一侧迷路切除后前庭系统的变化及银杏叶制剂(Egb761)促前庭代偿机制的研究
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摘要
前庭代偿是一种中枢过程。药物治疗可减轻前庭受损后早期严重的静态及
动态症状，并促进前庭代偿。银杏叶制剂（EGb761）是银杏叶标准提取物，由
于其广谱的药理作用，临床应用广泛。银杏叶制剂（EGb761）—金纳多可改善
眩晕、耳鸣及耳聋，并可促进前庭代偿，但其代偿机制尚未阐明。因此，研究
药物治疗促进前庭代偿的作用及机制，是耳科学前庭康复领域的一项重要课
题。本课题通过豚鼠UL的动物模型，采用电生理、组织超微结构、免疫组织化
学、分子生物学和动物行为学等检测方法，观察银杏叶制剂（EGb761）—金纳
多（以下简称EGb）对一侧迷路切除（UL）后行为学恢复的影响、前庭内侧核（medial
vestibular nucleus，MVN）胶质纤维酸性蛋白（glial fibrillary acid protein，GFAP）表达的
变化、Scarpa神经节的变化、MVN区Synaptophysin的表达、超微结构变化、N-
甲基-D-天门冬氨酸（NMDA）受体亚单位R_1mRNA表达的变化、谷氨酸免疫反应
物（GLU-IR）的影响，探讨EGb促进前庭代偿的作用及可能机制。现将研究结果
报告如下。
第四军医大学博士学位论文
一、银杏叶制剂0Gb761）一金纳多对豚鼠一侧迷路切除后静态和动态症状
代偿的影响
观察豚鼠UL后静态和动态症状的自然恢复及银杏叶制剂a 卜金纳
多对静态和动态症状恢复的影响。观察自发性眼震侣M、W仰平面头位偏斜baw
headmt．YHT广 ＊11平面头位偏斜（rol hea hh，Il4T）随时间恢复的差别。结果：
．UUL后与自发性眼震同时出现11y和RH T，且ITff较IOH明显：UL十E口b
组较自然恢复快，统计学分析有显著性差异卜001 卜②UL后旋转试验的眼震
频率明显下降，UL组术后70d眼震频率未恢复正常水平，90d恢复正常；
U’L＋EGb组 ZId眼震频率与正常己无显著差别。两侧优势偏向pV较示 UL组
7－50d结果异常；而UL＋EGb组自7d起DP在正常范围。参照旋转试验后眼震
频率恢复情况，两侧均衡性的恢复比眼震频率恢复快。提示EGb能促进静态和
动态症状的代偿，自发性眼震较头位偏斜恢复快而完全；两侧均衡性的恢复比
眼震频率恢复快。
二、豚鼠一侧迷路不同损伤模式前庭核区GFAP的表达及银杏叶制剂
m）一金纳多对其表达的影响
l．观察豚鼠 UL后不同存活时间前庭内侧核（mwha Vesi沏 nudeus，p
胶质纤维酸性蛋白W ibillny aCd prot叫GFAI，）的表达变化。结果UL后可诱
导双侧MVN区星形胶质细胞GFAP免疫反应增强，术侧大于未损侧，GFAP反
应在术后 10h己较正常对照增强，20h强于 10k此后 40h至 20d GFAP反应处于
下降趋势。提示UL后可诱导MVN区胶质细胞GFAP免疫反应增强。ULiGb
组 MVN区 GFAP的表达仍为双侧性，损毁侧更为明显，10h、40h弱于 UL组，
20d时己呈下降趋势。较同期UL组为低卜001 卜结果提示EGb能减轻同期W
后MYr－u区星形胶质细胞GFAP的免疫反应性，其作用可能与银杏制剂的神经俱
护作用白关。
6
第四军医大学博士学位论文
二．观察豚鼠庆大霉素肌注后不同存活时间卜WN区GF n的表达变化和旋
转试验后眼震的变化。结果：庆大霉素给药 10h后 NtW区双侧星形胶质细胞
GFAP免疫反应开始出现，20h、40h、6d逐渐增强，20d在观察期间反应最强。
提示庆大霉素给药诱导MVN区胶质细胞GFAP免疫反应有增强的趋势，可能与
庆大霉素对前庭系统渐进性损害、中枢系统的保护作用有关。
三、豚鼠一侧迷路切除后Scal’pa神经节的变化及银杏叶制剂O）一
金纳多对其影响
目前，去除初级前庭传入为迷路切除和前庭神经切断。UL后 10h． S啊a神
经节变化不明显，20h有明显变化，细胞大量死亡，有凋亡细胞，外周损伤较中
央区重：以后逐渐加重；而UL＋＊口b组的反应较UL明显减轻。提示＊C七对前
庭神经节具有保护作用及对凋亡的抑制作用。
四、银杏叶制剂（EGb761）一金纳多对一侧迷路切除后前庭核区
Synaptophysin表达的影响
SPtOPhysin是神经末梢突触小泡主要的膜整和蛋白，是分子水平突触密
度定量敏感的标志。以Sy呷tophysin免疫反应强度为标志，评价UL后MVN区
突触密度的变化。结果：UL后＊，受损侧 MVN区 Soaptophysin免疫反应强
度降低，术后20d有所增加，90d强度恢复较明显，但仍弱于正常对照。未损侧
syn叩o…吓h免疫反应强度在不同时间段与正常对照无显著差别。UL亿吐组，
术后 10h、20d、90d较同期 UL组 MVN区 Symptophysin免疫反应强度高。术后
90d与
1.Standard extract of Ginkgo Biloba enhancing static and dynamic syndromes compensation following UL in guinea pigs
After UL, guinea pigs manifest SN, head lift and other static syndrome.Recovery of the static syndrome" s with and without standard extract of Ginkgo biloba following UL were observed. UL+EGb recovered faster than UL.Standard extract of Ginkgo biloba could enhance the compensation of static syndrome and SN recuperated faster and more completely than head tilt. The UL group's post-lesional nystagmus frequency didn't recover until the 90th d, while UL+EGb group return to normal 21 d post-lesion. In addition, the UL group's directional preponderance (DP) was abnormal 50d post- lesion, but lesion plus EGb's return to normal from the 7th d post-lesion. The recovery of DP was faster than nystagmus frequency Therefore Ginaton could enhance dynamic compensation. And bilateral equilibrium's recovery was faster than that of nystagmus
