GABA转氨酶抑制剂—氨己烯酸致小鼠视网膜神经元突触改变以及与光毒性的关系
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摘要
氨己烯酸(Vigabatrin,VGB)为抗癫痫药物,由欧洲Sanofi-Aventis制药有限公司开发研制。其作用机制为,不可逆地与伽马氨基丁酸(gamma-aminobutyric acid,GABA)氨基转移酶(GABA-transaminase)结合,抑制GABA的降解从而提高脑内GABA浓度并发挥抗癫痫作用。临床研究结果表明,氨己烯酸为治疗严重癫痫患儿有效而安全的一种抗癫痫药,并对智碍的患儿也有治疗效果。目前临床主要用于治疗顽固性部分性癫痫发作,尤其对顽固性儿童癫痫发作适用。
然而随着氨己烯酸临床应用的日渐广泛,发现使用该药物的部分患者出现视野缺损,并进一步造成不可逆的视力损伤。为探索该药物的视网膜损伤机制,本课题组已经在大鼠的实验研究中发现,氨己烯酸主要造成大鼠视网膜视锥细胞的损伤,表现为感光细胞层的不规则改变以及神经胶质酸性蛋白(glialfibrillary acidic protein,GFAP)增生反应。为了进一步确定这种损伤的改变是否为种属特异性,即是否只表现在大鼠视网膜,我们使用BALB/c小鼠进行氨己烯酸腹腔注射,并观察视网膜改变。
与大鼠视网膜损伤类似,小鼠视网膜也表现出视锥细胞的损伤,但与大鼠视网膜不同的是,胶质细胞反应在小鼠视网膜为自发性反应,即GFAP免疫荧光染色为非特异性。在小鼠视网膜,氨己烯酸的视网膜损伤主要表现为第二级神经原细胞突触向外核层的伸展,同时伴有视杆细胞突触向外核层的退缩,而视锥细胞突触未发生退缩性变化。在这一过程中,双极细胞与视锥细胞之间的联结丧失,双极细胞与视杆细胞之间的突触连接可部分丧失。
体外研究表明,氨己烯酸的视网膜毒性与光毒性有关,同时非白化病动物实验也证明氨己烯酸的视网膜损伤选择性特异性的存在于白化病动物。受此启发,本课题在上述发现的基础上,把一组进行氨己烯酸治疗小鼠置于暗室环境中,视网膜免疫荧光染色发现,小鼠视网膜的突触改变被完全抑制。
目的:(1)研究氨己烯酸在小鼠视网膜的毒性改变,观察氨己烯酸在不同亚属间动物视网膜损伤的差异。(2)观察氨己烯酸的视网膜毒性与光毒性的关系,探索氨己烯酸视网膜损伤的可能预防机制。
方法:
第一部分。氨己烯酸在小鼠视网膜的毒性观察:(1)选用26只健康雄性BALB/c小鼠,16只作为治疗组,连续接受氨己烯酸腹腔注射,药物配制浓度为100mg/ml,溶解于0.9%NaCl溶液中,注射剂量为250mg/kg,持续注射30天。10只作为对照组,每日接受0.9%NaCl腹腔注射0.1ml。(2)第31天处死动物,取眼球后去除角膜和晶状体,眼杯进行冰冻切片(厚度8-10μm)。(3)免疫荧光染色:第一抗体分别为Anti-mouse cone arrestin(1:20,000,Luminaire junior,LUMIj),Anti-protein kinase Calpha(PKCα)(1:2000,Sigma),Anti-VGluT1,(1:2000,Chemicon),Anti-GoαK-20(1:100,Santa Cruz),Anti-calbindin D-28K(1:500,Chemicon),Anti-Goα(1:2000,Chemicon),Anti-bassoon(1:100,StrseeGen),DAPI(1:500,Molecular Probes,Eugene,OR),第二抗体为Goat anti-rabbit IgGor rabbit anti-mouse IgG conjugated to either Alexa TM594 or Alexa TM488(Molecular Probes,Eugene,OR)。(4)免疫荧光结果的观察与摄片。
第二部分。观察氨己烯酸的视网膜毒性与光毒性的关系:(1)选用30只健康雄性BALB/c小鼠,10只作为正常治疗组,置于正常饲养环境中,12小时光照与12小时暗室环境交替,每日接受氨己烯酸腹腔注射,药物配制浓度为100mg/ml,溶解于0.9%NaCl溶液中,注射剂量为250mg/kg,持续注射30天;10只作为暗室治疗组,24小时置于暗室环境中,接受药物治疗浓度与持续时间同正常治疗组;10只作为对照组,置于正常饲养环境中,12小时光照与12小时暗室环境交替,每日接受0.9%NaCl腹腔注射0.1ml。(2)第31天处死动物,取眼球后去除角膜晶体,眼杯进行冰冻切片(厚度8-10μm)制作。(3)免疫荧光染色:选用抗体同实验第一部分。(4)免疫荧光结果的观察与摄片。
结果:
第一部分:(1)氨己烯酸治疗组中的16只小鼠中有5只小鼠视网膜外核层出现不规则突起改变,伸向色素上皮层。(2)Anti-cone arrestin染色表明视锥细胞的外节出现损伤,但其突触仍位于外丛状层,并不发生退缩性改变。(3)胶质细胞染色GFAP表现为非特异性。(4)所有氨己烯酸治疗组小鼠经Anti-VGluT1和Anti-Bassoon染色,表现为视杆细胞突触由外丛状层向外核层退缩。(5)所有氨己烯酸治疗组小鼠经Anti-Goα和Anti-PKCα染色表明视锥和视杆ON-双极细胞突触由外丛状层向外核层伸展。(6)所有氨己烯酸治疗组小鼠水平细胞突触从外丛状层向外核层伸展。(7)随着视锥ON-双极细胞突触向外核层的伸展而视锥细胞突触仍位于外丛状层,两层细胞间突触失去联结。(8)双重染色显示,伴随视杆细胞突触的退缩和ON-双极细胞突触的伸展,两层细胞间的突触连接可部分丧失。
