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Effect of digitalis on central demyelinative conduction block in vivo.

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Effect of Digitahs on Central
Demyelinative Conduction Block in Vivo
Ryuji Kaji, MD, PhD, and Austin J. Sumner, MD
In searching for agents effective in treating multiple sclerosis,we studied the effect of a short-acting digitalis, ouabain,
on conduction block in an animai mode1 of central nervous system demyelination. The electrogenic sodiumipotassium
pump, which digitalis specifically inhibits, is responsible for part of the resting membrane potential and also the
activity-related membrane hyperpolarization following high-frequency impulses. The latter causes intermittent conduction block in demyelinated fibers. Therefore, digitalis might be expected to reverse demyelinative conduction
blocks by reducing the threshold at the blocking node. Somatosensory evoked potentials were monitored in 11 rats
with spinal cord demyelination before and after systemic administration of ouabain (0.1-0.6 mg or 0.2 1-1.58 mg/kg
IP). In al1 rats, slowed conduction velocity of the compound action potential through the lesion was significantly
reversed, and failure to transmit high-frequency impulses was improved upon. The amplitude of the cortical
somatosensory evoked potentials also increased significantly. Digitalis is a promising therapeutic agent for trial in
patients with multiple sclerosis.
Kaji R, Sumner AJ. Effect of digitalis on centrai demyelinative conduction block in vivo.
Ann Neurol 1989;25:159-165
Of the pathophysiological mechanisms responsible for
symptoms in patients with multiple sclerosis (MS),
conduction block is probably the most significant.
Nonetheless, there is much direct and circumstantiai
evidence that restoration of function in demyelinative
fibers can occur. For example, in the last century,
Charcot [1) observed an extensive demyeiination
plaque in an optic nerve of a patient who had shown
only minor visuai disturbance, and he concluded that
central nervous system (CNS) fibers could transmit
impulses after demyelination. Since that time, a substantial body of evidence has accumulated to indicate
that demyeiinative conduction block is potentially reversible, and appropriate pharmacological intervention
might be effective in symptomatic treatment for MS
121.
In a normaì myelinated fiber, saltatory conduction is
made possible by the foliowing electrical events at the
node of Ranvier. The nodal membrane reaches its
threshold by the outward capacitative current driven
by the preceding node, and then the inward ionic current is initiated resulting in an action potential, which
in turn drives current at the next node. The safety
factor of transmission is defined as a ratio of the current available at a node to the threshold current of that
node 131. The safety factor should be more than unity,
if conduction is to be successful. In a demyelinated
nerve fiber with conduction block, part of the nodal
current is dissipated as a consequence of increased
capacitance due to demyelination, and the safety factor
is reduced below unity owing to the decreased current
available at the node [4].
In the past, several attempts have been made to
increase the nodal current to overcome conduction
block but with limited success [2, 5-91. Recent evidente, however, has shown that an activity-related
increase in threshold is also an important cause of
the reduced safety factor associated with conduction
block following high-frequency impulse activity (ratedependent block). Bostock and Grafe [lo) demonstrated that conduction block in demyelinated ventral
root fibers foiiows impulse activities at frequencies as
low as 10 to 50 Hz. Kaji and coworkers [li) showed
that conduction failure occurs after stimulation of 50
Hz in CNS demyeiinated fibers. This rate-dependent
block has been attributed to membrane hyperpolarization produced by the electrogenic sodium/potassium
(Na/K) pump {lo). The pump is activated by a slight
increase of sodium in an axoplasm after impulse activity. Without impulse activity, the pump is aiso responsible for 7 to 10% of the resting membrane potentiai
[12, 131. Therefore, digitalis, a specific inhibitor of the
pump, might reverse rate-dependent blocks by preventing the hyperpolarization. It might also overcome
From the Department of Neurology, University of Pennsylvania,
Philadelphia, PA.
Address correspondence to Dr Kaji, Department of Neurology,
Kyoto University Hospital, Sakyo-ku, Kyoto, Japan 606.
Received May 6, 1988, and in revised form Jun 27 and Jui 26.
Accepted for pubiication Jui 31, 1988.
Copyright O 1989 by the American Neurologica1 Association
159
complete conduction blocks by reducing the resting
membrane potential, especialiy if its effects are relatively focal due to selective penetration at sites of demyelination. Despite its low permeability through the
blood-brain barrier 1141, a direct action of digitalis on
the CNS after systemic administration has been demonstrated [15-181. Also the blood-brain barrier is
more permeable at sites of acute demyelination 1191.
