ELSEVIER
THE
EFFECTS
OF TAXOL,
METHYLPREDNISOLONE,AND
~-AMIN~PYRIDINE
IN COMPRESSIVE
SPINALCORDINJURY:
A QUALITATIVE
EXPERIMENTALSTUDY
Miguel-A. Perez-Espejo, M.D., Ph.D.,* Siavash S. Haghighi, D.V.M., Ph.D., Edward H.
Adelstein, D.V.M., M.D.,** and Richard Madsen, Ph.D.***
Division of Neurosurgery, Department of Pathology, * * and Division of Biostatistics, * * *
University of Missouri-Columbia, Columbia, Missouri (*Also sponsored by the Spanish
Sanitary Research Foundation>
Perez-EspejoM-A, Haghighi SS,Adelstein EH, Madsen R. The
effects of taxol, methylprednisolone, and 4-aminopyridine in
compressing spinal cord injury: a qualitative experimental
study. Surg Neural 1996;46:350-7.
BACKGROUND
Tax01 is a diterpene alkaloid that stimulates tubulin production in cells. It may be effective in preserving the
cytoskeleton of spinal cord axons after injury.
METHODS
Thirty-nine rats were submitted to spinal cord compression. The animals were divided into three groups that
received taxol (18.75 mg/m2>, methylprednisolone
(30
mg/kg), or Caminopyridine (1 mg/kg). Tax01 was administered as one dose immediately after injury and two
additional doses on days 14 and 21. Methylprednisolone
was given as a single injection immediately postinjury.
Four-aminopyridine was administered on days 25,26, and
27. A group of nine injured animals served as a control
without any treatment. Evoked potentials were recorded
before, during, and 4 weeks postinjury. Behavioral tests
were measured to evaluate recovery of motor function.
RESULTS
The taxol and methylprednisolone-treated
animals demonstrated a significant improvement in comparison with
the control group. No functional improvement was found
at 1 mg/kg treatment of 4-aminopyridine in rats.
CONCLUSIONS
We conclude that taxol and methylprednisolone given
shortly after the compression injury improve functional
outcome after an incomplete spinal cord injury.
KEY
WORDS
Behavior, methylprednisolone, somatosensory evoked potentials, spinal cord injury, taxol.
Address reprint requests to: Siavash S. Haghighi, D.V.M., Ph.D., Department of Neurosurgery,
Center for Neurosciences,
Broad &Vine, Mail Stop
455, Philadelphia,
Pennsylvania
19102.
Received June 19, 1995; accepted February 22, 1996.
0090-3019/96/$15.00
PII SOO90-3019(96)00200
T
ax01 is a diterpene alkaloid that was isolated
from the bark of TQXUSbreuifolia [21]. It has a
unique mechanism of cytotoxic action as it promotes the formation of microtubule
polymers by
binding to the beta-subunit of tubulin, as well as
stimulating tubulin production.
At high doses, it
effectively prevents normal microtubule
function
and results in microtubular
aggregation and cell
death. The binding is reversible, and its site is different from the binding sites of colchicine and vinblastine. It is being used extensively as an anticancer agent and has been especially useful in the
treatment of ovarian cancer [4].
In this study, we propose to use taxol as an
agent to preserve spinal cord function after injury
and to compare it to the well-studied
effects of
4-aminopyridine
(4-AP) used in chronic injuries
[12,13] and methylprednisolone
(MP) used in
acute injuries [5,11,22]. The basis for the study is
that taxol preserves microtubules
and stimulates
tubulin production,
allowing for the stabilization
and preservation
of the cytoskeleton
of spinal
cord axons following injury.
We propose that taxol, when used at a low dose
following an acute spinal cord injury (SCl), will act
to protect the cytoskeleton
of spinal axons with
limited systemic effects. This could allow for the
maintenance of neuronal shape and the intracellular transport of vesicles and cellular organelles. The
effects of taxol are compared to both MP and 4-AP,
which are agents that have been reported to improve recovery of function after acute and chronic
SCI.
