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Axonal transport in the motor neurons of rats with neuropathy induced by p-bromophenylacetylurea.

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Axonal Transport in the Motor Neurons
of Rats with Neuropathy Induced
by p-Bromophenylacetylurea
Hiroshi Nagata, MD,* and Stephen Brimijoin, PhD
Axonal transport was studied in sciatic motor neurons of rats with neuropathy induced by p-bromophenylacetylurea
(BPAU) in dimethylsulfoxide solution. Control rats were treated with the vehicle alone. To label rapidly transported
proteins, the rats received an injection of 35S-methionineinto the ventral horn of the spinal cord at the L1 vertebral
level. Radiolabeled protein was collected at ligatures applied on the sciatic nerve at intervals thereafter. In animals
with severe motor weakness owing to treatment with BPAU, 400 mglkg, there was evidence of increased delivery of
labeled protein into the axon during the early period after isotope injection, but reduced delivery later. A dosedependent decrease in the amount of labeled protein recirculated by retrograde axonal transport was also noted. A
significant reduction in the amount of protein transported retrogradely was also detected during the latent subclinical
phase of the neuropathy. The velocity of rapid anterograde transport, examined in unligated sciatic nerves, was
unaffected by BPAU treatment. However, the lag time between precursor injection and the onset of transport was
shorter in BPAU-treated rats than in controls. This effect was not explainable on the basis of fluctuations in core body
temperature. The results are consistent with the view that disturbances of rapid anterograde and retrograde transport
play a role in the peripheral neurotoxicity of BPAU. Attention is directed to the possibility that the transport
disturbances and the subsequent neuropathy are related to alterations in the processing of rapidly transported membrane-limited organelles in the nerve cell bodies.
Nagata H, Brimijoin S: Axonal transport in the motor neurons of rats with neuropathy induced by
p-bromophenylacetylurea. Ann Neurol 19458-464, 1986
The mechanism of dying-back disorders or distal axonopathies of human peripheral nerve is a subject of
great clinical interest about which we have little solid
information and few plausible hypotheses at present
{S, 191. One idea that has received passing support is
that defects of axonal transport promote pathological
changes in distal nerve regions by blocking the supply
of critical macromolecules needed for the maintenance
of cell structure [4, 61. In fact, abnormal transport of
cytoskeletal proteins has been established as a likely
cause of the proximal axonopathy caused by p$’dipropio-iminonitrile administration (1 2, 131 and offered as a blanket explanation for filamentous neuropathology [ll]. More than a decade of intensive
investigation, however, has failed to link a true failure
of axonal transport to any distal axonopathy {S].
One of the more attractive strategies for investigating distal axonopathy involves the experimental induction of peripheral nerve disease by neurotoxicants. Because timing, dosage, and severity can be closely
controlled in model systems, one can demonstrate the
order of events in pathogenesis and perhaps show
causal interrelations. Using methology developed by
Bisby (21, Sahenk and Mendell 1231 recently provided
evidence that the toxic axonopathy induced by zinc
pyridinethione is associated with a defect in transport
turnaround. Jakobsen and Sidenius C17) have made
similar observations in acrylamide-induced neuropathy. The neurotoxicity of these compounds may be at
least partly caused by interference with the reversid of
rapid anterograde transport in the distal part of the
nerve cell, which normally shunts excess material into
retrograde transport for later disposal in the cell body.
Previous results from our laboratory suggested that
a defect in transport turnaround occurs in the distal
neurotoxicity induced by p-bromophenylacetylurea
(BPAU), a toxicant first described by Diezel and
Quadbeck {lo]. The toxicant is especially interesting
because the lengthy latent period before onset of
neurological dysfunction [9] allowed us to show that
transport abnormalities preceded other signs of axonal
damage {l5, 161. The abnormalities have not been
From the Department of Pharmacology, Mayo Clinic, Rochester,
Received Tulv 8, 1985. and in revised form Sept 5. Accepted for
publication Sept 27, 1985.
