铁螯合剂与银杏叶提取物合用防治顺铂耳毒性
|
摘要
目的：应用听性脑干反应（Auditory brainstem response，
ABR）、血清超氧化物歧化酶（superoxide dismutase,SOD）
活性和丙二醛（MDA）含量、光镜及扫描电镜技术，观察铁
螯合剂—去铁胺（Deferoxamine,DFO）和银杏叶提取物—金
纳多（Extract of Ginkgo Biloba leaves Injection,EGb）联合应
用对抗顺铂（Cisplatin,CDDP）耳毒性的作用。
方法：选成熟健康，耳廓反应灵敏，体重 350-400 克的
白毛红目豚鼠 40 只，雌雄不限，随机分为 5 组，每组 8 只。
分别为 CDDP 组、EGb 组、DFO 组、EGb+DFO 组及对照组。
Ⅰ组（CDDP 组）：连续 5 天腹腔注射顺铂 2 mg.kg-1.d-1；Ⅱ
组（EGb 组）：给顺铂前 2 天，腹腔注射 EGb14 mg·kg-1·d-1，
自第 3 天起加腹腔注射顺铂 2 mg.kg-1.d-1，共 7 天；Ⅲ组（DFO
组）：股内侧皮下注射去铁胺 100 mg.kg-1.d-1，注射 1 小时后
腹腔注射顺铂 2 mg.kg-1.d-1，共 5 天；Ⅳ组（EGb+DFO 组）：
给顺铂前 2 天，腹腔注射金纳多 14 mg.kg-1.d-1，自第 3 天起，
加股内侧皮下注射去铁胺 100 mg.kg-1.d-1，注射 1 小时后腹
腔注射顺铂 2 mg.kg-1.d-1，共 7 天；Ⅴ组（对照组）：连续 5
天腹腔注射生理盐水 2 ml.kg-1.d-1。给药前后分别测定各组动
物听性脑干反应。停药后 1 天，采集动物血清并以断头法处
死动物。测定各组动物血清 SOD 活性和 MDA 含量。光镜标
本制作: 各组动物于停药后 1 天以断头法处死动物，快速取
出听泡，暴露耳蜗，蜗顶钻孔，取出镫骨，挑破卵圆窗、蜗
1
中 文 摘 要
窗,用吸管以４%多聚甲醛（4℃，PH=7.4）,缓慢灌洗耳蜗。
然后将其浸于固定液中，次日取出，以０.1MPBS(PH=7.4)
清洗，置于 10%EDTA 中，脱钙 20 天，PBS 清洗，石蜡包埋，
平行蜗轴切片，行苏木精-伊红染色及骨髓铁染色，光镜观
察。扫描电镜标本制作：各组于停药后１天以断头法处死动
物，快速取出听泡，暴露耳蜗，蜗顶钻孔，取出镫骨，挑破
卵圆窗、蜗窗，用吸管以 2.5%戊二醛（4℃，PH=7.4）缓慢
灌洗耳蜗。然后将其浸于固定液中，次日取出，以
０.1MPBS(PH=7.4)清洗，在解剖显微镜下剥去耳蜗骨壳及
螺旋韧带，暴露基底膜，1%四氧化锇后固定 2 小时；０.1mol/l
磷酸缓冲液漂洗；2%单宁酸 30 分钟，2 次；０.1mol/l 磷酸
缓冲液漂洗 1 小时；梯度乙醇脱水；醋酸异戊酯过度；临界
点干燥；离子溅射镀膜；扫描电镜观察。采用统计学方法分
析处理数据并观察用药前后耳蜗毛细胞形态学变化。
结果：CDDP 组动物 ABR 阈值较其它各组明显升高
（P<0.01），EGb 组动物 ABR 阈值与对照组差异有显著性
（P<0.05），与其余各组间差异不显著（P>.05）。DFO 组
和 EGb+DFO 组与对照组及 EGb 组差异不显著（P>0.05）。
血清 SOD 活性和 MDA 含量检测表明，CDDP 组血清 SOD
活性较对照组明显降低（P<0.01），其它各组较对照组则差
异不显著（P>.05）。血清 MDA 含量以 CDDP 组升高最显著
（P<0.01），其余各组较对照组略有升高，其差异没有显著
性（P>.05）。光镜观察，CDDP 组耳蜗 Corti 器严重变形,
外毛细胞肿胀、变形、移位、内外隧道增宽,严重者,毛细胞
溶解,核部分或全部消失, Corti 器结构破坏,病变以 2、4 回
为重。EGb 组动物 Corti 器变形外毛细胞肿胀、变形、移位,
2
中 文 摘 要
间隙增宽,程度比 CDDP 组轻。DFO 组及 EGb+DFO 组动物
Corti 器结构基本正常或稍变形，毛细胞结构大致正常。对照
组动物 Corti 器结构正常，毛细胞完整无移位。此外在 CDDP
组耳蜗螺旋韧带及蜗轴中可见较多的铁颗粒和少数小块，
EGb 组耳蜗蜗轴中也有少量铁颗粒，而 DFO 组和 DFO+EGb
组耳蜗螺旋韧带及蜗轴中未见含铁血黄素沉积，提示 DFO
可减轻顺铂的骨髓抑制副作用。耳蜗扫描电镜显示 CDDP 组
动物耳蜗各回外毛细胞均有不同程度破坏，以底回和第二回
为最重，外毛细胞缺失、倒伏、粘连，内毛细胞亦有不同程
度破坏。EGb 组动物耳蜗各回外毛细胞亦有散乱、倒伏、缺
失，但比 CDDP 组略轻，内毛细胞轻度受损。DFO 组与
EGb+DFO 组外毛细胞偶有倒伏、散乱，内毛细胞基本排列
正常，与 CDDP 组相比受损明显减轻，听毛呈Ｖ字形，开口
向内，整齐排列为三排，内毛细胞的听毛排列为一排。
结论：铁螯合剂（DFO）与银杏叶提取物（EGb）合用，
可有效减轻 CDDP 的耳毒性作用，并可能减轻顺铂的骨髓抑