This study was designed to test whether a shortacting digitalis, ouabain, is effective in restoring conduction after systemic administration. An animal
mode1 of CNS demyeiination was studied by recording
somatosensory evoked potentiah (SEPs) 11i}.
aftor
dornyolination
-w -J-pM8mc
(O rnin)
CUABAIN 0.1
nig
i.p.
!
90 rnin
PQJ2
Methods
Eleven male Wistar rats (350-470 gm) were used for inducing spinal cord demyelination, and 3 rats were used for normal contro1 subjects. Detailed description of the methods
used to induce the lesion, the histology of the lesion, and the
physiological techniques are published elsewhere { 1I}.
Rats were anesthetized with ketamine (100 mg/kg, IP) and
xylazine (10 mg/kg). In some rats, pentobarbital(35 mg/kg)
was used to compare its effect with that of ketamine, as
ketamine may affect the activity of N d K pump {20}. In longterm serial recordings of spinal responses (Figs 1 and 2), the
anesthetics just mentioned were supplemented by inhalation
of 1to 4% halothane-oxygen. In recording COrtiCd responses
additional ketamine was injected to maintain anesthesia, and
halothane was not used because it reduced the amplitude of
the COrtiCal potential significantly { 11).
To induce a demyelinative lesion, laminectomy was performed at the leve1 of the sixth thoracic vertebra and 20 to
30 pl of anti-galactocerebroside (AGC) serum was injected
into the midline dorsal column ofT8-9 segment with a 30.5gauge needle and syringe mounted on a micromanipulator.
Rats injected with AGC serum showed hind-limb ataxia
three to five days following the injection and were reanesthetized at that time for SEP recording. Morphologically, the
lesion at three to five days following injection of AGC serum
usually showed fascicuiar demyelination surrounding the
area of axonal degeneration at the needle track, and the
edema had almost subsided by this time [1i). SEP findings at
this time period were stable over at least several hours of
serial recordings.
For recording SEPs, the tibial nerve at the ankle was stimulated at 10 or 50 Hz for the spinal responses (T-2 and L
responses) or at 5 Hz for the cortical response (P-15). A
screw electrode was placed in the skull overlying the primary
somatosensory cortex, and was used for recording cortically
generated SEP with a reference at the nose (P15, Fig 3).
Potentials were recorded bipolarly from the spinal cord with
shielded needle electrodes placed on the laminae of the second thoracic and second cervical vertebrae (T-2 response,
see Fig I). Recordings were also made bipolarly with the
shielded needle electrodes placed over the lumbar spine at a
distance of 80 mm from second thoracic or second cervical
electrodes (L response). The generators of the initial components of T-2 and L responses were confirmed to be the
presynaptic volleys in the T2-3 dorsal column and the cauda
160 Annals of Neurology Vol 25 N o 2 February 1989
ECO
T2 RESPONSE
o d n 0.2 nig i.p.
aubjn o 2 mg I.P.
M.c
I
1
Fig I. Effect of ouabain on the compound action potential
thmugh the demyelinative lesion (T-2 response; Rat 2). The upper and lower traces ofeach recording on the left are afer
stimukztion with 1O H z and 50 Hz, respectively. Electrocardiograna (EKG) are shown on the right. Before administration of
ouabain (O rnin), T-2 response after stimukation with 1O H z
had a signifcantly delayed latency when compared with the recording before demyelination (left, top), indicating slmued centrai conduction velocity. The waveform was also greatly simplijied, pmbably because of conduction block of some fibers. Afer
stimulation with 50 Hz, T-2 response was almost abolished,
representing rate-dependent block. By 150 minutes (total ouabain
dose: 0.3 mg), T-2 response afer 1 O H z had recovered a kxtency
almost identica1 with that before demyelination, and the amplitude of T-2 response afer 50 H z had also increased. The PQ
interval on the EKG was prolonged. Afer adding 0.2 mg of
ouabain (21O min), digitalis toxicity manijested itself as complete atrioventricukar block (right, bottom), and no further effict
on T-2 response was observed.
equina, respectively [i 1). Potentials were amplified with a
band pass of 20 to 2 k H z ( - 3 dB) and were averaged 50 to
250 times with an averaging computer (TD20, TECA Corporation, Pleasantville, NY). The analysis time was 20 msec
for T-2 and L responses and 50 msec for the cortical response (P-15) with a sampling period of 40,80, or 100 psec.