第二部分:(1)所有暗室治疗组小鼠经Anti-VGluT1和Anti-Bassoon染色表明视杆细胞突触由外丛状层向外核层的退缩在暗室治疗环境中可被抑制。(2)Anti-Goα和Anti-PKCα染色表明ON-双极细胞突触由外丛状层向外核层的伸展在去除光照条件下也被抑制。(3)Anti-calbindin D-28K染色显示,在暗室环境中水平细胞的突触向外核层的伸展也消失。
结论:(1)氨己烯酸在小鼠视网膜毒性改变可以表现为外核层的不规则突起改变,伴有视锥细胞的外节丧失,但视锥细胞突触仍位于外丛状层。上述改变与氨己烯酸造成的大鼠视网膜损伤改变类似。(2)GFAP染色在小鼠视网膜表现为非特异性染色,无法作为小鼠视网膜损伤的标志性染色。(3)氨己烯酸在小鼠视网膜损伤模型中,最显著的改变为视杆细胞和ON-双极细胞的突触移位,同时伴有水平细胞的突触向外核层伸展。(4)伴随着ON-双极细胞突触向外核层的伸展,ON-视锥双极细胞与视锥细胞突触失联结,ON-视杆双极细胞与视杆细胞突触部分失联结。(5)氨己烯酸的小鼠视网膜毒性有光依赖性,去除光毒性的影响,小鼠视网膜第一与第二及神经原之间的病理性突触改变可以被完全抑制。
Epilepsy affects 1%of the world population and can be life threatening. Vigabatrin,(gamma-vinyl GABA,or VGB),was widely prescribed for the treatment of epilepsy because it reduces the occurrence of seizures by increasing the GABA concentration,the main inhibitory neurotransmitter of the central nervous system.Vigabatrin irreversibly inhibits GABA transaminase,the GABA degrading enzyme.Unfortunately,chronic administration of VGB was found to induce a bilateral constriction of the visual field in 10 to 40%of treated patients.There have been several reports of altered visual acuity,colour discrimination or contrast sensitivity whereas other studies,such as the longitudinal cohort studies sponsored by the National Health Service of Scotland,have demonstrated preservation of central visual acuity and colour vision in patients with bilateral constriction.Retinal damages were described in albino rats and they included cone photoreceptor damage,disorganization of the photoreceptor layer and gliosis indicated by increased GFAP immunocytochemical labelling.The pathological changes in albino rats did not fully explain human symptoms.To further investigate the vigabatrin-elicited retinal toxicity and take advantage of genetically modified animals,we have examined retinal changes in vigabatrin-treated albino mice.Although the photoreceptor layer was occasionally disorganized,this symptom was less often encountered than in vigabatrin-treated rats.The cone photoreceptor damage could be detected as it expressed in albino rats,and retinal glial cells were not more intensely labelled in vigabatrin-treated mice than in control albino animals.However,rod photoreceptors were found to withdraw their synapses from the outer plexiform layer to their cell body as indicated by bassoon immunostaining of their synaptic ribbons or VGLUT1-immunolabelling of synaptic