Address reprint requests to Dr Nagata, in Rochester
‘Dr Nagata is on leave from the Department of Neurology, Kyoto
University, Kyoto, Japan.
fully characterized, however, and have not been
studied in the motor system, which is responsible for
most of the clinical manifestations of the neuropathy
(e.g., hindlimb weakness). We now report a systematic
investigation of the effects of BPAU o n axonal transport in motor neurons. The results strongly support
the concept of a pathogenic defect in the recirculation
of rapidly transported proteins in distal portions of the
nerve cell, while suggesting that the primary events
responsible for this defect may occur at the level of the
nerve cell body.
Materials and Methods
Induction and Grading of BPAU Neuropathy
BPAU was synthesized as described previously { l b ] . The
product, identified by melting point determination and nuclear magnetic resonance spectroscopy, was administered to
mature male albino rats (Holtzmann, Madison, WI) weighing
between 300 and 350 gm. The rats were injected intraperitoneally under light ether anesthesia with BPAU dissolved in dimethylsulfoxide (DMSO) at a concentration of
150 mglml. The standard protocol for induction of severe
neuropathy was two intraperitoneal injections of toxicant, of
200 mg/kg each, 7 days apart. Weight-matched control animals received equivalent volumes of DMSO vehicle.
The system for grading the BPAU-induced neuropathy
was modified from that of Cavanagh and co-workers {9].The
scores assigned were: 0 (normal function), 1 (waddling gait),
2 (splaying of the hindlimbs and progression by paddling), 3
(total hindlimb paralysis), and 4 (total hindlimb paralysis plus
marked forelimb weakness). Animals were evaluated frequently during the onset of neuropathy. In the case of doseresponse studies, the evaluations were made by a “blinded”
observer, unaware of the treatment schedule.
Isotope Injection
To label newly synthesized proteins in motor nerves, a
radioactive amino acid was injected into the ventral horn of
the spinal cord. Under pentobarbital anesthesia (40 mglkg
intraperitoneally) supplemented as needed with ether, an extensive laminectomy was performed to expose the spinal
cord from vertebral level T12 to L3. A solution of 35Smethionine (30 mCi/ml) was prepared by vacuum centrifugation and reconstitution in 0.9% NaC1. The isotope was delivered through a glass micropipette (tip diameter, 40 to 80
Fm) mounted on a micromanipulator. Each rat received 4 pl
at the L1 vertebral level on one side and two additional
injections of 2 pl at 1-mm intervals on the same side. Core
body temperature was frequently measured during the period of isotope injection and anesthesia by means of thermistor probes placed in the paraspinal musculature. In one series
of experiments, the temperature was “held” at 38°C with the
aid of a heat lamp.
Nerve Ligation and Measurements
of Protein Accumulation
At definite intervals after isotope injection, double collection
crushes were made on the sciatic nerve on the injected side
by silk ligatures (4-0 gauge), spaced 9 mm apart in the mid-
thigh region. Three hours after ligation, the rat was killed by
deep ether anesthesia and the sciatic nerve was removed.
The nerve was cut into 3-mm segments: two collection segments (just above the proximal and below the distal ligature),
and three interligature segments. The nerve segments were
treated overnight with 10% trichloroacetic acid to remove
free amino acids and were then digested in Soluene-100
(Packard Instruments, Downers Grove, IL) for scintillation
The residual radioactivity was assumed to reflect radiolabeled protein. The average radioactivity in the interligature
region was taken to reflect the concentration of this protein
at the time of ligation. The accumulation of labeled protein
in the collection segments was expressed as a percentage of
the interligature radioactivity: A = 1OO(C - ID), where A is
the accumulation, C is the radioactivity in the proximal or
distal collection segment, and I is the mean radioactivity in
the interligature region. This calculation made it possible to
normalize data from individual experiments in which the total amount of radiolabel exported into the axon varied
Measurements of Transport Velocity
The rats were killed at intervals after isotope injection and
the sciatic nerves were sectioned at the iliac notch. The
nerves were then cut into 3-mm segments and digested for
analysis of radiolabeled protein as described above. The
point where the steeply sloping edge of the radiolabel wavefront intersected the background radioactivity was determined for each nerve. This point was assumed to represent
the most distal position reached by fast transported protein.