制作用。其效果优于单独应用金纳多，但与单独应用去铁胺
效果未见明显差异。结果提示铁离子参与的自由基反应可能
是顺铂耳毒性机制之一。
Objective ： The protective effect of iron chelator
(Deferoxamine,DFO) and Extract of Ginkgo Biloba leaves
Injection (EGb) against ototoxicity of cisplatin (CDDP) was
studied by the test of auditory brainstem response (ABR),the
vitality of superoxide dismutase (SOD) in serum,the content of
the metabolite of lipid peroxidation (MDA) in serum, and
observesion of morphological change in hair cells with light
microscope,scanning electron microscope.
Methods ： Forty purebred guinea pigs which were
mature,healthy,sensitive to auricle reflex,300-400 gram.The sex
of them was not limited.They were randomly divided into five
groups.Each group had eight guinea pigs.They were CDDP
group,EGb group,DFO group,EGb+DFO group and control
group.GroupⅠreceived 2 mg·kg-1·d-1 CDDP transperitoneally
for five days.Group Ⅱ received 14 mg·kg-1·d-1 EGb two
days before 2 mg·kg-1·d-1 CDDP transpeiitoneally for seven
days.Group Ⅲ received 100 mg · kg-1 · d-1 DFO by
subcutaneous injection on the bosom of thigh one hour before 2
mg·kg-1·d-1 CDDP transpritoneally for five days.Group Ⅳ
received 14 mg·kg-1·d-1 EGb two days before DFO and
CDDP.Then it was added 100 mg·kg-1·d-1 DFO one hour before
4
英 文 摘 要
2 mg · kg-1 · d-1 CDDP for five days.Group Ⅴ recived
physiological saline(0.9%) transpritoneally for five
days.Auditory threshold was tested before the experiment and
after it.The next day,blood samples were obtained and all the
animals were sacrificed. The vitality of superoxide dismutase
(SOD) and the content of the metabolite of lipid peroxidation
(MDA) were tested in serum. Cochleas were stripped and fixed
by fixing solution.Light microscope observation:killed
animals,segregated otocyst from temporal bone quickly,exposed
cochlea,bored apical cochlea,took stapes out,unpacked ovoid
window and round window,poured cochlea with 4%
Polyoxymethylene (4 ℃ ,PH=7.4) and fixed in it for one
day,washed with 0.1M PBS (PH=7.4),decalcificated with 10%
Calcium Disodium Versenate for 20 days,washed with
PBS;embedded with petroline,used paraffin sectioning method
which direction was paralled with modiolus,used