655 Avenue
0 1996 by Elsevier Science Inc.
of the Americas,
New York, NY 10010
Effects of Taxol, Methylprednisolone,
and 4-Aminopyridine
MATERIALSANDMETHODS
DETERMINATION
OF TAXOL
DOSE
To test the doses of taxol to be used in this experiment, four Sprague-Dawley male rats weighing between 530 g to 590 g received a daily dose of 18.75
mg/m2 6 days a week for 2 weeks, which was close
to half the LDlO for five daily intraperitoneal
doses
according to the recent study by The National Cancer Institute [19]. All animals demonstrated
weakness, mild dehydration, loss of weight and hair, and
porphyrinic
staining around the snout. The only
necropsy finding consisted of a mild pericholangial
lymphoid infiltrate (N = 3).
ANIMAL
PREPARATION
AND
SURGICAL
PROCEDURE
Thirty-nine
male Sprague-Dawley
rats weighing
465 g to 585 g were used. Halothane anesthesia was
induced at 4% concentration.
The anesthetized animals were transferred to the operating table, and
the anesthesia was continued using a gas mask. The
animals were fixed to a stereotactic frame and were
placed in a prone position on a heating blanket to
maintain their body temperatures
at 36.5 2 1°C.
The electrocardiogram
was recorded
using a
physiograph.
EVOKED
POTENTIAL
RECORDING
TECHNIQUE
Cortical somatosensory
evoked potentials (CSEPs)
were recorded by placing an active needle electrode in the midline scalp. The reference electrode
was placed in contact with the hard palate using a
disc electrode. The time base was set at 70 msec.
Low/high cutoff filters were set at 10 and 500 Hz.
The number of averages was 175-250. The tibia1
nerve was stimulated by placing two needle electrodes in the plantar surface of the right hind paw
adjacent to the nerve. An isolated stimulus (0.2
msec in duration at 2.81 Hz) was given at 5 to 8 volts
using an isolation unit. The CSEPs were recorded
by a signal averager. At least two traces were
obtained to ensure the reproducibility
of the responses. After the baseline CSEPs were recorded,
and under sterile conditions, a midline incision at
the lower thoracic level was performed. A TlO-Tll
dorsal laminectomy
was performed. An aluminum
compression device (weighing 5 g) with a concave
contact surface (4 X 4 mm) was positioned on the
dorsal midline of the spinal cord. The compressive
injury was produced by placing a 45-g weight on the
platform for 1 minute.
Surg Neurol
1996;46:350-7
35 1
PHARMACOLOGIC
TREATMENT
After the compression
injury, the rats (N = 10)
received one single 30 mg/kg intraperitoneal
injection of MP or 18.75 mg/m’ of taxol (N = 10). The
taxol group received two more injections on the
14th and 21st days after injury. The dosing schedule
for the taxol-treated animals was adopted according to several phase I studies on taxol [ 171. The 4-AP
group (N = 10) received 1 mg/kg intraperitoneal
injections on the 25th, 26th, and 27th days postinjury. The control animals (N = 9) received no specific treatment. All animals were closely monitored
for 4 weeks.
POSTOPERATIVE
CARE
All animals received ampicillin 50 mg/kg intramuscularly before and every 6 hours after the surgery
up to 24 hours. Buprenorphine
0.01 mg/kg subcutaneously was also administered to relieve postoperative pain. The urinary bladder was expressed 4
times a day until full recovery of spontaneous
micturition.
BEHAVIORAL
TESTS
During a l-month observation period, each animal
was subjected to a behavior examination
using
three tests: the inclined plane [ 161, toe spreading,
and a modified Tarlov’s scale [lo]. These tests were
performed on days 3, 5, 7, 14, 21, and 28 for all
animals. The rats receiving 4-AP were examined on
the 26th and the 27th days postinjury. These tests
were performed, in a blind fashion, by a second
investigator and were scored as follows:
(a) The inclined plane (lP) is an objective method to
evaluate the rat’s motor behavior after SCI [ 161.