For precise information on the distance traveled, the sciatic
nerve was exposed from the iliac notch to the injection site
in the spinal cord, and the total length was measured with a
ruler. The maximal velocity of fast transport was calculated
by computer fitting of the data to the equation: D = V(T ti, where D is the distance traveled by the wavefront, V is the
velocity, T is the time elapsed between isotope injection and
nerve removal, and t is the time until onset of rapid transport. To avoid the confounding effects of amino acid diffusion, nerve regions within 40 mm of the injection site were
not examined.
Eflect of BPAU on Accumulation
of Radiolabeled Protein in Ligated Nerve
Rats with severe motor neuropathy resulting from
treatment with BPAU received intraspinal injections
of 35S-methionine and were subjected to sciatic nerve
ligation 8, 16, 24, 39, or 48 hours later (see Materials
and Methods). After 3 hours of ligation, the nerves
were removed and the acid-insoluble radioactivity of
various segments was determined. The accumulation
of radioactivity in proximal and distal collection segments was measured as an index of the protein delivered by fast anterograde or retrograde axonal transport, respectively.
With an early collection period (8 to 11 hours after
isotope injection), there was an appreciable accumula-
Nagata and Brimijoin: Transport in BPAU-Neuropathy 459
2 400
16-19 hr
w 200
2 4 - 2 7 hr
a 2oo
4 8 - 5 1 hr
r i g 1 . Accumulation of radiolabeled proteins in proximal and
distal collection segments of doubly ligated rat sciatic nerve.
Shaded columns = data from rats treated with p-bromophenylacetylurea. 200 mgikg, on separate occasions, 24 and 7 h y s before experiment. White columns = data from control rats simultaneously treated with equivalent volumes of dimethylsulfoxide
vehicle. The nerves were ligated 8 to 48 hours after injection of
"S-methionine into the ventral horn of the spinal cord and were
removed 3 hours laterfor analysis of acid-insoluble radioactivity.
The values shown are percentage increases above the mean
radioactivity of the interligature zone (see text) and are expressed
as mean (column height) t SEM (vertical bars). Each group
consisted of4 to 5 rats, except for thoJe groups killed at 16 t o 19
homs afer isotope injection, which had 10 rats each.
tion of labeled material in the proximal collection segment (Fig 1). It is interesting that the accumulation rate
was about 50% greater in BPAU-treated rats than in
controls, although the difference was not statistically
significant. With later collection periods, there was less
proximal accumulation in BPAU-treated rats than in
controls (Fig 1). The difference between the groups
was significant at 16 to 19 hours ( t = 2.43, p < 0.05),
and a two-way analysis of variance showed an overall
difference for the period from 16 to 51 hours ( F =
4.78, p < 0.05).
Distal accumulation was nor apparent at 8 to 11
hours but became measurable later (Fig 1).The rate of
accumulation was nearly the same in both groups of
rats at 16 to 19 hours and at 24 to 27 hours. At 39 to
42 hours, however, there was much less accumulation
in the BPAU-treated animals (t = 2.73, p < 0.05). An
overall difference for the entire observation period
(from 8 to 51 hours) was revealed by a two-way analysis of variance ( F = 5.99, p < 0.02).
A better appreciation of the time course of proximal
and distal accumulation can be obtained by summing
the values obtained at each collection interval to pro-
460 Annals of Neurology
Vol 19 No 5
May 1986
Fig 2. Cumulative accumulation of radiolabeled protein over a
two-day period. The mean values (relativepercentage accumulation) obtained from each successive 3-hour collection period (.Fee
Fig 1) were added to reconstruct the time course of accumulation
oftransported protein. (Circles = accumulation at the proximal
ligature; triangles = accumulation at the distal ligature; filled
symbols = p-bromophenylacety(urea-treated groups; open
symbols = control groups.)
duce a cumulative accumulation curve (Fig 2). In the
case of proximal collection segments, the cumulative
curve for the BPAU-treated group at first rose more
steeply than did the control curve, then more slowly.
As a result, the two curves converged and intersected
near the end of the 51-hour observation period. In the
case of distal collection segments, the two curves rose
nearly in parallel at first but diverged sharply from 27
hours on, as accumulation in the BPAU-treated rats
effectively ceased. This was taken as clear evidence for
reduction in the amount of labeled protein being returned by retrograde axonal transport.