haematine-eosin stain and marrow iron stain,observed with light
microscope. Scanning electron microscope observation:killed
animals,segregated otocyst from temporal bone quickly,exposed
cochlea,bored apical cochlea,took stapes out,unpacked ovoid
window and round window,poured cochlea with 2.5% Glutaric
Dialdehyde (4℃,PH=7.4) and fixed in it for 4-6 hours.Cochlea
shell and spiral ganglion were stripped and basilar membrane
was exposed thoroughly under anatomical microscope.They
were postfixed with 0.1% Osmium tetraoxide for 2
hours;washed with 0.1 mol/l PBS for 1 hour, dehydrated
5
英 文 摘 要
gradiently with alcohol,transited with acetate isoamyl ester,dried
at critical point,sputtered with golden ion,observed with
SEM.Data were analysized by SPSS.
Results ： the hearing threshold of ABR was higher
signifitcantly in CDDP group than in other groups (P<0.01) The
difference of auditory threshold value between EGb group and
control group was significant (P<0.05).And the difference of
auditory threshold betweenⅡ，Ⅲ，Ⅳ groups and control group
were not significant (P>0.05).The SOD in serum showed that
difference between CDDP group and other groups was
significant(P<0.01),while insignificant among other
groups(P>.05).The vitality of SOD was decreased obviously in
CDDP group.The content of the metabolite of lipid peroxidation
(MDA) in cochlea was higher significantly (P<0.01) in CDDP
group than that in other groups.But the content of MDA in other
groups were not raised significantly (P>0.05).Light microscope
showed that the spiral organ in CDDP group was distorted
serviously.The outer hair cells swelled,modificated,displaced
and the corti tunnel was broadened.Further more ,lytic necrosis
happe
ABR）、血清超氧化物歧化酶（superoxide dismutase,SOD）
活性和丙二醛（MDA）含量、光镜及扫描电镜技术，观察铁
螯合剂—去铁胺（Deferoxamine,DFO）和银杏叶提取物—金
纳多（Extract of Ginkgo Biloba leaves Injection,EGb）联合应
用对抗顺铂（Cisplatin,CDDP）耳毒性的作用。
方法：选成熟健康，耳廓反应灵敏，体重 350-400 克的
白毛红目豚鼠 40 只，雌雄不限，随机分为 5 组，每组 8 只。
分别为 CDDP 组、EGb 组、DFO 组、EGb+DFO 组及对照组。
Ⅰ组（CDDP 组）：连续 5 天腹腔注射顺铂 2 mg.kg-1.d-1；Ⅱ
组（EGb 组）：给顺铂前 2 天，腹腔注射 EGb14 mg·kg-1·d-1，
自第 3 天起加腹腔注射顺铂 2 mg.kg-1.d-1，共 7 天；Ⅲ组（DFO
组）：股内侧皮下注射去铁胺 100 mg.kg-1.d-1，注射 1 小时后