The maximum inclination of the plane at which a
rat could maintain itself for 5 seconds, the “capacity angle,” was recorded.
(b) Toe spreading. This reflex was elicited as the rat
was picked up by the body and the hind limbs
and allowed to hang free [lo]. The results for the
best limb were recorded.
(c) Modified Tarlov’s scale. To test hind limb motor
function during locomotion, an adaptation of the
modified Tarlov’s scale [lo] was used. After 1
month, the animals were anesthetized with sodium pentobarbital
(5 mg/kg), and CSEPs were
recorded.
STATISTICAL
ANALYSIS
The Kruskal Wallis test [l] was used to test for
differences in the mean responses among the four
groups of variables related to motor behavior and
the evoked responses. If the Kruskal Wallis tests
352
II
Surg Neurol
1996;46:350-7
Comparison of the Behavioral Scores (inclined Plane, Toe Spreading, and Tarlov’s Scale) in Nontreated Animals
and Treated Animals
WEIGHT
Control
Tax01
MP
4AP
Perez-Espejo et al
?
523.0
29.3
524.4 t 23.9
532.4 ? 34.4
535.2 ? 33.7
IPB
61.6
61.0
61.4
61.0
? 1.4
+ 0.9
k 0.9
t 1.0
Abbreviations:
MP, methylprednisolone-treated
and 28th day (lP28D); TQD, toe-spreading
reflex
Values are means -+ standard deviation.
IP3D
26.1
32.0
30.0
25.6
k
+
+
+
IP28D
2.4
3.6
4.7
2.1
51.4
54.8
54.7
51.0
+
+
+
2
2.7
2.5
3.7
5.5
TSSD
0.5
0.9
0.8
0.4
5
?
t
5
0.5
0.3
0.7
0.5
TS28D
TRLVQD
TRLV~~D
1.7 + 0.4
2.0 2 0.0
1.2 + 0.6
1.7 2 0.4
3.5
4.5
4.6
3.7
1.9 t- 0.3
1.4 2 0.7
1.7 -t 0.4
0.8 ? 0.6
t 0.7
? 0.7
? 0.8
? 1.1
animals; ‘LAP, kaminopyridine-treated
animals; IP, inclined plane scores at baseline, 3rd day (lP3D),
at 3rd day and 28th day (TS28D); TrlvJD, modified Tarlov’s scale at 3rd day and 28th day (Trlv28D).
RESULTS
were significant at a 0.05 level, multiple comparison
procedures were used to examine differences be
tween groups. Dunn’s method [8] was used for the
multiple comparisons.
The observed differences
that were significant using an 0.05 level for comparison were noted. Differences that were also significant at a 0.10 level using the more conservative
experimental rate were also noted. When comparing four groups, there were six pair comparisons,
hence a 0.10 experimental
rate corresponds
to a
0.10/6 = 0.0167 comparison rate. The choice of 0.10
for an experimental error rate is consistent with the
suggestion of Daniel [ 61.
EFFECT
OF DAILY
DOSAGE
OF
TAXOL
IN ANIMALS
The four animals which received 18.75 mg/m2/day
of taxol became weak with sluggish movements after 2 weeks. These animals presented dehydration
with hair loss. Eyes and snout showed circumferential porphyrin stain. Weight loss and diarrhea
were apparent in all animals. All the animals were
killed after 2 weeks. At necropsy, no histologic
changes were found except for a mild pericholangial lymphoid infiltrate.
EUTHANASIA
AND HISTOLOGIC
STUDIES
The animals were euthanized with transcardiac injection of sodium pentobarbital.
Ten mm of spinal
cord inclusive of the injured segment was immediately removed. Light microscopic,
electron microscopic (EM), and tubulin studies were performed in
seven animals in each group. A tissue slice from the
most rostra1 portion of the spinal cord segment was
frozen. These tissue specimens were treated with
phosphate buffer saline l/200 solution of mouse
monoclonal antibeta tubulin and mouse immunoglobulin G plus fluorescein isothiocyanate
isomer 1.
