睫状神经营养因子联合复光颗粒对外伤性视神经损伤修复作用的实验研究
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摘要
本文通过实验研究睫状神经营养因子（ciliary neurotrophic factor，CNTF）联合中药复光颗粒对白兔外伤性视神经病变（traumatic optic neuropathy，TON）治疗的病理形态学、超微结构、视觉电生理及生物力学特性的影响，探讨睫状神经营养因子和复光颗粒对TON可能的保护机制，为临床治疗TON提供一定的理论依据。
首先建立了轻、中、重不同程度的钳夹伤白兔视神经损伤模型，观察不同程度损伤后不同时间视神经视网膜组织学的变化，结果表明应用蚊式血管钳可制作白兔不同程度的视神经钳夹损伤模型，模型重复性好，致伤程度稳定，可用于临床研究。轻度损伤组视网膜及视神经损伤后病理形态改变不显著，视网膜神经节细胞（retinal ganglioncell，RGC）数量变化不明显，视神经结构和功能可大部分自行修复。中度损伤组视网膜及视神经病理形态改变明显，损伤时间越长，病理变化越明显。重度损伤组视网膜及视神经病理形态不可逆性改变，正常结构几乎完全消失，视网膜及视神经功能丧失。证明白兔中度损伤视神经模型可以作为TON发病机制及药物治疗效果研究的良好的动物模型。
在确定致伤程度稳定、重复性好的白兔TON中度钳夹伤模型后，建立正常对照组、损伤组、CNTF治疗组、复光颗粒治疗组、CNTF和复光颗粒联合治疗组。通过实验观察中度视神经钳夹伤白兔模型的病理形态学、超微结构、视觉电生理学及生物力学特性的变化，得出以下结论：视神经损伤后病理形态学改变包括RGC和神经纤维数目不断减少，出现RGC肿胀，核固缩、染色加深，染色质边聚、空化、变性，细胞核碎裂等细胞凋亡现象。视神经纤维水肿，胶质细胞肿胀，神经纤维断裂、结构模糊，坏死灶增多、扩大，各层神经组织明显变薄、萎缩。视神经损伤超微结构改变主要包括视神经和视网膜的神经纤维层线粒体肿胀、嵴变宽甚至空泡化，微丝和微管数目减少、结构异常，轴突数目减少，RGC细胞凋亡等结构的改变，损伤随时间的延长逐渐加重。视神经损伤后闪光刺激诱发电位变化包括P1波潜伏期延长，振幅降低，传导能力减弱。损伤后视神经生物力学改变包括抗拉伸承载能力减弱，拉伸最大载荷、最大应力、最大应变、弹性限度载荷、弹性限度应变、弹性限度应力明显小于正常神经。CNTF和复光颗粒能够在一定程度上减缓RGC和神经纤维的凋亡时间和数量，促进RGC和神经纤维的再生，阻止轴突的变性坏死，从而阻断RGC的死亡，保护视神经超微结构，为轴浆运输功能的恢复提供物质基础和载体，促进神经纤维再生，缩短视神经P1波的潜伏期，增加振幅，增强传导能力，增强视神经抗拉伸承载能力，促进视神经的修复，CNTF和复光颗粒联合应用效果更佳。
本文的创新点如下：
1、从病理形态学、超微结构、视觉电生理学及生物力学多角度观察兔视神经损伤模型的视神经及视网膜的改变。
2、建立了不同程度的钳夹伤兔视神经损伤模型，根据病理形态学变化筛选出可作为TON发病机制及药物治疗效果研究的有效动物模型。
3、采用纵向拉伸实验，分别获取正常对照组、损伤组、CNTF治疗组、复光颗粒治疗组、CNTF和复光颗粒联合治疗组兔视神经的最大载荷、最大应力、最大应变、弹性限度载荷、弹性限度应变、弹性限度应力等，利用回归分析方法建立视神经应力-应变关系表达式，绘制应力-应变曲线，并进行定量分析。
4、从病理形态学、超微结构、视觉电生理学及生物力学角度分别观察CNTF、复光颗粒以及CNTF和复光颗粒联合对兔视神经损伤的修复程度，结果证明CNTF和复光颗粒联合治疗效果更佳。
Traumatic optic neuropathy (TON) is the injury-induced damage of the optic nervefunction that results in sudden loss of vision and can occur after direct or indirect injury.Ophthalmologically, TONs result in changes of virtually all optic nerve functions includingvisual acuity, visual fields, pupillary reflexes and funduscopically detectable morphologicalchanges. Retrograde degeneration of the RGCs is the final common outcome underlyingTON.The axon injury initiates ganglion cell disease and death. The failure of the optic nerveto regenerate after injury remains a major clinical and scientific problem. TON will directlydamage the retinal ganglion cells, lead to the degeneration and apoptosis, and ultimatelycause the loss of visual function.Improving the survival ratio of RGCs,maintaining orbuilding the structures,accelerating transportation of axonal plasm,and improving themicroenvironment for optic nerve fiber to survive or regenerate, saving the visual function ofpatients is a major issue in the contemporary nerve biomedical field.