frequency
2. The expression of GFAP in the MVN following different modes of peripheral vestibular lesions in guinea pigs
U)GFAP staining enhancement can be induced in bilateral MVN following UL. However, that of the lesioned side is stronger than that of the unlesioned side The reaction became evident 10 h post-UL and was intense 20-40 h after lesion. Then it declined until 20 d, but still intenser than that of the control group If Ginaton is administered, the staining positive cells are less than that of the UL. But the significance of the reactive satrocytes in the vestibular compensation is still unknown. And Ginaton may play a role in sparing the EAA toxicity to some extent.It can be drawn that proliferation of astrocytes may to some extent serve as somewhat of protection for MVN
(2)Gentamycin can induce the proliferation of astrocytes in the MVN. 20d after gentamycin administration, the proliferation reached its peak.The reaction is maily through the peripheral vestibular system because gentamycin cannot transpass the blood-brain barrier The proliferation of astrocytes after gentamycin administration may contribute to the neuronal protection for glial cells play an important role in the regulation of glutamic acid and aspartate.
3.The influence of Ginaton on the Scarpa's ganglion after UL
UL and vestibualr neuroectomy was applied to remove the primary vestibular afferent After UL, Scarpa's ganglion were spared Therfore, it may still exert some effects on the vestibular system. The findings showed that lOhr after UL, the ganglion had no evident change under microscope But the change became severe at 20hr and aggravated gradually thereafter: The change in UL+EGb group was lessen than UL. It manifested that Ginaton had the effect of ganglion protection and the better way to remove the primary afferent was through neurotomy.In addition,Ginaton also had the function of suppression of ganglion apotosis
4. The influence of Ginaton on expression of synaptophysin in the MVN after UL
Synaptophysin is a major membrane integrated protein at the synaptic follicles. It acts as a sensitive marker for synaptic intensity at molecular level hi this expenment,synaptophysin was used to evaluate the change of synaptic density post-UL lOhr post UL, the immunoreactive intensity of synaptophysin declined in the lesioned side.lt increased slightly at 20d;and the intensity recovered significantly at 90d post UL, but still lower than that in control. In the UL+EGb group, the intensity of synaptophysin was stronger than that in the UL at 1 Oh and 20d But at 90 d, the UL+EGb was intense than UL and had no significant difference compared with the control. It suggested that in UL+EGb group the synaptic density recovered quickly. It underlied that vestibular compensation and the enhancing effect of Ginaton is involved in the structural resconstruction in the MVN.
