12-39 .hwp133
Taxol
, ,
Original Article
⋅Received1 June 2012 ⋅Revised14 August 2012 ⋅Accepted14 August 2012
⋅Correspondence to(Cho Chung sik) 621 Tel : +82-41-521-7531, Fax : +82-41-521-7007, E-mail : choo1o2@chollian.net
Effects of YideungJetong-Tang on Peripheral Neuropathy Induced by Taxol and Compression Injury in the Rat Sciatic Nerve
Jeong Ho Young, Kim Chul Jung, Cho Chung sik Dept. of Internal Medicine, College of Oriental Medicine, Dae-Jeon University
Background: Most antitumor agents have the side effect of chemotherapy-induced peripheral neuropathy (CIPN). Cancer patients who take antitumor agents suffer from CIPN, but there is no known treatment for it. Unlike the central nerve system, the peripheral nerve can self-repair, and the Schwann cell takes this mechanism. Objectives: In this study, we researched the effect of YideungJetong-Tang (YJT) extract on taxol-induced sciatic nerve damage, through in vitro and in vivo experiments. Also, we studied the effect of YJT extract on neurite recovery and anti-inflammatory effect after compression injury of sciatic nerve in vivo. Methods: Vehicle, taxol and taxol+YJT were respectively applied on sciatic nerve cells of rat in vitro, then the cells were cultured. The sciatic nerve cells and Schwann cells were then observed using Neurofilament 200, Hoechst, β -tubulin, S-100β, caspase-3 and phospho-Erk1/2. CIPN was induced by taxol into the sciatic nerve of rat in vivo, then YJT extract was taken orally. The axons, Schwann cells and neurites of the DRG sensory nerve were then observed using Neurofilament 200, β-tubulin, Hoechst, S-100β, phospho-Erk1/2 and caspase-3. YJT was taken orally after sciatic nerve compression injury, and the changes in axon of the sciatic nerve, Schwann cells and TNF-α concentration were observed. Results: The taxol and YJT treated group showed significant effects on Schwann cell recovery, neurite growth and recovery. In vivo, YJT compared with control group showed Schwann cell structural improvement and axons recovering effect after taxol-induced Schwann cell damage. After sciatic nerve compression injury, recovery of distal axon, changes of Schwann cell distribution, and anti-inflammatory response were observed in the YJT. Conclusions: Through this study, we found that after taxol-induced neurite damage of sciatic nerve in vivo and in vitro, YJT had significant effects on sciatic nerve growth and Schwann cell structural improvement. In vivo, YJT improved recovery of distal axons and Schwann cells and had an anti-inflammatory effect.
Key Words : Taxol, YideungJetong-Tang (YJT), sciatic nerve, Schwann cell, TNF-α

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, , ,
33 3(2012 9) J Korean Oriental Med 2012;33(3):133-146
33 3 (2012 9)
134
(388)
, 1.
wallerian
3 (axon) ,
Schwann cell ,
2. , ,
, , , , , , , 3, , , ,
4.

(Chemotherapy-Induced Peripheral Neuropathy : CIPN) , cisplastin, taxol, carboplatin, oxaliplatin 5. CIPN
,
6-9, 50-90%
10.
. , , , ,
.

, 11. (YideungJetong-Tang
: YJT)
(BogiJetong-Tang : BJT)
. BJT ,
12 CIPN13
. YJT BJT , , , , ,
, () . , , , ,

, ,

. YJT
taxol CIPN, YJT
.