vesicles.Cone photoreceptors maintained their terminals in the outer plexiform layer.In parallel,not only rod ON bipolar cells and horizontal cells but also cone ON bipolar cells exhibited dendrites sprouting into the photoreceptor nuclear layer. Contacts between withdrawing rod synaptic terminals and the growing postsynaptic neurones were not always maintained.This plasticity of retinal neurones which could explain the constriction of the visual field appeared as the main retinal damage in vigabatrin-treated albino mice.
VGB-elicited photoreceptor degeneration was reported to be light-dependent in vitro.This is consistent with the selective VGB sensitivity of albino but not pigmented animals.Base on these findings, we kept a group of albino mice in darkness during chronic VGB treatment to further assess the light dependence of VGB-elicited toxicity.As we hypothesized,the plasticity of retinal neurons was completely suppressed by darkness.
Purpose:
(1)To investigate the vigabatrin toxicity on albino mouse retina, evaluate the manifestation of retinal toxicity in diverse genetical modified animals.
(2)To detect the correlation between phototoxicity and vigabation-elicited retinal damage,explore the potential management of vigabatrin toxicity on retina.
Methods:
Part 1.Twenty six BALB/c male mice were separated to two groups. Sixteen of them received daily intraperitoneal injection of vigabatrin and lasted for thirty days.VGB was dissolved in 0.9%NaCl at a concentration of 100mg/ml and final injection dose was 250mg/kg as described for animal treatment of epilepsy.Ten animals received 0.1ml 0.9%NaCl daily injection as control group.On day 31,animals were sacrificed and enucleated,after removing the cornea and lens,eye cups were fixed and cryosection were prepared in 8-10μm thickness.The sections were immunostained separately with Anti-mouse cone arrestin (1:20,000,Luminaire junior,LUMIj),Anti-protein kinase C alpha(PKCα)(1:2000,Sigma),Anti-VGlur1,(1:2000,Chemicon),Anti-GoαK-20(1:100,Santa Cruz),Anti-calbindin D-28K(1:500,Chemicon),Anti-Goα(1:2000,Chemicon),Anti-bassoon(1:100,StrseeGen),DAPI(1:500, Molecular Probes,Eugene,OR),the second antibody is Goat anti-rabbit IgG or rabbit anti-mouse IgG conjugated to either Alexa TM594 or Alexa TM488 (Molecular Probes,Eugene,OR)。Final results were taken by Ropper scientific camera(Photometrics cool SNAP TM FX).