Conduction velocity of the compound action potentials
through the lesion (central conduction velocity) was calculated by the onset latency difference of T-2 and L responses and the distance between the electrodes. The normal
range of central conduction velocity was 35.85 to 49.35
*Or
OUABAIN
OUABAIN
381
39
37
ccv
(rnisec)
Fig 2 . Serial changes of SEPs and EKG after administration of
ouabain in a single animal (Rat I ) . The amplitude ratio of T-2
response afe. SO H z ofstimulation t o the response after 1O Hz
of stimulation (RSO/lO), the conduction velocity through the lesion (centraiconduction velocity, CCV), and P Q intemial in
EKG are shmn from top t o bottom. Obsewation was made wery
3 minutes (1-30 min) or evety 5 minutes (30-120 min).
m/sec (mean centrai conduction velocity in controls I+ 2.5
SD) [i i]. To quantitate rate-dependent blocks, the amplitude ratio of T-2 response after stimulation with 50 Hz to
that after stimulation with 10 Hz (R50/10) was calculated. A
ratio below 66% (mean ratio in controls -2.5 SD) was considered as evidence of rate-dependent block [i i]. The amplitude of the cortical response (P-15 amplitude) was measured
from the baseline or, if present, the peak of the preceding
negativity, and expressed as percentage of the originai amplitude before demyelination [i 1, 21). These physiological parameters before and after ouabain administration were statisticaily analyzed by paired t test.
In 8 rats, 0.1 to 0.2 mg of ouabain was administered intraperitoneally at one time and was repeated unti1 longlasting reversal of physiological findings was obtained, while
SEPs and electrocardiogram (EKG) were rnonitored. The
intravenous route of administration was not used in this
study because it was not technically practical to maintain a
secure intravenous line in every animai. The total dose remained at nontoxic levels ranging from 0.75 to 1.14 mg/kg,
except in 3 rats in which toxic levels were reached at doses of
1.08 to 1.58 mg/kg.
In the other 3 rats injected with AGC serum, single doses
of 0.4 mg (0.85-1.14 mg/kg) were given specificaily to observe changes in the cortical response. In 3 normal contro1
rats, single doses of 0.2 to 0.4 mg (0.57-1.05 rngikg) were
given to examine the effect of ouabain in normal CNS con-
duction. Rectai temperature of the animais was maintained
bemeen 36 and 37°C during the experiments.
Resdts
In ai1 animais at three to five days after injection of
AGC serum, SEPs showed the foiiowing characteristic
changes of demyelination (see Figs 1-3, Table) {li]:
(1) slowed centrai conduction velocities through the
lesion (31.75 I1.69 m/sec), (2) rate-dependent
blocks defined as reduced ratio of amplitude in T-2
response at stimulation of 50 Hz to that at 10 Hz
(R50/10; 32.25 I11.39%) or an abnormai delay of
the onset of T-2 response at 50 Hz compared with that
at 10 Hz (> 0.16 msec), and (3) decrease of the amplitude of the corticai response (P-15) compared with
that before injection of AGC serum.
Ouabain was injected intraperitoneaily at an initiai
dose of O. 1 mg in 8 animais that had been injected with
AGC serum. In 5 of 8 rats, slight recovery of delayed
centrai conduction velocity (> 2 m/sec) was recognized at this dose. The time required for this change
varied greatly from animai to animai; it ranged from 10
to 90 minutes after injection but was always concurrent with slight prolongation of the PQ interval (4-8
msec) in the EKG (see Figs 1 and 2). Hence, the variation was considered to be due to inconstancy of the
time it takes for ouabain to reach a criticai blood leve1
after intraperitoneai in jection and to penetrate selectively into the demyelinated site. R50/10 was also restored toward normai in 3 rats (see Fig 2). These
changes lasted as long as 30 minutes. No significant
changes of the corticai response were observed at this
dose.
Kaji and Sumner: Effect of Digitalis on Conduction Block 161
after
de rn y e Ii na t io n
-
(O min)
OUABNN
0 4 mg i p
---
--
flk/
-
I
O min
NORMAL S A L I N L
1 ml ~p
I
40 min
45 min
--=--dLF-
20 min
--
l
1-
I
I
-=--e-
40 rnin
I
l
75 mln
I
30 min
I
65 min
I
1 0 min
n
50 min
60 min
.
_I 20 uv
5 msec
After an additional dose of 0.2 mg of ouabain was
given 35 to 90 minutes later, centrai conduction velocities were normalized in al1 8 animals, and R50/10
reached to the normai range in 4 animals (see Figs 1
and 2; Table). EKG showed further prolongation of
the P Q interval, but no signs of digitalis toxicity were
observed. These effects usually lasted for at least 60
minutes. In 4 animals, slight increase in the amplitude
of the cortical response (P15) was noted, but the differences did not reach significance at this dose ( p =
0.115).