The central part of the spinal cord segments were
fixed in 2% glutaraldehyde
and specimens were
treated either for the EM or light microscopic studies (hematoxylineosin
stain), respectively. A video
camera was adapted to the microscope.
Images
were transferred using a video digital system to a
computer fed with an image-processing system. lmages were reconstructed
on the computer screen
and digitally contoured both for the total crosssectional area and the injured area of the spinal
cord. Quantitative
data were obtained from the
computer software (in pixels). These data were
used to obtain a table of “proportions”
(see Table 4
later) from the specimens of each group of animals,
to study the mean differences among these groups.
SPINAL-CORD-INJURED
ANIMALS
The 39 animals used in this study were randomly
assigned to different treatment groups. Postinjury,
taxol and MP-treated rats appeared to regain spontaneous micturition
faster, averaging 3.4 days and
3.5 days, respectively,
compared to control and
4-AP-treated animals, which averaged 4 days and
4.3 days. Transient hematuria was found in all
groups of animals, particularly in MP-treated rats
(iV = 8), in comparison
to the other groupscontrol (iV = 5), 4-AP (1 = 4) and taxol (N = 2).
All animals partially recovered hind limb movement and the ability to walk, with different degrees
of impairment. The baseline values for weight, IP
scores, toe-spreading reflex, and Tarlov score (lable 1) and the CSEPs latency, and amplitude (Table
2) are summarized.
Since the animals were randomly assigned to the treatment groups, the baseline values for IP scores, weight, latency, and amplitude of CSEPs were not expected to be different
and indeed the Kruskal Wallis test [l] indicated no
differences between these variables. At 28 days
postinjury,
comparison
of the variable changes
from baseline were defined as [(baseline value) (28-day value)]/baseline
value. Although none of
the animals fully recovered after 4 weeks, we found
a statistically significant improvement
of 1P scores
in the taxol- and MP-treated groups, on day 3 @ =
Effects of Taxol, Methylprednisolone,
and 4Aminopyridine
Surg Neurol
1996:46:350-7
353
Comparison of the Cortical Somatosensory Evoked Potential Latency and Amplitude, which were Obtained in
Different Groups Before and After Spinal Cord Injury
BASELJNE CSEPs
AMPLITUDE (mv)
Control
Tax01
MP
4-AP
LATENCY
(mSeC)
4 WEEKS ARER INJURY
AMPLITUDE (mv)
LATENCY
(msec)
2.96 k 0.95
14.49 + 0.65
1.43 ? 0.69
15.50 +- 2.56
2.68 2 0.67
2.64 ? 0.78
14.01 + 0.65
14.23 + 0.98
2.45 ? 0.78
1.25 -f 0.39
15.37 ? 1.06
16.30 ? 1.36
3.15 t 1.75
14.40 + 0.74
1.72 ? 0.63
16.47 +-0.36
Abbreviations:
MP, methylprednisolone-treated
Values are means 2 standard deviation.
animals;
4-AP, 4-aminopyridine-treated
animals.
MP also recovered CSEPs, but their latency was
longer (16.30 + 1.36 msec) than the taxol group
(Tables 2 and 3). The relative mean difference between baseline latency and the 28th-day latency
was smaller for the taxol-treated group (1.36 msec),
compared to the MP-treated group (2.07 msec).
However, these differences in the CSEP latency
were not statistically
significant (Table 3). The
taxol-treated animals had the highest amplitude recovery value (2.45 t 0.78 mV) at day 28 (Table 2)
which was significant Cp = 0.03, Table 3). The control and 4-AP groups were not quantitatively
com-
0.001) and at 28 days @ = 0.018). The IP improvement was consistent with the Tarlov’s score at 28
days @ = 0.006). Although
there was some improvement in the toespreading
reflex at 28 days in
these animals (Table l), it did not reach a significant level @ = 0.27).