The optic nerve is composed of retinal ganglion cells (RGCs), axons and glia. Damagecan occur to any part of the optic nerve, causing partial or complete loss of visual function.Therefore, the protection of optic nerves is one of the main focuses of research in the field ofmodern visual science. Increasing attention has been paid to the diagnosis and treatment ofoptic nerve injury, and the protection of optic nerves. This study aimed to verify the effectsof ciliary neurotrophic factor (CNTF) and/or compound light granules in the treatment ofoptic nerve injury in experimental rabbit models by morphological,ultrastructure,F-VEP andbiomechanical analyses, in a broader attempt to provide biomechanical basis for clinicalpractice.
1. Establishment and evaluation of TON models of rabbits
Establishing animal models of optic nerve injury is fundamental for nerve injuryresearch. Stable and reproducible animal model of mild, medium and severe optic nervecrush was established by using the mosquito clamp.This method was very simpleand convenient. In mild injury group, changes of morphology were slight, and visual functionwas fine. In medium injury group, pathological changes of optic nerve were obvious, and theinjury deteriorated gradually within4w observing time, however, part visual functionremained. With the lapse of time, pathological changes deteriorated quickly.In severe injurygroup, changes of morphology were irreversible sooner after injury, and the visual functionlost completely.The medium optic nerve crush model can be used to observe the therapyeffect of different treatment methods of TON.
2. The effects of CNTF and compound light granules on the pathological changes ofinjured optic nerve in rabbits.
The rabbits were randomly divided into Group A(normal control)，B(injury group)，C(CNTF group)，D(compound light granules group) and E(CNTF and compound lightgranules group) following traumatic optic nerve injury.The morphological changes in thelongitudinal profiles of the optic nerve were observed by hematoxylin-eosin staining andoptical microscopy. In normal control group, optic nerve fibers were arranged in a regularand parallel manner, the staining was uniform, axons and other contents were clearly seenand the glia were of similar sizes. In the injury group, optic nerve fibers were thin, tortuous,irregularly arrange, and the nuclei were not uniform. At3d after injury, nucleus pyknosis ofRGC was seen in injury group, then RGC loss were seen within2w, and the thickness ofretina become thin. With the lapse of time, these changes deteriorated quickly.In the CNTFgroup, optic nerve fibers were disordered, and the optic nerve appeared healthier and thedegree of injury was lighter than the model group.In the compound light granule group, aportion of optic nerve fibers were in a disordered arrangement, there was no thinning of theoptic nerve and glial nuclei were not uniform. These pathological changes of CNTF andcompound light granules group were more obvious in injury group at each point. In theCNTF+compound light granule group, optic nerve fibers were disordered, glial nuclei weresignificantly increased and were mostly in an ordered arrangement (a small amount were stillirregular), there was no thinning of the optic nerve and the degree of optic nerve injury waslighter than the CNTF and compound light granule groups. Compound light granules andciliary neurotrophic factor can prevent retinal tissue edema and alleviate optic nerve injury at the histological level, and the combined treatment is more effective than either treatmentalone.
3. The effects of CNTF and compound light granules on the ultrastructure of traumaticoptic neuropathy in rabbits at different times.