5.The influence of standard extract of Ginkgo biloba on the MVN infrastructure following UL in guinea pigs
Following UL, EGb can promote the recovery of the post-rotational nystagmus. On the aspect of ultrastruc
动态症状，并促进前庭代偿。银杏叶制剂（EGb761）是银杏叶标准提取物，由
于其广谱的药理作用，临床应用广泛。银杏叶制剂（EGb761）—金纳多可改善
眩晕、耳鸣及耳聋，并可促进前庭代偿，但其代偿机制尚未阐明。因此，研究
药物治疗促进前庭代偿的作用及机制，是耳科学前庭康复领域的一项重要课
题。本课题通过豚鼠UL的动物模型，采用电生理、组织超微结构、免疫组织化
学、分子生物学和动物行为学等检测方法，观察银杏叶制剂（EGb761）—金纳
多（以下简称EGb）对一侧迷路切除（UL）后行为学恢复的影响、前庭内侧核（medial
vestibular nucleus，MVN）胶质纤维酸性蛋白（glial fibrillary acid protein，GFAP）表达的
变化、Scarpa神经节的变化、MVN区Synaptophysin的表达、超微结构变化、N-
甲基-D-天门冬氨酸（NMDA）受体亚单位R_1mRNA表达的变化、谷氨酸免疫反应
物（GLU-IR）的影响，探讨EGb促进前庭代偿的作用及可能机制。现将研究结果
报告如下。
第四军医大学博士学位论文
一、银杏叶制剂0Gb761）一金纳多对豚鼠一侧迷路切除后静态和动态症状
代偿的影响
观察豚鼠UL后静态和动态症状的自然恢复及银杏叶制剂a 卜金纳
多对静态和动态症状恢复的影响。观察自发性眼震侣M、W仰平面头位偏斜baw
headmt．YHT广 ＊11平面头位偏斜（rol hea hh，Il4T）随时间恢复的差别。结果：
．UUL后与自发性眼震同时出现11y和RH T，且ITff较IOH明显：UL十E口b
组较自然恢复快，统计学分析有显著性差异卜001 卜②UL后旋转试验的眼震
频率明显下降，UL组术后70d眼震频率未恢复正常水平，90d恢复正常；
U’L＋EGb组 ZId眼震频率与正常己无显著差别。两侧优势偏向pV较示 UL组
7－50d结果异常；而UL＋EGb组自7d起DP在正常范围。参照旋转试验后眼震
频率恢复情况，两侧均衡性的恢复比眼震频率恢复快。提示EGb能促进静态和
动态症状的代偿，自发性眼震较头位偏斜恢复快而完全；两侧均衡性的恢复比
眼震频率恢复快。
二、豚鼠一侧迷路不同损伤模式前庭核区GFAP的表达及银杏叶制剂
m）一金纳多对其表达的影响
l．观察豚鼠 UL后不同存活时间前庭内侧核（mwha Vesi沏 nudeus，p
胶质纤维酸性蛋白W ibillny aCd prot叫GFAI，）的表达变化。结果UL后可诱
导双侧MVN区星形胶质细胞GFAP免疫反应增强，术侧大于未损侧，GFAP反
应在术后 10h己较正常对照增强，20h强于 10k此后 40h至 20d GFAP反应处于
下降趋势。提示UL后可诱导MVN区胶质细胞GFAP免疫反应增强。ULiGb
组 MVN区 GFAP的表达仍为双侧性，损毁侧更为明显，10h、40h弱于 UL组，
20d时己呈下降趋势。较同期UL组为低卜001 卜结果提示EGb能减轻同期W
后MYr－u区星形胶质细胞GFAP的免疫反应性，其作用可能与银杏制剂的神经俱
护作用白关。
6
第四军医大学博士学位论文
二．观察豚鼠庆大霉素肌注后不同存活时间卜WN区GF n的表达变化和旋
转试验后眼震的变化。结果：庆大霉素给药 10h后 NtW区双侧星形胶质细胞
GFAP免疫反应开始出现，20h、40h、6d逐渐增强，20d在观察期间反应最强。
提示庆大霉素给药诱导MVN区胶质细胞GFAP免疫反应有增强的趋势，可能与
庆大霉素对前庭系统渐进性损害、中枢系统的保护作用有关。
三、豚鼠一侧迷路切除后Scal’pa神经节的变化及银杏叶制剂O）一
金纳多对其影响
目前，去除初级前庭传入为迷路切除和前庭神经切断。UL后 10h． S啊a神
经节变化不明显，20h有明显变化，细胞大量死亡，有凋亡细胞，外周损伤较中
央区重：以后逐渐加重；而UL＋＊口b组的反应较UL明显减轻。提示＊C七对前
庭神经节具有保护作用及对凋亡的抑制作用。
四、银杏叶制剂（EGb761）一金纳多对一侧迷路切除后前庭核区
Synaptophysin表达的影响
SPtOPhysin是神经末梢突触小泡主要的膜整和蛋白，是分子水平突触密
度定量敏感的标志。以Sy呷tophysin免疫反应强度为标志，评价UL后MVN区
突触密度的变化。结果：UL后＊，受损侧 MVN区 Soaptophysin免疫反应强
度降低，术后20d有所增加，90d强度恢复较明显，但仍弱于正常对照。未损侧
syn叩o…吓h免疫反应强度在不同时间段与正常对照无显著差别。UL亿吐组，
术后 10h、20d、90d较同期 UL组 MVN区 Symptophysin免疫反应强度高。术后
90d与