Part 2.Thirty BALB/c male mice were separated to three groups.Ten animals received VGB daily intraperitoneal injection were kept in normal day-night cycle situation as VGB treatment group;another ten mice were kept in darkness during the whole process of VGB intraperitoneal injection as VGB darkness group;the residual ten animals which accept vehicle solution injection were also kept in normal day-night cycle situation as control group.The whole period of experiment also last thirty days,VGB concentration and dose of injection were the same as Part 1.On day 31, animals were sacrificed and enucleated,steps of cryosections and inmunostaining were repeated as Part 1.Final results were also recorded with Ropper scientific camera.
Results:
Part 1.(1) Areas with a highly disorganized outer nuclear layer were observed in vigabatrin-treated albino mice but not in all animals(5 of 16 treated mice)as treated rats.(2) Staining of cone arrestin showed outer segments of cones were altered in restricted areas as in VGB-treated rats but their terminals remained intensely labeled in out plexiform layer.(3) GFAP staining was not increased by the vigabatrin treatment.(4) Rod terminals were withdraw into the ONL close to photoreceptor nuclei in all vjgabatrin treated mice.(5)Bipolar cells sprouted their dendrites form out plexiform layer to the out nuclear layer in all VGB treated animals.(6) In all VGB-treated animals,horizontal extended their dendrites from out plexiform layer into the out nuclear layer like bipolar cells.(7)Double labelling indicated that the rod terminal withdrawal was associated with a loss of synaptic transmission between photoreceptors and their postsynaptic neurons.(8) Double labelling indicated that the connections between cone terminals and bipolar dendrites were lost with bipolar sprouting and cone terminals stable in OPL.
Part 2.(1) In VGB darkness group,withdraw of photoreceptor terminal were completely suppressed.(2) VGB-elicited sprouting of bipolar cell dendrites disappeared in dark situation.(3) The horizontal dendrites migration were also inhibited in VGB darkness group.
Conclusions:
(1) Vigabatrin treatment in albino mice could represented by the retinal architecture disorganization and partial out segment loss in some degree,which is similar to the rat retina damage.(2) GFAP staining is the prominent mark in rat retina damage,on contrast,this staining is unspecific reaction both in VGB treated mice and control group which means the glial staining is not an indicator of mouse retina impairment.(3) The hallmark of vigabatrin hazard on mouse retina is the retinal neuro-plasticity:rod dendrites withdraw and bipolar axons sprouting accompany with horizontal cell terminals.(4) Darkness could eliminate the distinctive neuro-plasticity completely on albino mouse retina demonstrated vigabatrin-induced damage is correlate with phototoxicity, which indicated a potential way of prevention of vigabatrin injury in clinic.