Radiolabeled Protein Accumulation in Early-Phase
BPAU Neuropathy
T o determine whether the effects of BPAU on axonal
transport preceded the appearance of clinical neuropathy, experiments were performed 4 days after treatment of rats with a single intraperitoneal injection of
the toxicant, 200 mg/kg. In this early phase of BPAU
neuropathy, the treated rats showed no disturbance of
gait or other signs of toxicity apart from minor wei,qht
loss (less than 10%). In the interest of efficiency we
chose a single collection period of 16 to 19 hours, an
interval during which preliminary experiments had
suggested there might be a difference in accumulation.
AS shown in Table 1, the distal accumulation of
labeled protein in early-phase BPAU neuropathy was
less than half that in control rats (p < 0.05). Proximal
accumulation was also reduced, although not to a statistically significant extent.
Table I. Accumulation Rate of "S-Methionine-Labeled Protein in Early BPAU-Induced Neuropathy
(Subclinical Phase, 4 Days after BPAU Administrationi and i n Advanced PhaJe Neuropathy (14 Days after Administration)"
Stage of
Relative Accumulation
Early phase
Advanced phase
127.8 2
122.7 2
135.7 2
88.9 Z
92.8 -+ 18.9
55.7 2 15.9b
71.5 2 11.3'
62.1 2 13.6
"The initial dose of BPAU was 200 mg/kg. To obtain advanced neuropathy, this dose was repeated after 1 week. Controls were treated with
corresponding volumes of dimethylsulfoxide vehicle. Collection ligatures were in place from 16 to 19 hours after isotope injection. Accumulation values are means t SEM.
hp < 0.01.
'p < 0.05.
Table 2. Alteration in Disability Score and Accumulation Rate of Labeled Protein
i n Rats Administered Various Doses of BPAU 14 Days Before Experimenta
Dose of BPAU
Relative Accumulation
Score of
269.0 t
325.9 t
186.3 2
145.3 2
146.1 5
173.9 2
155.4 2
102.7 2
"Controls were treated with dimethylsuifoxide vehicle only. Lgatures were in place from 24 to 40 hours after isotope iniection. Values are
means 2 SEM.
bSignificantdifference from controls (p < 0.05).
BPAU = p-bromophenylacetyluea.
Dose-Response Study
A dose-response study was carried out to characterize
further BPAU's ability to induce transport abnormalities. Body weight and neurological function were
measured at frequent intervals after treatment. Axonal
transport was assessed at 14 days by the doubleligature method, with a 24- to 40-hour period for collection of radiolabeled protein. Table 2 shows that
there were no apparent disturbances of motor function
after doses of 50 or 100 mg of BPAU per kilogram of
body weight, whereas moderate to severe disability
(scores 2 or 3) was induced by higher doses. Accumulation of labeled protein was largely unaffected by low
doses of BPAU (the apparent increases in rats treated
with 50 mglkg of toxicant were not significant). Both
proximal and distal accumulations of labeled protein
were significantly reduced in rats treated with the highest dose of toxicant (400 mgikg).
Unfortunately there were relatively few rats with
intermediate disability (scores of 1 or 2). This prevented a proper test of the correlation between disability and accumulation. However, it is worth noting that
the animals with hindlimb paralysis (disability score, 3 )
had lower accumulation than did animals with no
neurological signs (disability score, 0), regardless of the
BPAU dosage. Proximal accumulation was 130 t
15.1 relative units in disabled rats versus 238 t 17.8
in unaffected rats (p < 0.001). Distal accumulation was
101 2 11.7 units in disabled rats versus 165 & 7.4 in
unaffected rats (p < 0.001).
Transport VeIocity
Additional experiments were carried out to measure
the displacement of the waves of radiolabeled protein
in unligated sciatic nerves of 5 control rats and 5 rats
treated with BPAU, 400 mglkg, 7 days earlier. There
were large differences in absolute radiolabeling of the
nerves, probably owing to variable incorporation of
precursor by the ventral horn cells. The data were
therefore normalized by expressing the radioactivity of
each 3-mm nerve segment as a percentage of the average radioactivity for all segments of the same nerve,
distal to the iliac notch.