() 7-8, 200-250g male
, (Samyang Co.)
. 22-24oC, 50±10%
, (12 /)
.
.
2)
(Table 1). ()
. YJT 1,000
2 .
,
(-84oC)
. YJT 1 118g 23g 19% .
3)
Paclitaxel (taxol) Sigma
, 1/ 100% dimethylsulf- oxide (DMSO) -20
. Neurofilament 200 (Sigma, USA), β-Tubulin (Convence, USA), cleaved caspase 3 (Cell Signaling, USA), fluorescein goat anti-mouse IgG (Invitrogen, USA), rhodamine goat anti-rabbit IgG (Invitrogen, USA), Hoechst 33258 (Invitrogen, USA), phospho-p44/42 Erk1/2 kinase antibody (1:4,000, Cell Signaling, USA), goat anti-rabbit IgG-HRP (1:2,000, Santa Cruz Biotechnology, USA),
2 : Taxol
135
Herb Galenical name Amount(g) Astragali Radix 30 Ginseng Radix Alba 4 Angelicae Gigantis Radix 7.5 Cnidii Rhizoma 5
Paeoniae Radix Rubra 7.5 Salviae miltiorrhizae Radix 12 Persicae Semen 7.5 Carthami Flos 7.5 Spatholobi Caulis 12 Puerariae Radix 8 Uncariae Ramulus et Uncus 12 Albiziae Cortex 12
Total amount 118(g)
goat anti-mouse IgG-HRP(1:2,000, Santa Cruz Biotechnoloby, USA) .
4)
(rotary evaporator, Buchi B-480, Switzerland), (freeze dryer, Eyela FDU-540, Japan), (, Korea), thermo bath (ALB64, HanYoung, Korea), sonicator (model 100, Fisher scientific, USA), (Micro 17TR, Hanil, Korea), (80-6147-45, Amersham, USA), transfer unit (TE70, Amersham, USA), electrophoresis power supply (EPS 301, Amersham, USA), cryostat (CM 1850, LEICA, Germany), (Nikon DXM 1200F, Japan) .
2.

Banker Goslin 14.
coverslip poly-L-ornithine (0.1/, sigma) lam- inin (0.02/, collaborate research, USA)
pre-coating. Schwann cell DRG
sensory neuron , sciatic nerve lumbar 4-6 DRG sensory neuron
ice-cold Basal Media Eagle (BME) (Gibco, USA) . sciatic nerve DRG sensory neuron type XI collagenase (2,500U/, Sigma)
BME 37 90
. BME
3,000rpm 1 .
BME
pasteur pipette 16-20
3,000rpm 1
. Cell type trypsin (0.5/) BME 15 trypsin inhibitor (100/), EDTA (1mM) and DNase I (80/) BME 5 . {5% heat-inactivated FBS (fepal bovine serum), 5% horse serum, 2mM glutamine and 1% penicillin-streptomycin
BME} Schwann cell (1x104 cells per 12 coverslip in 24-well plate) DRG sensory neuron (1.5x102 cells neuron) 12 round coverslip
plating 37, 5 % CO2 incubator 12
. DRG sensory neuron taxol (0.01/), YJT (0.5/) DMSO 37, 5% CO2
48 .
136
(390)
(double immunofluorescence staining) , 4% paraformaldehyde, 4% sucrose (phosphate buf- fered saline; PBS) 45
. blocking buf- fer 4 16 . 1
2.5% bovine serum albumin (BSA, Sigma, USA), 2.5% horse serum blocking buffer 1:400
4 . 1
PBST (PBS plus 0.1% triton X-100) , 2.5% BSA, 2.5% horse serum
blocking buffer fluorescein-goat anti-mouse (green) rhodamine-goat anti-rabbit antibody(red) 1:400 1 30 2
. 2 3
PBST . Hoechst 2
0.25% Hoechst 33258 PBST PBST . 2 antibody
. sample
(Zeiss fluorescent microscope) 200 , images
Adobe Photoshop(ver. 5.5) green red
. photoshop program layer blending mode op- tions images
.
1 caspase-3 (1:500), Neurofilament 200 (1:400), β-tubulin (1:400), phospho-p44/42 Erk1/2 (1:400), S-100β(1:400) .
4 coverslip
(Schwann cell; 1x104 cells per 12 coverslip, DRG sensory neuron; 1.5x102 cells neuron)