Axon injury disrupts the connections of RGCs to their target, resulting in a loss oftarget-derived neurotrophic support. The molecular responses at the site of axon injuryinvolve an interruption of axonal transport. Retinal ganglion cell (RGC) axons coursethrough the optic nerve and carry all the visual information to the brain, but after injury, theyfail to regrow through the optic nerve and RGC cell bodies typically die, leading topermanent loss of vision. Retrograde degeneration of the RGCs is the final common outcomeunderlying TON.The axon injury initiates ganglion cell disease and death.
In injury control group,Lamellar separation of myelin can be seen.The numberof axons reduced, and parts of them collapse.The numbers of microfilaments andmicrotubules were both reduced significantly.The mitochondrions were swelled, crest gapwidened,or totally collapsed and disappeared. With the lapse of time, these changesdeteriorated quickly.Compound light granules and ciliary neurotrophic factor can acceleratetransportation of axonal plasm and protect the microstructures of optic nerve,which isvaluable for restorating the transportation of axonal plasm. Compound light granules andciliary neurotrophic factor can alleviate optic nerve injury at the ultrastrucure level, and thecombined treatment is more effective than either treatment alone.
4. The effects of CNTF and compound light granules on the Flash visual evobepotentials of traumatic optic neuropathy in rabbits at different times.
The bright flash VEP uses full-field illumination and elicits a mass response from theanterior visual pathway. Thus, responses from abnormal regions of the field are summedwith those from normal regions.
In normal group, the latency of P1wave was32.19±1.88ms，and the amplitude of P1wave was21.24±1.78μv. F-VEP of the healthy rabbits revealed typical PNP contours, whilethe waves in the injureded groups were low and flat.The latency period of P1waves waslengthened and the amplitude reduced. The delay of P1wave latency was found in injury group at3days、1week、2weeks and4weeks after injury compared with normal group,CNTF,compound light granule and CNTF+compound light granule groups and the amplitude waslower than normal group(P<0.05).
5. The effects of CNTF and compound light granules on the biomechanical changes ofinjured optic nerve in rabbits.
Under normal physiological conditions imposed by posture and movement, nerves areexposed to various mechanical stresses. Optic nerves extremity need toaccommodate a vastarray of mechanical stresses associated with the diverse repertoire of human movementrelated to function and participation in daily activities. The structural elements of optic nervemust support the ultimate function of conduction of electrical impulses through myriadpositions, postures, and movements that often stress the nerves over multiple limb segmentsand joints simultaneously. At a point, the amount of applied load starts to permanentlydeform particular elements of the nerve.
Tensile test showed that the maximum tensile load, stress and strain, and the elasticlimit load, stress and strain of the optic nerve in the normal control group were significantlyhigher than those in the model, CNTF, compound light granule and CNTF+compound lightgranule groups (P <0.05). Compared with model group, the above indexes were increased inthe CNTF, compound light granule and CNTF+compound light granule groups, with themost significant difference in the CNTF+compound light granule group (P<0.05). Wecould see that the normal optic nerve had the strongest tensile bearing capacity, followed bythe injured optic nerve in the CNTF+compound light granule group, the injured optic nervein the compound light granule group, and the injured optic nerve in the CNTF group. Theinjured optic nerve in the model group without any treatment had the weakest tensile bearingcapacity. These experimental findings indicate that compound light granules and ciliaryneurotrophic factor can alleviate optic nerve injury at the biochemical level, and thecombined treatment is more effective than either treatment alone.
This experiment study the effects of ciliary neurotrophic factor (CNTF) and/orcompound light granules in the treatment of optic nerve injury in experimental rabbit modelsby morphological、ultrastructure、F-VEP and biomechanical analyses. The present study found that CNTF and compound light granules play an important role in neural activity.CNTF and compound light granules can promote the survival of a variety of retinal ganglioncells and nerve fibers，and is important for nervous system development, differentiation andrestoration after clamp injury. CNTF and compound light granule promote RGCs survivaland growth in vitro, significantly delay RGCs death after optic nerve crush injury, andimprove survival rate. In summary,these studies detecte the relevant factors using animalmodel to prove that CNTF and compound light granules can increase the activity of RGCsand promote the growth of processes,and protect the injured RGCs with anti-apoptoticpathways and increase the amount of growth associated protein to promote the regenerationof processes. Provide a better experimental basis and theoretical basis for more in-depthstudy of traumatic optic neuropathy, also provide a new direction and possibilities for itstreatment.