Figure 3 shows typical profiles of radiolabel in sciatic
nerves removed from control and BPAU-treated rats
at different times after injection of 35S-methionineinto
the ventral horn. Although the sampling times are not
strictly comparable, the wavefronts are somewhat fur-
Nagata and Brimijoin: Transport in BPAU-Neuropathy
Fig 3 . Profiles of migrating waves of radiolabeled protein in unligated sciatic nerve 4.5 hours after precursor injection into the
spinal cord. Shown are typical distributions of acid-insoluble
radioactivity along consecutive 3-mm segments of nerve. The
values have been normalized as percentages ofthe mean radioactivity per segment in the sampled region. p-Bromophenylacetylurea (BPAU) treatment was 400 mglkg intraperitoneally carried out 7 days previously. The control was treated with
dimethysulfxide vehicle. Arrows mark the points designated as
“wavefronts”(i.e., leading edges of the waves of radiolabeled protein).
ther advanced in the BPAU-treated animals than
might be expected. This effect is not due to a true
acceleration of axonal transport, as can be seen from
Figure 4, which shows the position of the wavefronts
as a function of time. Computer fitting of these data
(see Materials and Methods, measurement of transport
velocity) indicates that the maximal velocity of transport in BPAU-treated rats (15.24 -+ 0.18 d h r ) was
almost identical to that in controls (15.62 ’-+ 0.35 mm/
O n the other hand, the same results indicate a real
difference in the lag time or delay between precursor
injection and release of labeled proteins into the axon.
According to the computer calculations, the lag time in
control nerves was 1.31 2 0.08 hour, whereas in the
nerves of BPAU-treated rats it was only 0.17 k 0.05
hour. The difference is highly significant (p < 0.001).
We considered the possibility that these differences
in lag time reflected different degrees of anesthesiainduced hypothermia during the interval before onset
of rapid transport. Direct measurements from the
paraspinal musculature during the 1.5-hour injection
and recovery period did show a fall in body temperature that was greater in control rats than in BPAUintoxicated rats (Fig 5). However, experiments on 4
control rats showed that lag time was not reduced
by maintaining the core temperature at a modestly
elevated level of 38°C throughout the period of
anesthesia (calculated value, 1.18 k 0.14 hour). The
shortened lag time in BPAU neuropathy is therefore not explained by resistance to anesthesia-induced
hypo thermia.
462 Annals of Neurology Vol 19 No 5
May 1986
Fig 4.Effect of p-bromophenylacetylurea (BPAU) on the maximal velocity of rapid anterograde transport. The vertical axis
shows the distance from ihe injection site in the spinal cord to
the leading edge of the wave of radiolabeled protein. The horizuntal axis shows the time between precursor injection and removal
of the nerve. The regression lines were computer fitted by an unweighted least-squares method. The intersection of these lines
with the horizontal axis indicates the lag time between precursor
injection and the onset of rapid transport. (Filled circles =
BPAU-treated rats; open circles = control rats.)
Fig 5 . Effect of p-bromophenylacetylurea (BPAU) on anesthtsiainduced hypothermia. Core body temperature was measured by
means of a calibrated thermistorprobe implanted in the paraspinal masmkatare of 9 controls and 6 rats treated with BP14 U
(400 mglkg, 7 days earlier).Mean values t SEM are shown.
Asterisks indicate signrficant differences between treated and control rats at a given time: “p < 0.0s; “*p < 0.01; ***p <
Previous investigations have demonstrated several
striking concomitants of BPAU-induced neuropathy:
(1) large accumulations of tubulomembranous material
in distal and preterminal axons [3, 22); (2) deficits in
the accumulation of radiolabeled protein distal to liga-
tures placed a few hours after radioisotope injection
into spinal ganglia ClS}; and ( 3 ) apparently normal velocity and total flux of protein moving by rapid anterograde transport in sensory nerves 1153. Considering these facts, it has been argued that the cause of
BPAU neuropathy may be an impairment of the turnaround of transported protein and organelles at the
nerve terminal [ l 51. Until now the argument has been
incomplete, however, since the full time course of
labeled protein accumulation was unknown. Furthermore, although motor dysfunction is the main clinical
manifestation of BPAU neuropathy, the abnormalities
of transport had not been studied in motor nerves.