digital image, i-solution software program
.
(i) DMSO (25)
(vehicle ) () taxol (1.25/)
(0.9% saline) (taxol ) () taxol (1.25/) YJT (400/)
(taxol + YJT ) . Taxol 25/
10 . taxol + YJT YJT, taxol
(0.9% saline) 5 1 1
. 3 .
(2)
(i) () (sciatic nerve injury; SNI) (0.9% saline) (saline ) ()
YJT (YJT )
. SD
30
. YJT YJT
saline (0.9% saline) 5 1 1 .
3 .
(3)
-20°C cryostat 20
.
. in vitro .
(4) Western blot
(i) DMSO (vehicle ) (ii) taxol (1.25 /) (taxol ) (iii) taxol (1.25/) YJT (400/)
(taxol + YJT ) sciatic nerve
DRG sensory neuron triton lysis buffer (20mM Tris, pH 7.4, 137mM NaCl, 25mM β
-glycerophosphate, pH 7.14, 2mM sodium py- rophosphate, 2mM EDTA, 1mM Na3VO4, 1%
2 : Taxol
137
(391)
Triton X-100, 10% glycerol, 5μg/ leupeptin, 5μg/ aprotinin, 2μM benzamidine, 0.5mM DTT, 1mM PMSF) . sam- ple , 10μg
western blot .
12% SDS-polyacrylamide gel (1.5M Trisma base, 10% sodium dodecyl sulfate, 30% acrylamide, 10% ammonium sulfate, TEMED)
PVDF membrane (Pall Corporation, USA)
. antibody
3% BSA, 0.1% Tween 20 TBS buffer membrane 1
4 16 blocking buffer
. membrane washing
1 blocking buffer (1×TBS buffer, 3% BSA, 0.1% Tween 20)
30 . membrane
goat anti-rabbit IgG anti-mouse IgG
2 1:2,000 30 .
membrane western blotting de- tection system Kodak Scientific Imaging Film (Eastman Kodak Co. USA) . 1 phos- pho-p44/42 Erk1/2 kinase antibody (1:4,000), cleaved caspase-3 antibody (1:1,500) .
(5) sample
Nikon

ACT-1 software . Photoshop image blend .
3)
, one-way ANOVA p 0.05
.
SPSS ver. 12 .


1) NF-200 Hoechst
Schwann cell
NF-200 taxol vehicle , taxol + YJT . Hoechst , taxol
Schwann cell taxol + YJT
vehicle (Fig. 1).
Fig. 1. Representative images of the growth process of DRG sensory neurons cocultured with
Schwann cells. Cells were cocultured in vitro as described in Materials and
Methods. Upper panel: Visualization of growth processes of DRG sensory neurons by immunofluorescence staining with
anti-NF-200 antibody (in green). Low panel: Individual nuclei in cultured cells were identified by Hoechst 33258 staining (blue). The same set of microscopic fields in each treatment was used for
NF-200 immunostaining and Hoechst nuclear staining. Decreases in neurite length by taxol treatment were recovered by YJT
treatment, and the number of Hoechst-stained nuclei, which was decreased by taxol treatment, was elevated to that of the vehicle
control. Scale bar: 100
Schwann cell
Taxol + YJT Schwann cell
DRG
, Hoechst 33258 Schwann cell
DRG
(Fig. 2).
138
Fig. 2. Colocalization of DRG sensory neurons and Schwann cells.
Representative images from co-cultured cells treated with taxol and YJT in vitro. S100β-stained Schwann cells together with individual nuclei as identified by Hoechst nuclear staining are
shown to be in close proximity to process growth of DRG sensory neurons (arrows). Scale bar: 50
Fig. 4. Comparison of individual nuclei of the sciatic nerve by Hoechst nuclear staining.
Individual drugs were treated in vivo as described in the Materials and Methods, and nuclei in the nerve were identified by Hoechst 33258 staining. (A) Representative images of longitudinal scaitic nerve sections. (B) Quantitative comparison of the number of nuclei among three experimental groups. N = 3, **p<0.01 (vs vehicle group), ++p<0.01 (vs Taxol group). Scale bar: 50
Fig. 3. Induction pattern of phospho-Erk1/2 proteins in DRG tissue after drug treatments in vivo.
After the treatments with vehicle, taxol, taxol plus YJT, DRG at lumber 5 were prepared and used for phospho-Erk1/2 protein
analysis by western blotting (A) and immunofluorescence staining (B). Strong phospho-Erk1/2 protein signals were detected by taxol and YJT cotreatments. (C) Immunofluorescence view of
phospho-Erk1/2 signals merged with Hoechst-stained nuclei for the sciatic nerve sections for taxol and YJT treated group. Scale
bar: 100