Injury immediately
obliterated
CSEPs in all ani-
mals (Figure 1). Analysis of the data at 4 weeks
showed the recovered CSEPs to have delay in latency (Table 2). All taxol-treated
rats recovered
CSEPs, with their latency being the shortest of all
groups: 15.37 + 1.06 msec. All animals treated with
Immediately after 50
gram injury
Four weeks
after injury
Control
Methylprednisolone
4-Aminopyridine
II_
70
0
35
70
Time (msec)
Representative traces of CSEPsfor each group of animals, at baseline (left column), immediately after SC1(center
column) and 4 weeks after SC1(right column). The traces for control animals and 4AP-treated animals correspond
to rats that did not fully recover CSEPs4 weeks after the SCI.
354
Surg Neurol
1996;46:350-7
Perez-Espejo et al
Comparison of Variables (Latency, Amplitude, InEl
clined Plane Score, Toe-Spread Score, and Tarlov
Score) among Treated and Nontreated Animals.
CA) Comoarisons at 4 weeks (28 davs).
VARIABLE
Latency
Amplitude
Inclined plane
Toe spread
Tarlov score
VAPLUE
.299
.030
.018
.272
.006
PAIR DIFFERENCES
Not significant
TxlXtl; Txl>4-AP; Txl>MP*
Ctl<MP*; Ctl<Txl*
Not significant
4-AP<MP; 4-AP<Txl, Ctl<MP*;
Ctl<Txl*
@) Comparison at 3 days. This is to look at early
responses. Since the two groups (control) and 4-AP
were both “control” groups as the treatment had not
yet started for 4-AP animals, they were combined.
PAIR
VARIABLE
Inclined plane
V&E
.OOl
DIFF’ERFWES’
Txl>Ctl*; MP>Ctl*
‘Pairs listed have means that are significantly
different
based on
Dunn’s method of multiple comparisons
and using a 0.05 comparison
error rate. Those indicated
by an asterisk (*) are significant
at a 0.10
experimental
error rate using a Bonferroni
adjustment.
Abbreviations:
Ctl, control group; LAP. Caminopyridine
group: Txl,
taxol group; MP, methylprednisolone
group.
pared with the taxol and MP-treated animals; but it
was taken into account that they showed incomplete recovery (Figure 1).
Among the 4AP group (N = lo), five animals
showed slight clinical improvement after 26,27, and
28 days postinjury, which was not more than 3
degrees for IP scores or 1 point for the modified
Tarlov’s scale (Table 1).
HISTOLOGIC
ANALYSIS
At light microscopy level, necrotic tissues and cavity formation were the most evident lesions in all
specimens (Figure 2). Central cord and dorsal columns, including the pyramidal tracts, located at the
dorsal white matter near the central canal in the rat,
were more seriously injured than anterior white
matter. Gross morphometric
analysis of specimens
showed smaller injured areas for the corresponding
groups of taxol and MP-treated animals in comparison with control and 4AP treated rats (Table 4).
The EM study showed disruption and bulging areas
of myelin sheath, vacuolization,
and widening of
periaxonal spaces in all specimens (Figure 3). As far
as the neuronal cytoskeleton
is concerned, microtubules were more dense and prominent in taxol
specimens (Figure 4) than in control, MP-treated,
and 4AP treated animals, where microfilaments
were predominant
(Figures 3, 5, 6). There was no
difference between control and the drugs tested on
immunofluorescence.
DISCUSSION
METHYLPREDNISOLONE
THERAPY
Steroids, particularly large doses of MP given as a
bolus injection shortly after the injury, significantly
enhance functional recovery [5,11]. This effect is
achieved either by the reduction of the injuryinduced lipid peroxidation,
by the facilitation
of
impulse generation, or by the enhancement of spinal cord blood flow [2,22].
