Conventional whole-cell voltage-clamp electrophysiology was used to record voltage-activated currents; patch electrodes contained a solution of the following composition: 120 mM CsF, 10 mM NaCl, 10 mM HEPES, 11 mM EGTA, 10 mM tetraethylammonium-Cl, 1 mM CaCl2, and 1 mM MgCl2, pH 7.3, 325 mOsM. Cells were viewed briefly using a fluorescence microscope (fluorescein isothiocyanate filter set) and were selected on the basis of their relative fluorescence intensity. In all experiments, membrane potential was held at –90 mV between voltage command protocols. Drugs were applied by bath perfusion. Data were acquired online (sampling frequency 10 kHz, filtered at 2 kHz) using an Axopatch 200B amplifier and pCLAMP 8.0 software (Axon instruments, Inc., Foster City, CA). Series resistance (80%) and capacitance currents were electronically compensated.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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23% inhibition
at 30 µM, n = 6, comparable with data obtained by
Akopian et al., 1996), the fact
that we never observed similar TTXr currents in wt cells strongly suggests
that the TTXr conductance was, indeed, sodium channel-mediated.
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Effect of Vinpocetine on rNaV1.8 Activation. Voltage-current relationships were established for rNaV1.8 channels by measuring peak current amplitude at various destination command voltages from a holding voltage of –90 mV. Perfusion of vinpocetine (30 µM) reduced maximal current amplitude (command potential, 10 mV) by approximately 50% (Fig. 3A). A plot of the corresponding fractional conductance (G/Gmax) elicited at each command voltage (Fig. 3B) revealed a negligible effect of vinpocetine on the voltage dependence of rNaV1.8 activation (V0.5 control = 1.0 ± 0.6 mV; V0.5 vinpocetine = –1.4 ± 0.9 mV).
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Effect of Vinpocetine on rNaV1.8 Inactivation. In common
with all other voltage-gated sodium channels, the number of rNaV1.8
channels available for activation is dependent upon the resting membrane
potential. Proportionally fewer channels are available for activation as the
resting membrane potential is moved progressively more depolarized, due to the
accumulation of channels in an inactivated, nonconducting state. The extent to
which this phenomenon occurs is a complex function of both time and voltage
parameters. Experimentally, this relationship can be examined, at least
empirically, and quantified by imposing constant duration prepulses to
sequentially depolarized potentials and then stepping to a common destination
voltage (Fig. 4A). A plot of
prepulse potential versus normalized peak current amplitude yielded a typical
steady-state inactivation relationship from which the half-inactivation
voltage (V0.5,inact) was determined by curve fitting
(Boltzman function). Consistent with previously published data
(Sangameswaran et al., 1996),
rNaV1.8 channels were found to have a relatively positive
V0.5,inact value that was moved 22 mV in the
hyperpolarizing direction (V0.5,inact control =
–34.1 ± 0.7 mV, n = 8;
V0.5,inact vinpocetine = –56.4 ± 1.0 mV,
n = 8) by vinpocetine (30 µM;
Fig. 4B).
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State-Dependent Inhibition of Sodium Currents by Vinpocetine.
Preliminary experiments revealed that the potency of vinpocetine was dependent
upon the membrane holding potential even when the destination command voltage
was held constant. Thus, vinpocetine (10 µM) produced a greater attenuation
(90%) of available current elicited by a step command to 10 mV from a
holding potential of –35 mV (corresponding to the
V0.5,inact for rNaV1.8)
(Fig. 5B) compared with similar
experiments performed from a more hyperpolarized holding potential of
–90 mV (50% attenuation) (Fig.
5A). This is a characteristic feature of "local
anesthetic" sodium channel blockers (e.g., lidocaine and mexilitine) and
suggested a higher affinity interaction for vinpocetine with the inactivated
channel state. More detailed experiments revealed the concentration-inhibition
curves for vinpocetine sodium channel block were left-shifted when holding
potential was clamped at the relatively more depolarized –35 mV compared
with –90 mV (Fig. 5C).
Vinpocetine was approximately 3-fold more potent (IC50(–90
mV) = 10.4 µM; IC50(–35 mV) = 3.5 µM) when
currents were evoked from a holding potential of –35 mV.
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Although we do not know the identity of the sodium channels responsible for
the background TTXs conductance in the ND7/23 cell line, we considered it of
interest to determine the influence of vinpocetine on this conductance.