腹腔注射顺铂 2 mg.kg-1.d-1，共 5 天；Ⅳ组（EGb+DFO 组）：
给顺铂前 2 天，腹腔注射金纳多 14 mg.kg-1.d-1，自第 3 天起，
加股内侧皮下注射去铁胺 100 mg.kg-1.d-1，注射 1 小时后腹
腔注射顺铂 2 mg.kg-1.d-1，共 7 天；Ⅴ组（对照组）：连续 5
天腹腔注射生理盐水 2 ml.kg-1.d-1。给药前后分别测定各组动
物听性脑干反应。停药后 1 天，采集动物血清并以断头法处
死动物。测定各组动物血清 SOD 活性和 MDA 含量。光镜标
本制作: 各组动物于停药后 1 天以断头法处死动物，快速取
出听泡，暴露耳蜗，蜗顶钻孔，取出镫骨，挑破卵圆窗、蜗
1
中 文 摘 要
窗,用吸管以４%多聚甲醛（4℃，PH=7.4）,缓慢灌洗耳蜗。
然后将其浸于固定液中，次日取出，以０.1MPBS(PH=7.4)
清洗，置于 10%EDTA 中，脱钙 20 天，PBS 清洗，石蜡包埋，
平行蜗轴切片，行苏木精-伊红染色及骨髓铁染色，光镜观
察。扫描电镜标本制作：各组于停药后１天以断头法处死动
物，快速取出听泡，暴露耳蜗，蜗顶钻孔，取出镫骨，挑破
卵圆窗、蜗窗，用吸管以 2.5%戊二醛（4℃，PH=7.4）缓慢
灌洗耳蜗。然后将其浸于固定液中，次日取出，以
０.1MPBS(PH=7.4)清洗，在解剖显微镜下剥去耳蜗骨壳及
螺旋韧带，暴露基底膜，1%四氧化锇后固定 2 小时；０.1mol/l
磷酸缓冲液漂洗；2%单宁酸 30 分钟，2 次；０.1mol/l 磷酸
缓冲液漂洗 1 小时；梯度乙醇脱水；醋酸异戊酯过度；临界
点干燥；离子溅射镀膜；扫描电镜观察。采用统计学方法分
析处理数据并观察用药前后耳蜗毛细胞形态学变化。
结果：CDDP 组动物 ABR 阈值较其它各组明显升高
（P<0.01），EGb 组动物 ABR 阈值与对照组差异有显著性
（P<0.05），与其余各组间差异不显著（P>.05）。DFO 组
和 EGb+DFO 组与对照组及 EGb 组差异不显著（P>0.05）。
血清 SOD 活性和 MDA 含量检测表明，CDDP 组血清 SOD
活性较对照组明显降低（P<0.01），其它各组较对照组则差
异不显著（P>.05）。血清 MDA 含量以 CDDP 组升高最显著
（P<0.01），其余各组较对照组略有升高，其差异没有显著
性（P>.05）。光镜观察，CDDP 组耳蜗 Corti 器严重变形,
外毛细胞肿胀、变形、移位、内外隧道增宽,严重者,毛细胞
溶解,核部分或全部消失, Corti 器结构破坏,病变以 2、4 回
为重。EGb 组动物 Corti 器变形外毛细胞肿胀、变形、移位,
2
中 文 摘 要
间隙增宽,程度比 CDDP 组轻。DFO 组及 EGb+DFO 组动物
Corti 器结构基本正常或稍变形，毛细胞结构大致正常。对照
组动物 Corti 器结构正常，毛细胞完整无移位。此外在 CDDP
组耳蜗螺旋韧带及蜗轴中可见较多的铁颗粒和少数小块，
EGb 组耳蜗蜗轴中也有少量铁颗粒，而 DFO 组和 DFO+EGb
组耳蜗螺旋韧带及蜗轴中未见含铁血黄素沉积，提示 DFO
可减轻顺铂的骨髓抑制副作用。耳蜗扫描电镜显示 CDDP 组
动物耳蜗各回外毛细胞均有不同程度破坏，以底回和第二回
为最重，外毛细胞缺失、倒伏、粘连，内毛细胞亦有不同程
度破坏。EGb 组动物耳蜗各回外毛细胞亦有散乱、倒伏、缺
失，但比 CDDP 组略轻，内毛细胞轻度受损。DFO 组与
EGb+DFO 组外毛细胞偶有倒伏、散乱，内毛细胞基本排列
正常，与 CDDP 组相比受损明显减轻，听毛呈Ｖ字形，开口
向内，整齐排列为三排，内毛细胞的听毛排列为一排。
结论：铁螯合剂（DFO）与银杏叶提取物（EGb）合用，
可有效减轻 CDDP 的耳毒性作用，并可能减轻顺铂的骨髓抑
制作用。其效果优于单独应用金纳多，但与单独应用去铁胺
效果未见明显差异。结果提示铁离子参与的自由基反应可能
是顺铂耳毒性机制之一。
Objective ： The protective effect of iron chelator
(Deferoxamine,DFO) and Extract of Ginkgo Biloba leaves
Injection (EGb) against ototoxicity of cisplatin (CDDP) was
studied by the test of auditory brainstem response (ABR),the
vitality of superoxide dismutase (SOD) in serum,the content of
the metabolite of lipid peroxidation (MDA) in serum, and
observesion of morphological change in hair cells with light
microscope,scanning electron microscope.
