延迟性、多次经巩膜电刺激对轴突横断的视网膜节细胞的神经保护作用
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摘要
中枢神经系统的损伤和修复一直是学术界研究的重点和难点。通常在成年哺乳动物中,中枢神经系统的损伤导致神经细胞的死亡和不可逆的轴突退化。视网膜节细胞属于中枢神经系统的一部分,也具有中枢神经细胞的特点,因此,视神经横断成为研究中枢神经系统损伤的重要动物模型。电刺激作为一种可靠的神经恢复方法,被广泛应用于外周神经系统中。如在坐骨神经的损伤模型中,电刺激可以促进受损的神经元存活,并促进轴突再生。在耳蜗螺旋神经节细胞的损伤模型中,慢性电刺激可以有效的促进神经元的存活。近期研究发现,在视网膜节细胞轴突横断后即刻进行眼部电刺激可以在视神经切断后7天促进神经元的存活,证实了电刺激对中枢神经系统的受损神经细胞有促进存活的作用。对于中枢神经系统,有研究表明在视神经横断当时给予1小时的电刺激,即可激活IGF-1系统,促使视网膜节细胞存活。本研究的第一部分,研究延迟及多次电刺激对轴突横断的视网膜节细胞存活的神经保护作用。结果显示在视神经切断后即刻、3天、5天给予巩膜电刺激时,在视神经切断后7天进行视网膜节细胞计数,刺激组的视网膜节细胞存活数显著高于对照组。我们对切断后3天这个时间点进行了详细研究。发现在这个时间点进行电刺激时,其神经保护作用可以持续至14天,其视网膜节细胞的存活数显著高于对照组。随后我们又增加了电刺激的次数,从切断后当时开始刺激,每3天刺激1次,直到第14天,视网膜节细胞的存活数又显著高于第3天单次刺激组。本研究的第二部分,研究延迟电刺激对轴突横断的视网膜节细胞的保护机制。我们对3天单次刺激组进行了免疫组化染色,发现3天刺激组的IGF-1表达高于假手术对照组,且主要集中于Müller细胞分布区。该结果显示延后电刺激可能激活Müller细胞,并促进IGF-1的释放,发挥神经保护作用。为了证实延后电刺激是否激活Müller细胞,我们对视网膜进行GFAP染色分析,发现Müller细胞可以表达GFAP,延后电刺激可以进一步增强这种作用。但对于星形胶质细胞这种反应不很明确,有待进一步证实。我们还对延后电刺激与小胶质细胞的关系进行了研究。发现延后电刺激可以抑制小胶质细胞的活性,从而减轻小胶质细胞对受损视网膜节细胞的损伤,起到神经保护作用。此外,电刺激对于视网膜节细胞也会产生直接作用,经免疫组化检测,我们发现电刺激组的p-Akt的表达高于对照组。我们推测电刺激通过激活视网膜节细胞内p-Akt/Akt途径发挥神经保护作用。因此,经巩膜延后电刺激发挥的神经保护作用是通过多系统的联合作用过程,这种方法可望为基础研究和临床治疗开辟思路。
Injury and recovery of central nervous system are the focal point and nodus in the academic circles. Injury of central nervous system usually leads to neurocyte death and nonreversible axon degeneration in adult mammal. RGCs belongs to central nervous system , and the characters of RGCs are similar as neurons of central nervous system . Many studies about central nervous system have been carried out using the transection of optic nerve as model system. Electrical stimulation is a kind of treatment to injury in peripheral nervous system. It has been reported that electrical stimulation can induce axotomized sciatic nerve to extend axons in vivo and in vitro. Moreover, chronic electrical stimulation by a cochlear implant promotes survival of spiral ganglion neurons after neonatal deafness, and electrical stimulation enhances the survival of axotomized retinal ganglion cells in vivo. In central nervous system , it is reported that transcorneal electrical stimulation rescues axotomized retinal ganglion cells by activating endogenous retinal IGF-1 System. In the first part of this study, we investigated the neuroprotective effect of delayed and repeated electrical stimulation on axotomized RGCs in adult rats . Our result showed that delayed and repeated electrical stimulation could enhance the survival of axotomized RGCs in adult rats. Treatment with electrical stimulation at the third day or the fifth day after ON transection induced a significant increase in the number of FG-labeled RGCs, when compared with the control animals. Electrical stimulation was carried on at the third day after ON axotomy, and the neuroprotective effect kept on 11 days. We performed ES repeatly, once every 3 days, from 0 day to the 14th day after ON axotomy. The survival number of RGCs was more than those without ES at the third day. Given these lines of evidence, we hypothesized that delayed electrical stimulation may improve the survival of axotomized RGCs in vivo. To test this hypothesis, in the present study, we examined, on day 7 after ON transection, the level of IGF-1 in the retinas with or without electrical stimulation 3 days after ON transection in adult rats. The express of IGF-1 in Müller cells with ES was more than those without ES. This indicate that ES activate IGF-1 system and promote the survival of RGCs. To test the state of Müller cells , we examined, on day 7 after ON transection, the level of GFAP in the retinas with or without electrical stimulation 3 days after ON transection in adult rats. The express of GFAP in Müller cells with ES was more than those without ES. This indicated that ES activated Müller cells and promoted the survival of RGCs. The reaction was not conspicuous in astrocyte. We also found the inhibition effect induced by ES in microglias, and those reduced the damage to RGCs. The direct effect to RGCs induced by ES was observed in our experiment. p-Akt signal pathway was activate by ES in RGCs, and apoptosis of RGCs was inhibited. Therefore, TsES was a useful neuroprotective method for clinical research, and the mechanism of TsES was complex.