Vehicle phospho-Erk1/2
. taxol phospho-Erk1/2 . taxol + YJT phospho-Erk1/2
(Fig. 4A,B). Taxol + YJT
phospho-Erk1/2 Schwann cell (Fig. 3C).
2. Schwann cell
1) Hoechst
Taxol vehicle Schwann cell . taxol + YJT
Schwann cell vehicle
(Fig. 4A). Vehicle taxol Schwann cell taxol + YJT Schwann cell
(Fig. 4B).
2Caspase 3 Hoechest
Taxol caspase 3 tax- ol + YJT (Fig. 5A). Taxol Hoechst caspase 3
Schwann cell (Fig. 5B).
3) Caspase 3 Hoechst
Taxol caspase 3 tax- ol + YJT (Fig. 6A). Taxol Hoechst caspase 3
Schwann cell (Fig. 6B).
2 : Taxol
139
Fig. 5. Caspase 3 signals in the sciatic nerves after drug treatments.
After the treatments with vehicle, taxol, taxol plus YJT in vivo the nerves were prepared and used for immunofluorescence staining for caspase 3 protein signals. (A) Strong caspase 3 signals were seen in taxol-treated nerves (in red). (B) Immunofluorescence view of caspase 3 protein signals merged with Schwann cell
nuclei. Scale bars in (A) and (B): 100 μm and 50
Fig. 6. Determination of apoptotic cell death. Schwann cells were treated with vehicle, taxol, taxol plus YJT in vitro. Fixed cells were used for immunostaining with anti-caspase
3 primary antibody and rhodamine-conjugated secondary antibody (in red). (A) Immunofluorescence view of caspase 3
signals in cultured Schwann cells. (B) Morphological features of caspaase 3-positive Schwann cells which had been treated with
taxol. Scale bar: 50
Fig. 7. Morphological characteristics in Schwann cells after different treatments.
Schwann cells prepared from intact sciatic nerve were treated with vehicle, taxol, taxol plus YJT in vitro. Fixed cells were used for
immunostaining with anti-S100β primary antibody and rhodamine-conjugated secondary antibody (in red). Scale bar:
50
Fig. 8. Comparison of phospho-Erk1/2 signals in Schwann cells in vitro.
Fixed cells were used for immunostaining with phospho-Erk1/2 primary antibody and fluorescein-conjugated secondary antibody
(in green). (A) Immunofluorescence view of phospho-Erk1/2 signals in cultured Schwann cells. (B) Morphological features of Erk1/2 positive Schwann cells which had been treated with taxol plus YJT. It was noted that intense phospho-Erk1/2 signals were identified in non-nuclear cytoplasmic zone. Scale bars in (A) and
(B): 100 and 50