The present results demonstrate that BPAU does
impair the turnaround of rapidly transported proteins
in motor nerves, but probably not by reducing the rate
of this process. There is a delay between the onset of
accumulation of labeled protein proximal to a midthigh nerve crush and the onset of accumulation distal
to the crush. This delay reflects the time required for
fast-moving proteins to reach the distal part of the
nerve by anterograde axonal transport, to reverse direction, and to return by retrograde transport. In our
experiments, the total delay was on the order of 10
hours, as can be seen from Figure 2, and there was no
apparent difference between BPAU-treated and control preparations. The similar delays are consistent
with the finding that the maximal velocity of rapid
transport was unaffected by the toxicant; they also suggest that the time required for turnaround per se is
normal in BPAU neuropathy.
By contrast, our results show that BPAU treatment
definitely reduced the amount of labeled protein
turned around for retrograde axonal transport, especially during the second day after isotope injection.
This effect was dose related, was correlated with the
severity of motor dysfunction, and was apparent during the latent phase of the neuropathy (i.e., before the
onset of symptoms). Impairment of turnaround and
retrograde transport is therefore a reasonable candidate as a pathogenic mechanism. This suggestion is
compelling because impaired turnaround could lead
directly to the preterminal accumulations of membranous material that characterize BPAU-induced neuropathy C33.
Besides the deficit of retrograde transport, some evidence of BPAU-induced abnormality in rapid anterograde transport was uncovered by the present study.
First, although the anterograde flux of labeled protein
in BPAU-treated nerves may initially have been above
normal, it later fell to about 60% of control. Second,
although the maximal velocity of anterograde transport
was unaffected by BPAU, the lag time before onset of
transport was much reduced. These could be linked
effects. That is, an altered export of newly synthesized
protein from the cell bodies may explain the altered
time course of radiolabel accumulation in ligated nerve.
In particular, premature export could account for an
early increase in accumulation and for a later decrease.
The lag between injection of labeled amino acid arid
onset of rapid anterograde transport reflects the time
required for two major events, ribosomal protein synthesis and Golgi processing, including glycosylation
and the assembly of “transport-competent” organelles
C141. Protein synthesis is rapid and is unlikely to be
shortened by any toxicant. Golgi processing, on the
other hand, is a conceivable target for BPAU. Furthermore, if this processing were curtailed, the altered surface chemistry of the membranous particles delivered
for axonal transport might well cause abnormal behavior later, e.g., during transport turnaround.
The biochemical mechanism of BPAU-induced neuropathy, like that of other dying-back neuropathies or
distal axonopathies, is still obscure. It is believed that
some toxic neuropathies arise from an attack on glycolysis or other energy-transducing processes {24).
Such an event could lead to localized deficits in
adenosine triphosphate at distal sites with high energy
utilization, like the nodes of Ranvier. In turn, these
deficits could cause local failure of rapid axonal transport, an energy-intensive process [l, 18, 20, 211. The
end result might express itself physiologically as a reduction in the amount of endogenous protein returned
by retrograde transport, and ultrastructurally as a
paranodal accumulation of transported organelles.
However, a thorough recent search failed to detect any
effects of BPAU or BPAU metabolites on energy
transduction in rat sciatic nerve 171.
Obviously, more direct biochemical methods will be
needed to unravel the tangled question of the mechanism by which BPAU and related toxicants induce peripheral neuropathy. We suggest that the
pathogenesis may begin in the nerve cell body. It is
certainly worth focusing on the possibility that the primary event is an alteration in the processing of membrane-limited organelles being assembled for delivery
into the axon (a mechanism that would distinguish
BPAU from zinc pyridinethione, which appears to
cause a “pure” turnaround defect without cell body
changes C231). In the meanwhile, the present results
firmly establish BPAU-induced neuropathy on the list
of experimental nerve diseases that are important
models for the dying-back disorders of human peripheral nerve.
Supported partially by Grant NS 18170 from the National Institute
of Neurological and Communicative Disorders and Stroke Dr
Nagata is the recipient of a postdoctoral fellowship from the Muscular Dystrophy Association of America
We thank Drs Gerald Carlson and David l n d e r for valuable help in
the synthesis of BPAU, and Luanne Wussow for preparation of the
charts and editorial assistance with the manuscript
Nagata and Brimi join: Transport in BPAU-Neuropathy 463
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