Injury and recovery of central nervous system are the focal point and nodus in the academic circles. Injury of central nervous system usually leads to neurocyte death and nonreversible axon degeneration in adult mammal. RGCs belongs to central nervous system , and the characters of RGCs are similar as neurons of central nervous system . Many studies about central nervous system have been carried out using the transection of optic nerve as model system. Electrical stimulation is a kind of treatment to injury in peripheral nervous system. It has been reported that electrical stimulation can induce axotomized sciatic nerve to extend axons in vivo and in vitro. Moreover, chronic electrical stimulation by a cochlear implant promotes survival of spiral ganglion neurons after neonatal deafness, and electrical stimulation enhances the survival of axotomized retinal ganglion cells in vivo. In central nervous system , it is reported that transcorneal electrical stimulation rescues axotomized retinal ganglion cells by activating endogenous retinal IGF-1 System. In the first part of this study, we investigated the neuroprotective effect of delayed and repeated electrical stimulation on axotomized RGCs in adult rats . Our result showed that delayed and repeated electrical stimulation could enhance the survival of axotomized RGCs in adult rats. Treatment with electrical stimulation at the third day or the fifth day after ON transection induced a significant increase in the number of FG-labeled RGCs, when compared with the control animals. Electrical stimulation was carried on at the third day after ON axotomy, and the neuroprotective effect kept on 11 days. We performed ES repeatly, once every 3 days, from 0 day to the 14th day after ON axotomy. The survival number of RGCs was more than those without ES at the third day. Given these lines of evidence, we hypothesized that delayed electrical stimulation may improve the survival of axotomized RGCs in vivo. To test this hypothesis, in the present study, we examined, on day 7 after ON transection, the level of IGF-1 in the retinas with or without electrical stimulation 3 days after ON transection in adult rats. The express of IGF-1 in Müller cells with ES was more than those without ES. This indicate that ES activate IGF-1 system and promote the survival of RGCs. To test the state of Müller cells , we examined, on day 7 after ON transection, the level of GFAP in the retinas with or without electrical stimulation 3 days after ON transection in adult rats. The express of GFAP in Müller cells with ES was more than those without ES. This indicated that ES activated Müller cells and promoted the survival of RGCs. The reaction was not conspicuous in astrocyte. We also found the inhibition effect induced by ES in microglias, and those reduced the damage to RGCs. The direct effect to RGCs induced by ES was observed in our experiment. p-Akt signal pathway was activate by ES in RGCs, and apoptosis of RGCs was inhibited. Therefore, TsES was a useful neuroprotective method for clinical research, and the mechanism of TsES was complex.
引文
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