5) Phospho-Erk1/2
Phospho-Erk1/2 taxol + YJT
(Fig 8A). , taxol + YJT
phospho-Erk1/2
(Fig. 8B).
6) S100β
, saline
injury site zone distal zone S100β
. YJT ,
distal zone Schwann cell S100β
(Fig. 9A). Schwann cell YJT , Schwann cell
Schwann cell
(Fig. 9B).
140
Fig. 10. Comparison of axon integrity after taxol and YJT treatments.
Individual drugs were treated in vivo as describe in the materials and methods, and the nerve were analyzed by immunoflorescence staining with anti-NF-200 antibody (upper) or with anti-tubulin
antibody (lower) to visualize nerve fibers treatments. Notice decreased axon staining by taxol treatment and recovery by YJT
treatments. Scale bars: 100
Fig. 9. Effects of YJT treatment in vivo on Schwann cell distribution in the injured sciatic nerve.
(A) Schwann cells were identified by immunofluorescnece staining of S100β proteins in Schwann cells. (B) Merged images of
S100β-stained Schwann cells with nuclear distribution. Scale bars in (A) and (B): 100 and 50
Fig. 11. Induction pattern of phospho-Erk1/2 proteins in the sciatic nerve after drug treatments.
After the treatments with vehicle, taxol, taxol plus YJT in vivo the nerves were prepared and used for phospho-Erk1/2 protein analysis by western blotting (A) and immunofluorescence
staining (B). phospho-Erk1/2 protein signals were found in vehicle control, downregulated by taxol treatments, and
upregulated again by taxol and YJT cotreatments. (C) Merged images of Erk1/2 signals and Hoechst-stained nuclei. Notice that Erk 1 and 2 proteins are detected as two bands at 42 kDa and
44 kDa. Scale bars in (B) and (C): 100 and 50
Fig. 12. Comparison of nerve fiber elongation of the sciatic nerve after injury in vivo.
Nerve fibers were identified by immunofluorescence staining of NF-200. Images for proximal and distal zones were separated at
5 mm distance from the injury site. Scale bar: 100
(394)
1) NF-200, β-tubulin

-tubulin taxol + YJT
(Fig. 10).
2 : Taxol
141
Fig. 13. Effects of YJT treatments on the production of TNF-α levels in the injured sciatic nerves in
vivo. After the treatments with sciatic nerve injury (SNI) with saline and
YJT. the nerves were used for western blot (A) and immunofluorescence staining for TNF-α. In (A), proximal and distal nerve stumps were separately analyzed, and in (B), the distal portion of the nerve from 3 experimental groups were
analyzed (upper panel). TNF-α signals in the nerve (SNI plus saline) were merged with S100β to localize TNF-α in Schwann cells. Data show that TNF-α are highly colocalized in Schwann
cells. Scale bar: 100
2) Phospho-Erk1/2
Phospho-Erk1/2 taxol ve- hicle , taxol + YJT
vehicle (Fig. 11A). taxol + YJT vehicle
taxol phospho-Erk1/2
(Fig. 11B). Hoechst
Schwann cell phospho-Erk1/2
taxol + YJT phos- pho-Erk1/2
(Fig. 11C).
3) NF-200
saline distal zone proximal zone, injury site zone
. , YJT distal zone (Fig. 12).
4.
1) TNF-α, S100β
Saline proximal zone distal zone TNF-α . YJT saline prox- imal zone distal zone TNF-α
(Fig. 13A). , distal zone
TNF-α S100β Schwann cell
(Fig. 13B).

, , , , (1,2 ) ,
, 3, , wallerian ,
, , , DTR
,
15. , 16,
. CIPN European organization for Research
and Treatment of Cancer Chemotherapy Induced Peripheral Neuropathy (EORTC CIPN20)17
, 38.7,
22.0
18.
,
,
. ,
(tingling), (burning sensation),
19-20.

Gabapentin Amitryptyline .
Gabapentin
21, CIPN
22.
Amitriptyline
, CIPN
23.
142
(396)
microtubule . , micro- tubule polymerization apoptosis
5.
taxol CIPN taxol
microtubule
bundle ,
apoptosis
24. taxol microtubule ,
25. Schwann cell glia

26. Schwann cell

, , 27-28. Cdc2 cyclin B1 G2 S
29, ,
Schwann cell cdc2 Schwann cell
30.
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.
.
,
.

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.
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. YJT
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,
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. YJT ,
,
31
, ,
.