To determine the dose required for the maximum
effect of ouabain on T-2 response, another 0.2 to 0.3
mg of ouabain was injected within 40 to 60 minutes in
3 animals (0.5-0.6 mg or 1.08-1.58 mglkg in total). In
all 3 animals, no further significant changes in T-2 response were observed. In 2 animais, ouabain injection
Fig 3. Eflect of ouabain on cortical somatosensory aiokedpotential (SEP) (Rat 4). Left: Serial recordings of the cortical SEPs
after administration of ouabain. The response before demyelination (top) is shown for comparison. The amplitude of P-15
(negative-to-positivedefiection is indicated by bar) was signij5cantly increased at 40 to 65 minutes. The latency was also
siightly recovered. Right: Serial recordings of tbe cortical response
afe. injection of nomalsaline solution in the same animal (Rat
4).No signifcant changes were obsewed.
was followed by complete atrioventricular block with a
fatal outcome (see Fig 1).
Three rats were given a single dose of 0.4 mg (0.851.14 mg/kg) to examine the specific effect of ouabain
on the cortical response. Seriai changes were recorded
over a 90-minute period in rats that did not receive
halothane and were compared with changes after injection of normal saline solution in the same animal (see
Fig 3, Table). In al1 animals, after administration of
Eflect of Ouabain on Physiological Parameters
Before ouabain
After ouabainb
p (paired t )
CCV (m/sec)
R50/10 (%)
31.75
1.69
36.76 2 1.66
<0.001
32.25 +: 11.37
56.63 +: 18.53
0.001
"Relative to the amplitude before demyelination.
bMaximum vaiue.
CCV = centrai conduction velocity.
162 Annals of Neurology Vol 25 N o 2 February 1787
P-15 Amplitude (%)"
15.05 2 4.00
44.21 r 27.81
0.039
ouabain, amplitudes of the cortical response were restored into the normal range in 40 to 65 minutes with
slight latency shortening, although the waveforms of
the individuai responses were not restored to those
that were present before demyelination. No cardiac
toxicity was noted at this dose. Normal saline solution
did not produce significant changes of the cortical potential over a 60-minute period.
No significant physiological effects, except for slight
increase in central conduction velocity (< 2 m/sec),
were observed after ouabain administration in 3 normal contro1 rats. No significant difference in the physiological findings existed between animals anesthetized
with ketamine and those treated with pentobarbital.
Discussion
The present study demonstrated that systemically administered ouabain, a short-acting digitalis, can transiently reverse conduction disturbances in an animal
model of CNS demyelination. Except for 2 rats in
which fatal complete atrioventricular block developed
at high dosage with no beneficial effect on the CNS,
no digitalis toxicity was observed. Therefore, CNS demyelinative conduction changes have been reversed at
doses without side effects.
Doses of ouabain used for intraperitoneal injection
in the animals in this study were higher than those
used for intravenous administration in humans 122) or
in other animals 1171 to produce cardiac action. Because ouabain is poorly absorbed after intraperitoneal
injection, the effective blood leve1 was reached only
after injecting a large amount of ouabain inuaperitoneaily in our model.
Although digitalis has a relatively low permeability
through the blood-brain barrier [14}, its action on
CNS has been amply demonstrated [15-17). Its side
effects on CNS at toxic doses have been well known
since the classic description of digitalis by William
Withering in 1785 1231. Therapeutic doses of digitalis
were once used clinically to treat hydrocephalus in infants, as it inhibits production of cerebrospinal fluid
18). Since prolongation of atrioventricular conduction
has been attributed to the CNS action of digitalis C161,
the P Q interval on the EKG may be a good indicator
of the CNS concentration of digitalis. In our model of
CNS demyelination, the blood-brain barrier at the site
of the lesion may be partially destroyed as in human
MS [ 1i}. Therefore, the effect of digitaiis in the demyelinative lesion may be more pronounced than in other
intact portions of the CNS, promoting focal action on
the electrogenic pump where it wili be most therapeuticdi+ effective.
Complete conduction block, fdure to uansmit highfrequency impulses (rate-dependent block), and
slowed conduction velocity have been shown to be the
characteristics of demyelination in peripheral 14, 10,
241 and centrai [25} nerve fibers. Although it has not
been possible to observe these changes in single demyelinated CNS fibers in our model, we consider that
decreased amplitudes of P-15, rate-dependent blocks
of T-2 response, and slowed centrai conduction velocities through the lesion correspond to the characteristics just mentioned [il].