Experiments similar to those described above were conducted using the wt cell
line, and revealed a similar potency of vinpocetine and a similar state
dependence of the drug on the wt TTXs current. Thus, vinpocetine was
6-fold more potent at blocking currents elicited from the
half-inactivation voltage for TTXs currents
(IC50(–65 mV) = 3.8 µM) than from
the full-activation voltage (IC50(–120
mV) = 24.5 µM).
Vinpocetine Block of rNaV1.8 Sodium Channels Is
Frequency-Dependent. Voltage-gated sodium channels require a period of
membrane repolarization to reprime after depolarization-induced activation. In
the case of particular native TTXr channels in dorsal root ganglion neurons,
repriming has been previously reported to be rapid
(Elliott and Elliott, 1993;
Rush et al., 1998). We have
found a similar property for rNaV1.8 in ND7/23 cells
(Dong et al., 2001); in other
words, these channels seem to require only brief periods of membrane
repolarization to reestablish their availability and, hence, can sustain
relatively high-frequency duty cycles. Repriming rates are usually studied
using a series of paired pulse experiments in which two depolarizing pulses
(designed to achieve full activation) are separated by a series of variable
but precise interpulse intervals. A comparison of peak current amplitude
elicited by the second pulse with respect to the first provides an index of
channel availability at the specified interpulse interval. However, similar
information can be derived from frequency-response relationships of the sort
depicted in Fig. 7. A
comparison of the fractional availability of rNaV1.8 channels is
provided by the amplitude of each second pulse in the series in relation to
the initial amplitude, the pulse interval being the reciprocal of the
stimulation frequency. These experiments revealed approximately 80% of the
rNaV1.8 channel population to be available for activation by the
second stimulus at the shortest interval (50 ms) tested
(Fig. 6). However, the same
pulse interval in the presence of vinpocetine (30 µM) resulted in a
significant reduction in channel availability (20%), suggesting that the
majority of channels had failed to reprime during the 50-ms interval
(Fig. 6). As the interval
between successive paired pulses was increased, progressively more channels
recovered, despite the presence of vinpocetine, although an interval of
10 s was required to ensure a degree of repriming (80%) comparable with
that seen in the absence of the drug (Fig.
6).
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A corollary to the slowing of repriming by vinpocetine is that the drug should promote an accumulation of blocked channels during periods of high-frequency stimulation. Figure 7 provides some indication of accumulation, particularly at higher stimulation frequencies. The control experiments (Fig. 7A) reveal that there is no loss of channel availability at 0.1-Hz stimulation, whereas at 10 Hz approximately 60% of the total channel population remains available at the end of a 25-sequence pulse train. The data obtained from similar experiments repeated in the presence of vinpocetine (10 µM) revealed clear evidence of frequency-dependent channel block by the drug (Fig. 7B). At the lowest stimulation frequency (0.1Hz) approximately 20% of the available channels were rapidly taken out of commission by vinpocetine, and there is a small but noticeable accumulation of blocked channels throughout the remaining stimuli. Increasing the stimulation frequency revealed additional, rapidly equilibrating channel blockade that seemed to saturate at frequencies above 1 Hz (Fig. 7B). The frequency dependence is better appreciated by considering the extra fractional block elicited at each stimulation frequency (Fig. 7C). Analyzing the data in this way revealed clear evidence of frequency-dependent block by vinpocetine up to stimulation frequencies of 1 Hz, approximately 50% additional TTXr conductance is eliminated by the drug at this frequency.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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), although the
possibility of hitherto unidentified splice variants may add to this
complexity. The majority of sodium channels are highly sensitive to channel
block by TTX, yet two family members, NaV1.8 and NaV1.9,
stand out as being distinct in their relative resistance to TTX, whereas a
third family member, NaV1.5, occupies an intermediate TTX
sensitivity (Goldin, 2000).