首先建立了轻、中、重不同程度的钳夹伤白兔视神经损伤模型，观察不同程度损伤后不同时间视神经视网膜组织学的变化，结果表明应用蚊式血管钳可制作白兔不同程度的视神经钳夹损伤模型，模型重复性好，致伤程度稳定，可用于临床研究。轻度损伤组视网膜及视神经损伤后病理形态改变不显著，视网膜神经节细胞（retinal ganglioncell，RGC）数量变化不明显，视神经结构和功能可大部分自行修复。中度损伤组视网膜及视神经病理形态改变明显，损伤时间越长，病理变化越明显。重度损伤组视网膜及视神经病理形态不可逆性改变，正常结构几乎完全消失，视网膜及视神经功能丧失。证明白兔中度损伤视神经模型可以作为TON发病机制及药物治疗效果研究的良好的动物模型。
在确定致伤程度稳定、重复性好的白兔TON中度钳夹伤模型后，建立正常对照组、损伤组、CNTF治疗组、复光颗粒治疗组、CNTF和复光颗粒联合治疗组。通过实验观察中度视神经钳夹伤白兔模型的病理形态学、超微结构、视觉电生理学及生物力学特性的变化，得出以下结论：视神经损伤后病理形态学改变包括RGC和神经纤维数目不断减少，出现RGC肿胀，核固缩、染色加深，染色质边聚、空化、变性，细胞核碎裂等细胞凋亡现象。视神经纤维水肿，胶质细胞肿胀，神经纤维断裂、结构模糊，坏死灶增多、扩大，各层神经组织明显变薄、萎缩。视神经损伤超微结构改变主要包括视神经和视网膜的神经纤维层线粒体肿胀、嵴变宽甚至空泡化，微丝和微管数目减少、结构异常，轴突数目减少，RGC细胞凋亡等结构的改变，损伤随时间的延长逐渐加重。视神经损伤后闪光刺激诱发电位变化包括P1波潜伏期延长，振幅降低，传导能力减弱。损伤后视神经生物力学改变包括抗拉伸承载能力减弱，拉伸最大载荷、最大应力、最大应变、弹性限度载荷、弹性限度应变、弹性限度应力明显小于正常神经。CNTF和复光颗粒能够在一定程度上减缓RGC和神经纤维的凋亡时间和数量，促进RGC和神经纤维的再生，阻止轴突的变性坏死，从而阻断RGC的死亡，保护视神经超微结构，为轴浆运输功能的恢复提供物质基础和载体，促进神经纤维再生，缩短视神经P1波的潜伏期，增加振幅，增强传导能力，增强视神经抗拉伸承载能力，促进视神经的修复，CNTF和复光颗粒联合应用效果更佳。
本文的创新点如下：
1、从病理形态学、超微结构、视觉电生理学及生物力学多角度观察兔视神经损伤模型的视神经及视网膜的改变。
2、建立了不同程度的钳夹伤兔视神经损伤模型，根据病理形态学变化筛选出可作为TON发病机制及药物治疗效果研究的有效动物模型。
3、采用纵向拉伸实验，分别获取正常对照组、损伤组、CNTF治疗组、复光颗粒治疗组、CNTF和复光颗粒联合治疗组兔视神经的最大载荷、最大应力、最大应变、弹性限度载荷、弹性限度应变、弹性限度应力等，利用回归分析方法建立视神经应力-应变关系表达式，绘制应力-应变曲线，并进行定量分析。
4、从病理形态学、超微结构、视觉电生理学及生物力学角度分别观察CNTF、复光颗粒以及CNTF和复光颗粒联合对兔视神经损伤的修复程度，结果证明CNTF和复光颗粒联合治疗效果更佳。
Traumatic optic neuropathy (TON) is the injury-induced damage of the optic nervefunction that results in sudden loss of vision and can occur after direct or indirect injury.Ophthalmologically, TONs result in changes of virtually all optic nerve functions includingvisual acuity, visual fields, pupillary reflexes and funduscopically detectable morphologicalchanges. Retrograde degeneration of the RGCs is the final common outcome underlyingTON.The axon injury initiates ganglion cell disease and death. The failure of the optic nerveto regenerate after injury remains a major clinical and scientific problem. TON will directlydamage the retinal ganglion cells, lead to the degeneration and apoptosis, and ultimatelycause the loss of visual function.Improving the survival ratio of RGCs,maintaining orbuilding the structures,accelerating transportation of axonal plasm,and improving themicroenvironment for optic nerve fiber to survive or regenerate, saving the visual function ofpatients is a major issue in the contemporary nerve biomedical field.