32. Schwann cell
GAP-43
33,
ginsenoside apoptosis
34.

35, 36.
31. YJT , , ,

, ,

. , YJT DRG
. DRG taxol
Schwann cell , in vitro DRG Schwann cell
NF-200, Hoechst
. , taxol DRG , YJT
. , Hoechst Schwann cell , taxol Schwann cell YJT
vehicle (Fig. 1). DRG Schwann cell
in vitro
NF-200, S100β , Hoechest 33258
. Taxol + YJT DRG Schwann cell DRG
2 : Taxol
143
(397)
. Hoechst 33258 Schwann cell DRG
(Fig. 2).
in vivo phospho-Erk1/2
. Western
, lumbar 5 vehicle taxol phos pho-Erk1/2
, YJT phospho-Erk1/2
(Fig. 3A, B). , taxol + YJT
Hoechst phos- pho-Erk1/2 Schwann cell
(Fig. 3C). , DRG
, taxol DRG
Schwann cell YJT
. , taxol + YJT DRG Schwann cell
, Schwann cell DRG . , taxol + YJT phospho-Erk1/2
Schwann cell . YJT taxol Schwann cell
phospho-Erk1/2
Schwann cell , DRG Schwann cell
DRG
. . Schwann cell
. Hoechest 33258 in vivo
. Taxol Schwann cell
, YJT vehicle
(Fig. 4A). , taxol Schwann cell , YJT
(Fig. 4B). caspase 3
Hoechst in vivo
. Vehicle caspase 3
, taxol , YJT (Fig. 5A). Hoechst
caspase 3 Schwann cell
, taxol capase 3
Schwann cell (Fig. 5B). Caspase 3 Hoechst in vitro
. in vivo
vehicle caspase 3
, taxol caspase 3 , YJT (Fig. 6A). Hoechst
caspase 3 Schwann cell
, taxol caspase 3
Schwann cell (Fig. 6B). S100β rhodamine in vitro
. Taxol
Schwann cell , YJT
Schwann cell
(Fig. 7). Phospho-Erk1/2 in vitro
. phospho-Erk1/2 taxol + YJT (Fig. 8A). phos- pho-Erk1/2
(Fig. 8B). in vivo S100β
. saline injury site zone distal zone S100β
, YJT distal zone
(Fig. 10A). , YJT
Schwann cell Schwann cell (Fig. 9B).
, Schwann cell , taxol
Schwann cell apoptosis ,
Schwann cell , YJT
Schwann cell
. , taxol caspase 3
, Schwann cell apoptosis
. , phospho-Erk1/2 Schwann cell
. ,
YJT , distal zone Schwann cell
. , YJT Schwann cell
33 3 (2012 9)
144
(398)
apoptosis , phospho-Erk1/2
, distal zone
Schwann cell . YJT Schwann cell
. ,
. NF-200 β-tubulin
in vivo . NF-200 , taxol vehicle
, YJT . β-tubulin taxol
, YJT
(Fig. 10). Phospho-Erk1/2 in vivo
. Vehicle , taxol
phospho-Erk1/2 , YJT vehicle (Fig. 11A). YJT phospho-Erk1/2
(Fig. 11B). Hoechst , taxol + YJT phospho-Erk1/2
(Fig. 11C). in vivo
NF-200 .
saline distal zone prox- imal zone injury site zone
, YJT
(Fig. 12). , taxol
YJT
. , phos- pho-Erk1/2 , taxol
Schwann cell
. ,
, YJT distal zone
. YJT Schwann cell , Schwann cell

.
. TNF-α S100β in
vivo . Saline
proximal zone distal zone
TNF-α , YJT
(Fig. 13A). , distal zone TNF-α S100β
, TNF-α S100β
Schwann cell (Fig. 13B). ,
TNF-α, , ,
S100β ,
YJT
. YJT
. , taxol Schwann
cell DRG YJT
, . , YJT ,
Schwann cell
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,

.
,

.

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