Several previous studies have shown vinpocetine to be a sodium channel
blocker, these studies have used rat cultured cerebrocortical neurons
(Molnar and Erdo, 1995) or
guinea pig cortical synaptosomes (Tretter
and Adam-Vizi, 1998). Although the precise details of the sodium
channel isoforms expressed in these preparations are unknown, it is reasonable
to assume that the sodium conductances were likely to be predominantly, if not
exclusively, mediated by TTX-sensitive channels. Whole-cell voltage-clamp
analysis of the effects of vinpocetine on sodium currents recorded from
cerebrocortical neurons (Molnar and Erdo,
1995) revealed a potency (IC50 = 44 µM) comparable
with that of the established sodium channel blocker phenytoin (IC50
= 50 µM). A subsequent study revealed a similar blocking effect of
vinpocetine on sodium currents recorded from rat cardiac ventricular myocytes
(Wei et al., 1997). Although,
once again, the precise molecular identity of the conductance was not
established, this study is of interest because cardiac myocytes are known to
express the TTX-insensitive NaV1.5 channel isoform. Our data
suggest that vinpocetine is appreciably (>10-fold) more potent
(IC50(–65 mV) = 3.8 µM) at blocking
TTXs than Molnar and Erdo
(1995) found in their studies.
The difference may be due, at least in part, to methodological differences,
although the latter studies used a similar holding potential (–60 mV), a
key factor governing apparent potency. We consider a more likely explanation
may be biological (channel isoform) differences.
The present study was undertaken as a result of the continued clinical use
of vinpocetine and, specifically, sought to explore the action of the alkaloid
derivative on a molecularly identified sodium channel isoform,
rNaV1.8. This sodium channel is of particular interest in view of
its selective expression pattern. In the rat, the protein is only found in a
subpopulation of peripheral sensory afferent nerves
(Akopian et al., 1996;
Novakovic et al., 1998).
Moreover, NaV1.8 displays gating characteristics that are different
to the other sodium family members and, as mentioned previously, is
pharmacologically novel in terms of its resistance to site I toxins. The
possibility exists, therefore, for additional pharmacological divergence
between NaV1.8 and other sodium channel isoforms although, at least
to date, there have been no reports of small molecules that are capable of
discriminating between the various members of the sodium channel family.
Expression analysis, using the whole-cell voltage-clamp approach, revealed
the clonal ND7/23 cell line to be a suitable heterologous host cell line
capable of sustaining robust rNaV1.8 expression that could be
studied, in isolation, by the simple addition of TTX to the extracellular
perfusate (Dong et al.,
2001).
Vinpocetine had negligible effect on the voltage characteristics of
rNaV1.8 activation but produced a clear hyperpolarizing shift in
the inactivation curve. This profile is consistent with vinpocetine binding
selectively to the inactivated state of the channel, the functional
consequence of this effect would be to limit the dynamic range of membrane
potentials over which rNaV1.8 would likely operate. These data
suggested that the binding of vinpocetine was state-dependent, and this was
confirmed by determining the potency of the drug at different resting membrane
potentials. Although these experiments revealed vinpocetine to be more
effective during sustained depolarized states the difference in affinity is
marginal (3-fold) compared with other known sodium channel blockers. For
example, similar but more marked differences in state-dependent affinity have
been described previously for other sodium channel blockers, notably the local
anesthetics (e.g., lidocaine) (Balser et
al., 1996) and certain anticonvulsants (phenytoin, carbamazepine,
and lamotrigine; Catterall,
1999), observations that are consistent with the concept of the
modulated receptor model (Hille,
1992). It must be considered likely that vinpocetine acts in a
similar manner and that the higher apparent affinity of the drug for the
inactivated state reflects a slower dissociation rate from that state. Also
consistent with this mechanism is the phenomenon of use dependence. Repetitive
and brief membrane depolarizations force sodium channels to cycle through
activation, inactivation, and repriming states. The ability of a given channel
to follow such activity at high cycle rates is, primarily, a function of the
rate of recovery from inactivation, the repriming rate. Native TTXr channels
have been shown previously to display rapid repriming kinetics. The
use-dependent block exerted by vinpocetine is likely to reflect the slow rate
of dissociation of the drug from blocked channels during repolarization,
effectively slowing the repriming rate. At low-frequency stimulations (e.g.,
0.1 Hz) the drug off-rate is presumably fast enough to ensure recovery of the
majority of the available channels before the next depolarizing pulse in the
cycle. As the stimulation frequency is increased, the interpulse interval
decreases accordingly and the result is manifest as a proportional increase in
the drug-bound channels at the onset of the subsequent depolarization. The
frequency-dependent component of vinpocetine's effects on rNaV1.8,
although clear, is modest compared with that observed for other sodium channel
blockers studied under the same conditions (X. W. Dong, unpublished
observations). A previous study (Wei et
al., 1997) that examined the effect of vinpocetine (40 µM) on
cardiac myocyte sodium channels found no evidence of use-dependent block. This
apparent contradiction may represent a genuine difference attributed to
different channel isoforms or may reflect different experimental conditions.