Methods ： Forty purebred guinea pigs which were
mature,healthy,sensitive to auricle reflex,300-400 gram.The sex
of them was not limited.They were randomly divided into five
groups.Each group had eight guinea pigs.They were CDDP
group,EGb group,DFO group,EGb+DFO group and control
group.GroupⅠreceived 2 mg·kg-1·d-1 CDDP transperitoneally
for five days.Group Ⅱ received 14 mg·kg-1·d-1 EGb two
days before 2 mg·kg-1·d-1 CDDP transpeiitoneally for seven
days.Group Ⅲ received 100 mg · kg-1 · d-1 DFO by
subcutaneous injection on the bosom of thigh one hour before 2
mg·kg-1·d-1 CDDP transpritoneally for five days.Group Ⅳ
received 14 mg·kg-1·d-1 EGb two days before DFO and
CDDP.Then it was added 100 mg·kg-1·d-1 DFO one hour before
4
英 文 摘 要
2 mg · kg-1 · d-1 CDDP for five days.Group Ⅴ recived
physiological saline(0.9%) transpritoneally for five
days.Auditory threshold was tested before the experiment and
after it.The next day,blood samples were obtained and all the
animals were sacrificed. The vitality of superoxide dismutase
(SOD) and the content of the metabolite of lipid peroxidation
(MDA) were tested in serum. Cochleas were stripped and fixed
by fixing solution.Light microscope observation:killed
animals,segregated otocyst from temporal bone quickly,exposed
cochlea,bored apical cochlea,took stapes out,unpacked ovoid
window and round window,poured cochlea with 4%
Polyoxymethylene (4 ℃ ,PH=7.4) and fixed in it for one
day,washed with 0.1M PBS (PH=7.4),decalcificated with 10%
Calcium Disodium Versenate for 20 days,washed with
PBS;embedded with petroline,used paraffin sectioning method
which direction was paralled with modiolus,used
haematine-eosin stain and marrow iron stain,observed with light
microscope. Scanning electron microscope observation:killed
animals,segregated otocyst from temporal bone quickly,exposed
cochlea,bored apical cochlea,took stapes out,unpacked ovoid
window and round window,poured cochlea with 2.5% Glutaric
Dialdehyde (4℃,PH=7.4) and fixed in it for 4-6 hours.Cochlea
shell and spiral ganglion were stripped and basilar membrane
was exposed thoroughly under anatomical microscope.They
were postfixed with 0.1% Osmium tetraoxide for 2
hours;washed with 0.1 mol/l PBS for 1 hour, dehydrated
5
英 文 摘 要
gradiently with alcohol,transited with acetate isoamyl ester,dried
at critical point,sputtered with golden ion,observed with
SEM.Data were analysized by SPSS.