Undoubtedly, complete conduction blocks in CNS
fiber tracts are associated with significant functional
deficits. Recent evidence indicates that rate-dependent
blocks are also important in causirig clinical signs { 1i].
Since the information transmitted in CNS fibers is encoded in frequencies of impulses ranging up to 250 Hz
or more [26, 271, the failure to transmit high-frequency impulses of more than 50 Hz could render
the information uninterpretable by the postsynaptic
neuron. Slowed conduction may also have clinical significance because the exact timing of arrivai of impulses may be critical in some CNS fiber tracts 128).
A blocker of the voltage-dependent potassium channel, 4-aminopyridine (4-AP), has been shown to reverse complete conduction block due to demyelination
by prolonging the action potential in demyelinated
fibers [6, 91. Despite its action of restoring conduction,
4-AP had no significant effect on internodal conduction time or conduction velocity [b) and had little effect on rate-dependent blocks 181. Several clinical trials
of 4-AP have been associated with serious side effects,
especially convulsions [2, 7, 291, although in a successfu1 trial reported by Stefoski and coworkers 1301 patients with MS did not have serious side effects. Kaji
and associates {8] showed that 4-AP reverses CNS
conduction block in the same animai model as was
used in this study, but in al1 animals convulsions developed at the doses required to restore conduction.
Ouabain, on the other hand, did not appear to have
serious side effects in this model and was strikingly
effective in reversing rate-dependent blocks. Increased
velocities of the compound action potential through
the lesion (central conduction velocities) after ouabain
administration seem to be due to increased conduction
velocity in individual fibers rather than restoration of
conduction in the fastest conducting fibers. A marked
decrease of internodal conduction time was observed
in a single fiber study in which the effect of ouabain on
demyelinative conduction block was examined [3 1,
unpublished observation). Therefore, digitalis has
ameliorating effects on all three conduction disturbances associated with demyelination: complete conduction block, rate-dependent block, and slowed conduction velocity.
Bostock and Grafe [lo] showed that rate-dependent
block is caused by a marked increase in nodal
threshold due to membrane hyperpolarization, which
in turn is produced by activation of the elecuogenic
Na/K pump triggered by a sight increase in sodium in
Kaji and Sumner: Effect of Digitalis on Conduction Block
163
the axoplasm. To prove the mechanism of action of
digitalis as an inhibitor of the pump, we studied the
effect of ouabain in a demyelinated single fiber with
conduction block in rat ventral roots 1311. As predicted, ouabain was able to restore conduction without
change in the current at the driving node.
Significant rate-dependent block, in which the N d K
pump plays an important role, was observed only in
demyelinated fibers and not in normal myelinated
fibers {lo, 11, 31). Similarly, nontoxic doses of digitalis in this study had significant effects on conduction
only in demyeiinated axons. The reason for this remains unknown. A few possibilities may explain these
findings: Increase in axoplasmic sodium causing increased pump activity may be more substantial in demyelinated fibers than in normal fibers, since they have
to maintain a long-duration, inward sodium current to
overcome capacitative current loss due to demyelination {4, 32). As in the potassium channel distribution
in myelinated fibers, the pump may be distributed
more densely in the paranodal region or the internode
than in the nodal region, and the number of functional
pumps may increase after demyelination 112). Gangliosides, which are normal constituents of myelin as well
as neuronal axolemma {33), may activate the pump
c343.
An increasing number of studies have shown that
substances with actions similar to those of ouabain
(ouabain-like compounds) can be extracted from the
brain {35, 36). Physiologically, ouabain-like compounds may modulate the excitability of CNS neurons
137). It is possible that ouabain-like compounds contribute to the normal functional recovery from CNS
demyelination in patients with MS, and supplementing
ouabain may well be tolerated by those patients. However, a question remains as to whether or not ouabain
is able to restore biologically meaningfiul conduction. It
has been shown that spontaneous functional recovery
follows CNS demyelination by at least two mechanisms: continuous conduction through the demyelinated segment 138) and CNS plasticity to compensate
for the loss of conduction E391 or to reinterpret trains
of impulses modified by the rate-dependent block
[ l i ) . The present study did not give any insight into
the interaction of exogenous digitalis and spontaneous
recovery processes. In this context, demonstration of
the clinical usefulness of digitalis will have to await
clinical trials in patients with MS.
This study was supported in part by a grant from the National
Multiple Sclerosis Society (RG-2099-A-1).
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