The manifestation of use-dependent block is a complex interaction between
channel and drug kinetics, a simple change in drug concentration can result in
a profoundly different use-dependent profile.
We describe vinpocetine as a potent (IC50 = 3 µM)
rNaV1.8 channel blocker, although it is more meaningful to consider
whether the affinity of the drug for the NaV1.8 channel is relevant
in relation to the plasma levels attained in typical clinical settings. The
reported Cmax values, achieved in human subjects after a
10-mg dose of vinpocetine, are around 30 to 60 ng
ml–1
(Vereczkey et al., 1979;
Lohmann et al., 1992),
corresponding to around 100 to 200 nM. However, the drug as a very high volume
of distribution and readily partitions into the brain
(Gulyas et al., 1999) and,
presumably, other fatty tissues that are likely to include the peripheral
nerves. Hence, true tissue exposure levels may be somewhat higher than the
circulating plasma level and, in any event, are within the range that might be
expected to produce some attenuation of sodium channel function. It is
somewhat harder to predict, with respect to therapeutic efficacy, the relative
contribution of sodium channel block compared with the many other
pharmacological actions of the drug. However, similar potencies have been
claimed for an antioxidant action (Horvath
et al., 2002) and phosphodiesterase E-1 inhibition
(Chiu et al., 1988), suggesting
that sodium channel block may impart a significant contribution to overall
efficacy (Bonoczk et al.,
2000).
In summary, the present data demonstrate that vinpocetine is capable of
blocking rNaV1.8 sodium channels at concentrations that may be
therapeutically relevant. The nature of these experiments reveal this to be a
direct effect on the channel (probably the "local anesthetic"
pharmacophore) and not secondary to an action on Ca2+ or
K+ channels, although an action at either of these additional
targets could contribute to an overall effect on neuronal excitability. The
continued clinical use of the drug in the neurotrauma arena and the absence of
reported serious side effects may warrant expansion of vinpocetine's clinical
utility to examine a potential benefit in the control of neuropathic pain
(Lai et al., 2000) and bladder
hyperreflexia (Yoshimura et al.,
2002) conditions that have been linked to inappropriate
NaV1.8 sodium channel activity.
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Footnotes |
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ABBREVIATIONS: TTX, tetrodotoxin; GFP, green fluorescent protein; DMEM, Dulbecco's modified Eagle's medium; TTXs, tetrodotoxin sensitive; TTXr, tetrodotoxin resistant, wt, wild-type.
Address correspondence to: Dr. Tony Priestley, CNS/CV Biological Research, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033. E-mail: tony.priestley{at}spcorp.com
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A. E. Medina, T. E. Krahe, and A. S. Ramoa Restoration of Neuronal Plasticity by a Phosphodiesterase Type 1 Inhibitor in a Model of Fetal Alcohol Exposure J. Neurosci., January 18, 2006; 26(3): 1057 - 1060. [Abstract] [Full Text] [PDF]
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J. J. Devaux and S. S. Scherer Altered Ion Channels in an Animal Model of Charcot-Marie-Tooth Disease Type IA J. Neurosci., February 9, 2005; 25(6): 1470 - 1480. [Abstract] [Full Text] [PDF]
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E. K. Wittmack, A. M. Rush, M. J. Craner, M. Goldfarb, S. G. Waxman, and S. D. Dib-Hajj Fibroblast Growth Factor Homologous Factor 2B: Association with Nav1.6 and Selective Colocalization at Nodes of Ranvier of Dorsal Root Axons J. Neurosci., July 28, 2004; 24(30): 6765 - 6775. [Abstract] [Full Text] [PDF]
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) and
vinpocetine (30 µM; 
) conditions. Vinpocetine reduced peak current
amplitude but did not change in the shape of the current-voltage relationship.
B, activation curves (mean ± S.E.M., n = 7) for
rNaV1.8 conductance in the absence (
V0.5, inact = 22.3 mV) of the steady-state
inactivation curve.
), 3 Hz (
), and 10 Hz (
).
Peak-current amplitudes (mean ± S.E.M., n = 6–8) were
normalized to that of the first response at each frequency and are shown
plotted against pulse number. The additional fractional block elicited at each
stimulation frequency is shown in C to better illustrate the use-dependent
sodium channel block by vinpocetine.