The lipid peroxidation
process plays a crucial
role in the evolution of the secondary changes in
the injured spinal cord. This fact has been linked to
the postinjury microvascular damage and hypoperfusion, which lead to the secondary
ischemic
events in the tissue [ 141. Therefore, the importance
of prompt treatment
(less than 8 hours after
trauma) has been recognized. This fact has also
been stressed in the Second National Acute Spinal
Cord Injury Study [5]. This study also confirms the
beneficial effect of early treatment with steroids in
spinal injury. We found a significant improvement
of IP scores in the MP-treated groups on day 3 and
at 28 days postinjury.
The IP improvement
was
consistent with the Tarlov’s score at 28 days.
4-AMINOPYRIDINE
THERAPY
In chronic SCI, the demyelination
process has been
proven to be an important factor contributing
to
long-term sensory and motor impairments, The loss
of myelin sheath promotes the exposure of K+
channels on axons, which leads to an excessive Kf
efflux into the extracellular
space, thus opposing
depolarization
and interfering with conduction
in
demyelinating axons [ 131. Therefore, blockers of Kf
channels, such as 4AP, should facilitate propagation of impulses through
demyelinated
axons.
Four-AP has been shown to be effective in restoring
some sensory and motor functions in chronic but
incomplete SC1 models using a 1 mg/kg intravenous
(IV) dose, which appears to be within the limit of
safety in animals. In chronic and incomplete SC1
patients, 1835 mg IV of 4AP has been successfully
used with improvement
in sensory scores, chronic
pain, and spasticity [ 121. However, only slight improvement has been observed in motor function. In
a recent clinical trial, 4AP was administered
to
eight patients in a randomized, doubleblind,
crossover fashion. The treatment with 4AP was associated with significant but temporary neurologic im-
Effects of Taxol, Methylprednisolone,
and 4Aminopyridine
Surg Neurol
1996;46:350-7
355
Cross sections from the spinal cord at 28 days postinjury. Necrotic tissue and cavity formations are evident in all
specimens: (A) control; (B) taxol; (C) methyprednisolone; (D) 4aminopyridine.
provement in five of six incomplete SC1 patients.
Since the effect of 4-AP persisted 48 hours after
termination
of the drug infusion, authors speculated that there were other possible factors involved that were independent of the primary action
of 4-AP on K+ channels [13].
In our study, we have hypothesized
that 4-AP
administration
should improve the neurologic outcome when given to chronically injured animals at
days 25, 26, and 27 postinjury.
The neurologic
scores obtained on day 28 were not significantly
better than those of the control animals. The fact
that we have not seen any improvement
in our
animals does not exclude possible beneficial effects
of this compound. It is possible that we have missed
the transient neurologic improvement occurring after administration
of 4-AP or that animals in this
1 Gross Morphometric Analysis of Proportions of In0Cord
jured Areas from the Whole Section of the Spinal
Control group
Tax01 group
Methylprednisolone group
4-Arninopyridine group
Values
are means
of percentages
36.29
22.89
26.22
38.77
-C standard
deviation
+
2
2
?
21.74
17.88
16.13
17.22
Electron-microscopic appearance of the spinal cord
specimen 28 days after spinal cord injury in a control animal. Note disruption and bulging areas (asterisk)
of myelin sheath. Vacuolization and widening of periaxonal spaces are also evident. Microfilaments are predominant in the cytoskeleton. (X 4.500).
356
Perez-Espejo et al
Surg Neurol
1996;46:350-7
Electron micrograph of a taxol-treated spinal cord
qqand1 more
specimen. Microtubules
are evident
dense in some areas
(X
(small
(large
arrows)
arrows)
received minimal demyelination,
haps remyelination
has occurred.
group
(X
in the 4-AP treated
20.000).
and per-
TAXOL
THERAPY
Taxol’s mechanism of action was proposed in 1979
by Schiff and coworkers [ 181. Tax01 binds to microtubules, which are made of subunits of tubulin assembled molecules [9]. Tubulin, the main structural
protein of microtubules,
is composed of polypeptides alpha-tubulin and beta-tubulin. They can convert quickly between assembly and disassembly
with growth dependent
on a tubulin-guanosine
triphosphate
cap at the plus end of the organelle.