Results ： the hearing threshold of ABR was higher
signifitcantly in CDDP group than in other groups (P<0.01) The
difference of auditory threshold value between EGb group and
control group was significant (P<0.05).And the difference of
auditory threshold betweenⅡ，Ⅲ，Ⅳ groups and control group
were not significant (P>0.05).The SOD in serum showed that
difference between CDDP group and other groups was
significant(P<0.01),while insignificant among other
groups(P>.05).The vitality of SOD was decreased obviously in
CDDP group.The content of the metabolite of lipid peroxidation
(MDA) in cochlea was higher significantly (P<0.01) in CDDP
group than that in other groups.But the content of MDA in other
groups were not raised significantly (P>0.05).Light microscope
showed that the spiral organ in CDDP group was distorted
serviously.The outer hair cells swelled,modificated,displaced
and the corti tunnel was broadened.Further more ,lytic necrosis
happe
引文
1 Rybak LP,Whitworth C,Somani S.Application of antioxidants
and other agents to prevent cisplatin
ototoxicity.Laryngoscope,1999,109(11):1740~1744
2 Teranishi M,Nakashima T,Wakabayashi T.Effect of alpha
tocopherol on cisplatin induced ototoxicity in guinea
pigs.Hear Res,2001,151(1-2):61~70
3 Watanabe K,Hess A,Michel O,et al.Nitric oxide synthase
inhibitor reduces the apoptotic change in the cisplatin treated
cochlea of guinea pigs.Anticancer Drugs,2000,11(9):731~733
4 Dehane N,Lautermann J,Petrat F,et al.Cisplatin
ototoxicity:involvement of iron and enhanced formation of
superoxied anion radicals.Toxicol Appl
Pharmacol.,2001,174(1):27~34
5 Fukaya H,Kanno H.Experimental studies of the protective
effect of ginkgo biloba extract (GBE) on cisplatin induced
ototoxicity in rats.Nippon Jibiinkoka Gakkai
Kaiho,1999,102(7):907~909
6 Bienvenu P,Caron L,Gasparutto D,et al.Assessing and
counteracting the prooxidant effects of anticancer
drugs.EXS,1992,62:257~265
44
综 述
7 Kameyama Y,Gemba M,The iron chelator deferoxamine
prevents cisplatin-induced lipid peroxidation in rat kidney
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7 Kameyama Y,Gemba M,The iron chelator deferoxamine
prevents cisplatin-induced lipid peroxidation in rat kidney
cortical slices.Jpn J Pharmacol,1991,57(2):259~262
8 Kim YK,Jung JS,Lee SH,et al.Effects of antioxidants and
Ca2+ in cisplatin-induced cell injury in rabbit renal cortical
slices.Toxicol Appl Pharmacol,1997,146(2):261~269
9 Watanabe H,Kanno H,Experimental studies of the protective
effect of deferoxamine mesilate on cisplatin induced
toxicity.Nippon Jibiinkoka Gakkai
kaiho,1998,101(8):967~978
10 杨义芳，吴国友。银杏叶药理研究概况。现代应用药学，
1995，12（6）：5~7
11 钱欣梅，张向阳。金纳多对突发性耳聋病人血液流变学
和血清 SOD、LPO 的影响。中国微循环，2000，4（3）：
173~176
12 Maitra I,Marcocei L,Droy Lefaix MT,et al.Peroxyl radical
scavenging activity of Ginkgo biloba extract
EGb761.Biochem Pharmacol,1995,49(11):1649~1651
13 丁勤学，刘耕陶。全国红豆杉和银杏等药用植物基础应
用研究学术研讨会资料汇编（贵州），1998：50
14 侯金程，谷京城，赵力奎，等。银杏叶提取物对顺铂耳
毒性保护作用的实验研究。锦州医学院学报，2002，23
（4）：11~13
15 王筠默。银杏叶的药理研究。中草药，1998，29（增刊）：
9
16 Fitzl G,Welt K,Schaffranictz L.Myocardium-protective
45
综 述
effects of Ginkgo biloba extract(EGb761) in old rats against
acute isobaric hypoxia.An electron microscopic
morphometric study I. Protection of cardiomyocytes.Exp
Toxicol Pathol,1996,48(1):81~86
17 Ni Y,Zhao B,Hou J,et al.Preventive effect of Ginkgo biloba
extract on apoptosis in rat cerebelar neuronal cells induced
by hydroxyl radicals.Neurosci Lett,1996,214(23):115~119
18 Masson F,Neliat G,Drieu K,et al.Effexts of extract of Ginkgo
biloba on the action potential and associated transmembrane
ionic currents in mammal cordis myocytes:inhibition of
isoprenaline-induced chlolide current.Drug Dcv
Res,1994,32(1):29~32