然而随着氨己烯酸临床应用的日渐广泛,发现使用该药物的部分患者出现视野缺损,并进一步造成不可逆的视力损伤。为探索该药物的视网膜损伤机制,本课题组已经在大鼠的实验研究中发现,氨己烯酸主要造成大鼠视网膜视锥细胞的损伤,表现为感光细胞层的不规则改变以及神经胶质酸性蛋白(glialfibrillary acidic protein,GFAP)增生反应。为了进一步确定这种损伤的改变是否为种属特异性,即是否只表现在大鼠视网膜,我们使用BALB/c小鼠进行氨己烯酸腹腔注射,并观察视网膜改变。
与大鼠视网膜损伤类似,小鼠视网膜也表现出视锥细胞的损伤,但与大鼠视网膜不同的是,胶质细胞反应在小鼠视网膜为自发性反应,即GFAP免疫荧光染色为非特异性。在小鼠视网膜,氨己烯酸的视网膜损伤主要表现为第二级神经原细胞突触向外核层的伸展,同时伴有视杆细胞突触向外核层的退缩,而视锥细胞突触未发生退缩性变化。在这一过程中,双极细胞与视锥细胞之间的联结丧失,双极细胞与视杆细胞之间的突触连接可部分丧失。
体外研究表明,氨己烯酸的视网膜毒性与光毒性有关,同时非白化病动物实验也证明氨己烯酸的视网膜损伤选择性特异性的存在于白化病动物。受此启发,本课题在上述发现的基础上,把一组进行氨己烯酸治疗小鼠置于暗室环境中,视网膜免疫荧光染色发现,小鼠视网膜的突触改变被完全抑制。
目的:(1)研究氨己烯酸在小鼠视网膜的毒性改变,观察氨己烯酸在不同亚属间动物视网膜损伤的差异。(2)观察氨己烯酸的视网膜毒性与光毒性的关系,探索氨己烯酸视网膜损伤的可能预防机制。
方法:
第一部分。氨己烯酸在小鼠视网膜的毒性观察:(1)选用26只健康雄性BALB/c小鼠,16只作为治疗组,连续接受氨己烯酸腹腔注射,药物配制浓度为100mg/ml,溶解于0.9%NaCl溶液中,注射剂量为250mg/kg,持续注射30天。10只作为对照组,每日接受0.9%NaCl腹腔注射0.1ml。(2)第31天处死动物,取眼球后去除角膜和晶状体,眼杯进行冰冻切片(厚度8-10μm)。(3)免疫荧光染色:第一抗体分别为Anti-mouse cone arrestin(1:20,000,Luminaire junior,LUMIj),Anti-protein kinase Calpha(PKCα)(1:2000,Sigma),Anti-VGluT1,(1:2000,Chemicon),Anti-GoαK-20(1:100,Santa Cruz),Anti-calbindin D-28K(1:500,Chemicon),Anti-Goα(1:2000,Chemicon),Anti-bassoon(1:100,StrseeGen),DAPI(1:500,Molecular Probes,Eugene,OR),第二抗体为Goat anti-rabbit IgGor rabbit anti-mouse IgG conjugated to either Alexa TM594 or Alexa TM488(Molecular Probes,Eugene,OR)。(4)免疫荧光结果的观察与摄片。
第二部分。观察氨己烯酸的视网膜毒性与光毒性的关系:(1)选用30只健康雄性BALB/c小鼠,10只作为正常治疗组,置于正常饲养环境中,12小时光照与12小时暗室环境交替,每日接受氨己烯酸腹腔注射,药物配制浓度为100mg/ml,溶解于0.9%NaCl溶液中,注射剂量为250mg/kg,持续注射30天;10只作为暗室治疗组,24小时置于暗室环境中,接受药物治疗浓度与持续时间同正常治疗组;10只作为对照组,置于正常饲养环境中,12小时光照与12小时暗室环境交替,每日接受0.9%NaCl腹腔注射0.1ml。(2)第31天处死动物,取眼球后去除角膜晶体,眼杯进行冰冻切片(厚度8-10μm)制作。(3)免疫荧光染色:选用抗体同实验第一部分。(4)免疫荧光结果的观察与摄片。
结果:
第一部分:(1)氨己烯酸治疗组中的16只小鼠中有5只小鼠视网膜外核层出现不规则突起改变,伸向色素上皮层。(2)Anti-cone arrestin染色表明视锥细胞的外节出现损伤,但其突触仍位于外丛状层,并不发生退缩性改变。(3)胶质细胞染色GFAP表现为非特异性。(4)所有氨己烯酸治疗组小鼠经Anti-VGluT1和Anti-Bassoon染色,表现为视杆细胞突触由外丛状层向外核层退缩。(5)所有氨己烯酸治疗组小鼠经Anti-Goα和Anti-PKCα染色表明视锥和视杆ON-双极细胞突触由外丛状层向外核层伸展。(6)所有氨己烯酸治疗组小鼠水平细胞突触从外丛状层向外核层伸展。(7)随着视锥ON-双极细胞突触向外核层的伸展而视锥细胞突触仍位于外丛状层,两层细胞间突触失去联结。(8)双重染色显示,伴随视杆细胞突触的退缩和ON-双极细胞突触的伸展,两层细胞间的突触连接可部分丧失。
第二部分:(1)所有暗室治疗组小鼠经Anti-VGluT1和Anti-Bassoon染色表明视杆细胞突触由外丛状层向外核层的退缩在暗室治疗环境中可被抑制。(2)Anti-Goα和Anti-PKCα染色表明ON-双极细胞突触由外丛状层向外核层的伸展在去除光照条件下也被抑制。(3)Anti-calbindin D-28K染色显示,在暗室环境中水平细胞的突触向外核层的伸展也消失。
结论:(1)氨己烯酸在小鼠视网膜毒性改变可以表现为外核层的不规则突起改变,伴有视锥细胞的外节丧失,但视锥细胞突触仍位于外丛状层。上述改变与氨己烯酸造成的大鼠视网膜损伤改变类似。(2)GFAP染色在小鼠视网膜表现为非特异性染色,无法作为小鼠视网膜损伤的标志性染色。(3)氨己烯酸在小鼠视网膜损伤模型中,最显著的改变为视杆细胞和ON-双极细胞的突触移位,同时伴有水平细胞的突触向外核层伸展。(4)伴随着ON-双极细胞突触向外核层的伸展,ON-视锥双极细胞与视锥细胞突触失联结,ON-视杆双极细胞与视杆细胞突触部分失联结。(5)氨己烯酸的小鼠视网膜毒性有光依赖性,去除光毒性的影响,小鼠视网膜第一与第二及神经原之间的病理性突触改变可以被完全抑制。