The optic nerve is composed of retinal ganglion cells (RGCs), axons and glia. Damagecan occur to any part of the optic nerve, causing partial or complete loss of visual function.Therefore, the protection of optic nerves is one of the main focuses of research in the field ofmodern visual science. Increasing attention has been paid to the diagnosis and treatment ofoptic nerve injury, and the protection of optic nerves. This study aimed to verify the effectsof ciliary neurotrophic factor (CNTF) and/or compound light granules in the treatment ofoptic nerve injury in experimental rabbit models by morphological,ultrastructure,F-VEP andbiomechanical analyses, in a broader attempt to provide biomechanical basis for clinicalpractice.
1. Establishment and evaluation of TON models of rabbits
Establishing animal models of optic nerve injury is fundamental for nerve injuryresearch. Stable and reproducible animal model of mild, medium and severe optic nervecrush was established by using the mosquito clamp.This method was very simpleand convenient. In mild injury group, changes of morphology were slight, and visual functionwas fine. In medium injury group, pathological changes of optic nerve were obvious, and theinjury deteriorated gradually within4w observing time, however, part visual functionremained. With the lapse of time, pathological changes deteriorated quickly.In severe injurygroup, changes of morphology were irreversible sooner after injury, and the visual functionlost completely.The medium optic nerve crush model can be used to observe the therapyeffect of different treatment methods of TON.
2. The effects of CNTF and compound light granules on the pathological changes ofinjured optic nerve in rabbits.
The rabbits were randomly divided into Group A(normal control)，B(injury group)，C(CNTF group)，D(compound light granules group) and E(CNTF and compound lightgranules group) following traumatic optic nerve injury.The morphological changes in thelongitudinal profiles of the optic nerve were observed by hematoxylin-eosin staining andoptical microscopy. In normal control group, optic nerve fibers were arranged in a regularand parallel manner, the staining was uniform, axons and other contents were clearly seenand the glia were of similar sizes. In the injury group, optic nerve fibers were thin, tortuous,irregularly arrange, and the nuclei were not uniform. At3d after injury, nucleus pyknosis ofRGC was seen in injury group, then RGC loss were seen within2w, and the thickness ofretina become thin. With the lapse of time, these changes deteriorated quickly.In the CNTFgroup, optic nerve fibers were disordered, and the optic nerve appeared healthier and thedegree of injury was lighter than the model group.In the compound light granule group, aportion of optic nerve fibers were in a disordered arrangement, there was no thinning of theoptic nerve and glial nuclei were not uniform. These pathological changes of CNTF andcompound light granules group were more obvious in injury group at each point. In theCNTF+compound light granule group, optic nerve fibers were disordered, glial nuclei weresignificantly increased and were mostly in an ordered arrangement (a small amount were stillirregular), there was no thinning of the optic nerve and the degree of optic nerve injury waslighter than the CNTF and compound light granule groups. Compound light granules andciliary neurotrophic factor can prevent retinal tissue edema and alleviate optic nerve injury at the histological level, and the combined treatment is more effective than either treatmentalone.
3. The effects of CNTF and compound light granules on the ultrastructure of traumaticoptic neuropathy in rabbits at different times.
Axon injury disrupts the connections of RGCs to their target, resulting in a loss oftarget-derived neurotrophic support. The molecular responses at the site of axon injuryinvolve an interruption of axonal transport. Retinal ganglion cell (RGC) axons coursethrough the optic nerve and carry all the visual information to the brain, but after injury, theyfail to regrow through the optic nerve and RGC cell bodies typically die, leading topermanent loss of vision. Retrograde degeneration of the RGCs is the final common outcomeunderlying TON.The axon injury initiates ganglion cell disease and death.