1.Standard extract of Ginkgo Biloba enhancing static and dynamic syndromes compensation following UL in guinea pigs
After UL, guinea pigs manifest SN, head lift and other static syndrome.Recovery of the static syndrome" s with and without standard extract of Ginkgo biloba following UL were observed. UL+EGb recovered faster than UL.Standard extract of Ginkgo biloba could enhance the compensation of static syndrome and SN recuperated faster and more completely than head tilt. The UL group's post-lesional nystagmus frequency didn't recover until the 90th d, while UL+EGb group return to normal 21 d post-lesion. In addition, the UL group's directional preponderance (DP) was abnormal 50d post- lesion, but lesion plus EGb's return to normal from the 7th d post-lesion. The recovery of DP was faster than nystagmus frequency Therefore Ginaton could enhance dynamic compensation. And bilateral equilibrium's recovery was faster than that of nystagmus
frequency
2. The expression of GFAP in the MVN following different modes of peripheral vestibular lesions in guinea pigs
U)GFAP staining enhancement can be induced in bilateral MVN following UL. However, that of the lesioned side is stronger than that of the unlesioned side The reaction became evident 10 h post-UL and was intense 20-40 h after lesion. Then it declined until 20 d, but still intenser than that of the control group If Ginaton is administered, the staining positive cells are less than that of the UL. But the significance of the reactive satrocytes in the vestibular compensation is still unknown. And Ginaton may play a role in sparing the EAA toxicity to some extent.It can be drawn that proliferation of astrocytes may to some extent serve as somewhat of protection for MVN
(2)Gentamycin can induce the proliferation of astrocytes in the MVN. 20d after gentamycin administration, the proliferation reached its peak.The reaction is maily through the peripheral vestibular system because gentamycin cannot transpass the blood-brain barrier The proliferation of astrocytes after gentamycin administration may contribute to the neuronal protection for glial cells play an important role in the regulation of glutamic acid and aspartate.