Epilepsy affects 1%of the world population and can be life threatening. Vigabatrin,(gamma-vinyl GABA,or VGB),was widely prescribed for the treatment of epilepsy because it reduces the occurrence of seizures by increasing the GABA concentration,the main inhibitory neurotransmitter of the central nervous system.Vigabatrin irreversibly inhibits GABA transaminase,the GABA degrading enzyme.Unfortunately,chronic administration of VGB was found to induce a bilateral constriction of the visual field in 10 to 40%of treated patients.There have been several reports of altered visual acuity,colour discrimination or contrast sensitivity whereas other studies,such as the longitudinal cohort studies sponsored by the National Health Service of Scotland,have demonstrated preservation of central visual acuity and colour vision in patients with bilateral constriction.Retinal damages were described in albino rats and they included cone photoreceptor damage,disorganization of the photoreceptor layer and gliosis indicated by increased GFAP immunocytochemical labelling.The pathological changes in albino rats did not fully explain human symptoms.To further investigate the vigabatrin-elicited retinal toxicity and take advantage of genetically modified animals,we have examined retinal changes in vigabatrin-treated albino mice.Although the photoreceptor layer was occasionally disorganized,this symptom was less often encountered than in vigabatrin-treated rats.The cone photoreceptor damage could be detected as it expressed in albino rats,and retinal glial cells were not more intensely labelled in vigabatrin-treated mice than in control albino animals.However,rod photoreceptors were found to withdraw their synapses from the outer plexiform layer to their cell body as indicated by bassoon immunostaining of their synaptic ribbons or VGLUT1-immunolabelling of synaptic vesicles.Cone photoreceptors maintained their terminals in the outer plexiform layer.In parallel,not only rod ON bipolar cells and horizontal cells but also cone ON bipolar cells exhibited dendrites sprouting into the photoreceptor nuclear layer. Contacts between withdrawing rod synaptic terminals and the growing postsynaptic neurones were not always maintained.This plasticity of retinal neurones which could explain the constriction of the visual field appeared as the main retinal damage in vigabatrin-treated albino mice.
VGB-elicited photoreceptor degeneration was reported to be light-dependent in vitro.This is consistent with the selective VGB sensitivity of albino but not pigmented animals.Base on these findings, we kept a group of albino mice in darkness during chronic VGB treatment to further assess the light dependence of VGB-elicited toxicity.As we hypothesized,the plasticity of retinal neurons was completely suppressed by darkness.
Purpose:
(1)To investigate the vigabatrin toxicity on albino mouse retina, evaluate the manifestation of retinal toxicity in diverse genetical modified animals.
(2)To detect the correlation between phototoxicity and vigabation-elicited retinal damage,explore the potential management of vigabatrin toxicity on retina.