Microtubules
interact
with. proteins
called
microtubule-associated
proteins, which control axonal growth [15]. Microtubules
represent major
structural elements in growing axons [3].
Experiments with H3 taxol suggest that microtubules have a single set of saturable taxol-binding
Electron micrograph of the spinal cord in a
Ia
methylprednisolone-treated
animal: cytoskeleton is
mainly composed of microfilaments
20.000).
(X
Microfilaments are predominant
rats’ cytoskeleton
10.000).
sites located on the tubulin dimers [19]. Tax01 stabilizes microtubules
and shifts the dynamic equilibrium towards microtubule
assembly. Previous
experimental
studies with taxol in peripheral neuropathy showed that myelinated and regenerated
axonal branches growing after sciatic nerve injury
had a high aggregation or assembly of microtubules, while the degenerating branches showed an
unexpected
lower concentration
of microtubules
Lm.
In the nervous system, peripheral neurotoxicity
has frequently been observed after 6- to 24-hour
infusions of taxol. Toxicity has been rare at doses
below 170 mg/m’ in humans. The value of microtubule stability has not been suggested as a possible
mechanism to lessen the development of secondary
changes after SCI. It seems paradoxical that a compound, which promotes peripheral neuropathy
at
high doses, may have a beneficial or protective
effect on incomplete spinal cord injuries when given
in small doses. This is an important step, since low
concentrations
of taxol have recently been found to
suppress the rate and extent of shortening at plus
ends associated with increase in microtubule polymerization, and only at high doses are microtubule
dynamics completely suppressed [ 71.
In this study we found a significant improvement
in IP scores in the taxol-treated group, on the 3rd
day and at 28 days postinjury. The IP improvement
in this group was consistent with the Tarlov’s score
at 28 days. Analysis of the evoked-responses
data
showed all taxol-treated rats recovered CSEPs, with
their latency being the shortest of all groups. As far
as the CSEP amplitude, the taxol group had the
highest recovery value on day 28. In our model,
although both latency and amplitude of the CSEPs
correlated with behavioral recovery for each group
Effects of Taxol, Methylprednisolone,
and 4-Aminopyridine
of animals, the taxol group showed the highest improvement
in amplitude, which was statistically
significant.
In our study, the animals treated with low doses
of taxol administered shortly after the compressive
SC1 did well as far as behavioral and electrophysiologic studies were concerned. In addition, our data
suggested comparable beneficial results if only one
megadose of MP (30 mg/kg) in a single bolus injection was given shortly after the SCI. Both taxol and
MP-treated animals also showed less injury area in
gross morphometric
analysis of specimens. In addition, in the taxol-treated
animals, microtubules
were more dense and prominent than in the rest of
the samples. We did not find any beneficial effect of
4-AP when this drug was administered
at a 1 mg/
kg/day dosage.
The results of this study show that taxol has a
significant effect on the recovery of function after
spinal injury. We postulate, but do not prove, that
this is the result of microtubule
stabilization
and
increased tubulin synthesis. New studies are in
progress that will specifically address those issues.
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COMMENTARY
This is an interesting animal pilot study comparing
the efficacy of taxol with methylprednisolone
and
4-aminopyridine.
The injury was caused by compression, and outcome measures included motor
scores and voltage and latency of evoked potentials. The study is of interest since a beneficial effect
was found for taxol, which indicates that a previously untested pharmacologic
strategy may be
worth pursuing: preservation of microtubules. On a
minor note, I am not clear as to why a chronic effect
drug (4aminopyridine)
was included in this drug
screen.
Howard M. Eisenberg, M.D.
Division of Neurological Surgery
University of Maryland School of Medicine
Baltimore, Maryland
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