3.The influence of Ginaton on the Scarpa's ganglion after UL
UL and vestibualr neuroectomy was applied to remove the primary vestibular afferent After UL, Scarpa's ganglion were spared Therfore, it may still exert some effects on the vestibular system. The findings showed that lOhr after UL, the ganglion had no evident change under microscope But the change became severe at 20hr and aggravated gradually thereafter: The change in UL+EGb group was lessen than UL. It manifested that Ginaton had the effect of ganglion protection and the better way to remove the primary afferent was through neurotomy.In addition,Ginaton also had the function of suppression of ganglion apotosis
4. The influence of Ginaton on expression of synaptophysin in the MVN after UL
Synaptophysin is a major membrane integrated protein at the synaptic follicles. It acts as a sensitive marker for synaptic intensity at molecular level hi this expenment,synaptophysin was used to evaluate the change of synaptic density post-UL lOhr post UL, the immunoreactive intensity of synaptophysin declined in the lesioned side.lt increased slightly at 20d;and the intensity recovered significantly at 90d post UL, but still lower than that in control. In the UL+EGb group, the intensity of synaptophysin was stronger than that in the UL at 1 Oh and 20d But at 90 d, the UL+EGb was intense than UL and had no significant difference compared with the control. It suggested that in UL+EGb group the synaptic density recovered quickly. It underlied that vestibular compensation and the enhancing effect of Ginaton is involved in the structural resconstruction in the MVN.
5.The influence of standard extract of Ginkgo biloba on the MVN infrastructure following UL in guinea pigs
Following UL, EGb can promote the recovery of the post-rotational nystagmus. On the aspect of ultrastruc
引文
1 于立身主编．前庭功能检查技术 北京．人民军医出版社．1994，36-37
2 IgarashiM Vestibularcompensation. ActaOtolaryngol.1984.406:78-82
3 Clausen CF Vestibularcompensation ActaOtolaryngol. 1994.513 33-36
4 蒙卡斯尔VB主编 韩济生 乔健大 张英才 等译．医学生理学．上册．北京：科学出社．1988，755-774
5 李学佩 编著 神经目科学 贵州：贵州科技出版社，1991 51-75
6 Herdman SJ Advances in the tremnent of vestibular disorders Physical therapy. 1997;77(6)602-618
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2 Gilchrist DPD. Smith PF. Darlington CL. ACTH(4-10) accelerates ocular motor recovexy following vestibular deafferentation. Nenrosci Lett 1990.118(1):14-16
3 Gispen WH. Therapeutic potential for melanocortins in peripheral nerve disease. Trends in Pharmocoi Sci. 1990.11(6):221-222.
4 Gerritsen Van Der Hoop R. Vecht CJ. Van der MEL, et al. Prevention of cisplatin neurotoyacity with an ACTH-(4-9)analouge in patients with ovarian cancer New Engl Med 1990;322(1)89-94.
5 Mountjoy KG. Robbins LS. Mortrud MT. et al The clorung of a family of genes that encode the melanocortin receptors Science 1992:257(5074)1248-1251
6 Flohr H. Luneberg U Effects of ACTH-(4-10) on vestibular compensation Brain Res 1982:248(1)169-173
7 Luneberg U, Flohr H Effects of melanocortins on vestibular compensation In. Pompeiano O, Allum JHJ. eds Progress in brain research, vol 76 Amsterdam. Elsevier: 1988;76:421-429
8.Luneberg U, Flohr H. Richter-Landsberg C ACTH/MSH-like neuropeptides and lesion-induced plastic process, In: Keller EL. Zee. DS. eds Adaptive processes in visual and oculomotor systems. New York. Pergamon: 1988.409-416
9 Luneberg U, Flohr H Influncc of melanocortin fragments on vestibular compensation. In:Lacour M, Toupet M. Deruse P. Christen Y. eds Vestibular compensation. Facts. theories and clinical perspectives. Paris Elsevier: 1989 161-174
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14． Trifiletti RR. Pranzatelli MR ACTH binds to [~3H]MK-801-labelled rat hippocampal NMDA receptor. Eur J Phamiocol. 1992;26(4) 377-379．
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16 Gispen WH, Buitelaar J. Wiegant VM. et al. Interaction between ACTH fragments, brain opiate receptors and morphine-induced analgesia Eur J Pharmocol. 1976． 39(2) :393-397．
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