In injury control group,Lamellar separation of myelin can be seen.The numberof axons reduced, and parts of them collapse.The numbers of microfilaments andmicrotubules were both reduced significantly.The mitochondrions were swelled, crest gapwidened,or totally collapsed and disappeared. With the lapse of time, these changesdeteriorated quickly.Compound light granules and ciliary neurotrophic factor can acceleratetransportation of axonal plasm and protect the microstructures of optic nerve,which isvaluable for restorating the transportation of axonal plasm. Compound light granules andciliary neurotrophic factor can alleviate optic nerve injury at the ultrastrucure level, and thecombined treatment is more effective than either treatment alone.
4. The effects of CNTF and compound light granules on the Flash visual evobepotentials of traumatic optic neuropathy in rabbits at different times.
The bright flash VEP uses full-field illumination and elicits a mass response from theanterior visual pathway. Thus, responses from abnormal regions of the field are summedwith those from normal regions.
In normal group, the latency of P1wave was32.19±1.88ms，and the amplitude of P1wave was21.24±1.78μv. F-VEP of the healthy rabbits revealed typical PNP contours, whilethe waves in the injureded groups were low and flat.The latency period of P1waves waslengthened and the amplitude reduced. The delay of P1wave latency was found in injury group at3days、1week、2weeks and4weeks after injury compared with normal group,CNTF,compound light granule and CNTF+compound light granule groups and the amplitude waslower than normal group(P<0.05).
5. The effects of CNTF and compound light granules on the biomechanical changes ofinjured optic nerve in rabbits.
Under normal physiological conditions imposed by posture and movement, nerves areexposed to various mechanical stresses. Optic nerves extremity need toaccommodate a vastarray of mechanical stresses associated with the diverse repertoire of human movementrelated to function and participation in daily activities. The structural elements of optic nervemust support the ultimate function of conduction of electrical impulses through myriadpositions, postures, and movements that often stress the nerves over multiple limb segmentsand joints simultaneously. At a point, the amount of applied load starts to permanentlydeform particular elements of the nerve.
Tensile test showed that the maximum tensile load, stress and strain, and the elasticlimit load, stress and strain of the optic nerve in the normal control group were significantlyhigher than those in the model, CNTF, compound light granule and CNTF+compound lightgranule groups (P <0.05). Compared with model group, the above indexes were increased inthe CNTF, compound light granule and CNTF+compound light granule groups, with themost significant difference in the CNTF+compound light granule group (P<0.05). Wecould see that the normal optic nerve had the strongest tensile bearing capacity, followed bythe injured optic nerve in the CNTF+compound light granule group, the injured optic nervein the compound light granule group, and the injured optic nerve in the CNTF group. Theinjured optic nerve in the model group without any treatment had the weakest tensile bearingcapacity. These experimental findings indicate that compound light granules and ciliaryneurotrophic factor can alleviate optic nerve injury at the biochemical level, and thecombined treatment is more effective than either treatment alone.
This experiment study the effects of ciliary neurotrophic factor (CNTF) and/orcompound light granules in the treatment of optic nerve injury in experimental rabbit modelsby morphological、ultrastructure、F-VEP and biomechanical analyses. The present study found that CNTF and compound light granules play an important role in neural activity.CNTF and compound light granules can promote the survival of a variety of retinal ganglioncells and nerve fibers，and is important for nervous system development, differentiation andrestoration after clamp injury. CNTF and compound light granule promote RGCs survivaland growth in vitro, significantly delay RGCs death after optic nerve crush injury, andimprove survival rate. In summary,these studies detecte the relevant factors using animalmodel to prove that CNTF and compound light granules can increase the activity of RGCsand promote the growth of processes,and protect the injured RGCs with anti-apoptoticpathways and increase the amount of growth associated protein to promote the regenerationof processes. Provide a better experimental basis and theoretical basis for more in-depthstudy of traumatic optic neuropathy, also provide a new direction and possibilities for itstreatment.
引文
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