Methods:
Part 1.Twenty six BALB/c male mice were separated to two groups. Sixteen of them received daily intraperitoneal injection of vigabatrin and lasted for thirty days.VGB was dissolved in 0.9%NaCl at a concentration of 100mg/ml and final injection dose was 250mg/kg as described for animal treatment of epilepsy.Ten animals received 0.1ml 0.9%NaCl daily injection as control group.On day 31,animals were sacrificed and enucleated,after removing the cornea and lens,eye cups were fixed and cryosection were prepared in 8-10μm thickness.The sections were immunostained separately with Anti-mouse cone arrestin (1:20,000,Luminaire junior,LUMIj),Anti-protein kinase C alpha(PKCα)(1:2000,Sigma),Anti-VGlur1,(1:2000,Chemicon),Anti-GoαK-20(1:100,Santa Cruz),Anti-calbindin D-28K(1:500,Chemicon),Anti-Goα(1:2000,Chemicon),Anti-bassoon(1:100,StrseeGen),DAPI(1:500, Molecular Probes,Eugene,OR),the second antibody is Goat anti-rabbit IgG or rabbit anti-mouse IgG conjugated to either Alexa TM594 or Alexa TM488 (Molecular Probes,Eugene,OR)。Final results were taken by Ropper scientific camera(Photometrics cool SNAP TM FX).
Part 2.Thirty BALB/c male mice were separated to three groups.Ten animals received VGB daily intraperitoneal injection were kept in normal day-night cycle situation as VGB treatment group;another ten mice were kept in darkness during the whole process of VGB intraperitoneal injection as VGB darkness group;the residual ten animals which accept vehicle solution injection were also kept in normal day-night cycle situation as control group.The whole period of experiment also last thirty days,VGB concentration and dose of injection were the same as Part 1.On day 31, animals were sacrificed and enucleated,steps of cryosections and inmunostaining were repeated as Part 1.Final results were also recorded with Ropper scientific camera.
Results:
Part 1.(1) Areas with a highly disorganized outer nuclear layer were observed in vigabatrin-treated albino mice but not in all animals(5 of 16 treated mice)as treated rats.(2) Staining of cone arrestin showed outer segments of cones were altered in restricted areas as in VGB-treated rats but their terminals remained intensely labeled in out plexiform layer.(3) GFAP staining was not increased by the vigabatrin treatment.(4) Rod terminals were withdraw into the ONL close to photoreceptor nuclei in all vjgabatrin treated mice.(5)Bipolar cells sprouted their dendrites form out plexiform layer to the out nuclear layer in all VGB treated animals.(6) In all VGB-treated animals,horizontal extended their dendrites from out plexiform layer into the out nuclear layer like bipolar cells.(7)Double labelling indicated that the rod terminal withdrawal was associated with a loss of synaptic transmission between photoreceptors and their postsynaptic neurons.(8) Double labelling indicated that the connections between cone terminals and bipolar dendrites were lost with bipolar sprouting and cone terminals stable in OPL.
Part 2.(1) In VGB darkness group,withdraw of photoreceptor terminal were completely suppressed.(2) VGB-elicited sprouting of bipolar cell dendrites disappeared in dark situation.(3) The horizontal dendrites migration were also inhibited in VGB darkness group.
Conclusions:
(1) Vigabatrin treatment in albino mice could represented by the retinal architecture disorganization and partial out segment loss in some degree,which is similar to the rat retina damage.(2) GFAP staining is the prominent mark in rat retina damage,on contrast,this staining is unspecific reaction both in VGB treated mice and control group which means the glial staining is not an indicator of mouse retina impairment.(3) The hallmark of vigabatrin hazard on mouse retina is the retinal neuro-plasticity:rod dendrites withdraw and bipolar axons sprouting accompany with horizontal cell terminals.(4) Darkness could eliminate the distinctive neuro-plasticity completely on albino mouse retina demonstrated vigabatrin-induced damage is correlate with phototoxicity, which indicated a potential way of prevention of vigabatrin injury in clinic.
引文
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