黄体酮对多发性硬化的治疗作用及相关机制的初步研究
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摘要
多发性硬化是一种典型的中枢神经系统脱髓鞘疾病。其典型病程表现为缓解-复发,进行性加重,其发病机理迄今尚不清楚。因而,目前还没有有效的治疗方法。病理学研究业已证实,神经症状进行性加重的根本原因在于中枢神经系统发生脱髓鞘病变后,神经系统本身的自发性髓鞘再生不完全,以至于本来完整的轴突由于长期裸露,从而发生继发性损伤。因此,促进多发性硬化患者中枢神经系统的髓鞘再生是治疗多发性硬化的有效方法。黄体酮是目前临床上应用广泛的孕激素药物,价廉易得。近年来已经发现黄体酮对中枢神经系统少突胶质细胞分化、髓鞘形成以及髓鞘再生均有明确的促进作用。
MBP蛋白是髓鞘的重要组成部分,对维持髓鞘的膜状板层结构有重要作用。当髓鞘结构被破坏时,MBP从髓鞘上游离。检测脑脊液、血液中MBP蛋白的含量,可以间接了解中枢神经系统髓鞘的情况。而PDGF-αR是少突胶质前体细胞发育过程早期表达的蛋白之一,是少突胶质前体细胞的重要标记。随着少突胶质前体细胞逐渐分化成熟,PDGF-αR消失。另外,Olig1作为碱性螺旋-环-螺旋结构的重要成员,在少突胶质细胞系细胞表达。它是MBP、PLP1、MAG等髓鞘特异蛋白基因的上游基因,可以促进髓鞘特异蛋白基因的表达,同时抑制星形胶质细胞特异蛋白基因GFAP的表达。Olig1因子在神经系统的发育过程中可能不发挥作用,而对髓鞘修复有重要作用。既往通过免疫组化的研究证实,在老年大鼠脑组织中,由于Olig1蛋白低水平表达,髓鞘再生不完全。新近研究发现,Olig1蛋白在髓鞘生成和髓鞘再生过程中发生细胞核与细胞浆之间的移位。Olig1蛋白只有定位于细胞核时才能发挥调控作用。多发性硬化患者脑组织病理研究也证实,Olig1蛋白位于细胞浆的Olig1+细胞的分化停留在幼稚阶段,不能分化成成熟的少突胶质细胞,重新形成髓鞘,完成髓鞘再生的过程。Olig1蛋白在髓鞘再生过程中发生核-浆移位,可能是髓鞘再生是否完全的关键因素。
实验性变态反应性脑脊髓炎是研究多发性硬化的成熟的动物模型。因此,本研究采用黄体酮治疗实验性变态反应性脑脊髓炎,运用神经功能评分、髓鞘染色、电镜等多种方法观察黄体酮的治疗效果。同时运用免疫组化、Western Blot、实时RT-PCR等技术,就其作用机制进行初步探讨。研究结果如下:
1.黄体酮治疗组和对照组大鼠的神经功能评分没有明显区别。实验中采用的神经功能评分方法是相似研究中常用的评分方法,但是比较粗糙,不能精确表现出大鼠的神经功能状况。因此,根据评分结果,还不能定论黄体酮可以减轻实验性变态反应性脑脊髓炎大鼠的神经症状。但是电镜检查见黄体酮治疗组的髓鞘密度高于对照组,LFB染色后黄体酮治疗组的正常髓鞘的光密度值也高于对照组,而且Marchi’s染色后黄体酮治疗组退变髓鞘的光密度值低于对照组,提示黄体酮可以明显促进EAE大鼠脑组织的髓鞘再生。
2.PDGF-αR在少突胶质前体细胞的发育早期表达。壮年大鼠脑组织中PDGF-αR+细胞根据细胞的突起数量和突起的分支数量不同,可以分为I、II、III型。突起的数量越少,突起分支的数量越少,细胞越幼稚。在嗅球和海马,幼稚的I型细胞密度最高,提示其可能是髓鞘再生时少突胶质前体细胞的生发中心。在小脑和脑干未见明确的PDGF-αR+细胞。提示在髓鞘再生时,少突胶质前体细胞需要移行更远的距离到达小脑和脑干,或者由于少突胶质前体细胞已经分化到比较成熟的阶段,PDGF-αR消失,其增殖能力受限,以至于这些部位的髓鞘再生困难,因此对慢性损伤也更加敏感。
3.黄体酮1)治疗组脑组织中髓鞘碎片的光密度值低于对照组。2)治疗组MBP蛋白含量也低于对照组。3)治疗组和对照组的PDGF-αR蛋白在病程早期没有明显变化,在病程中一过性降低,后又逐渐恢复至正常大鼠水平。治疗组和对照组之间没有明显区别。4)治疗组和对照组大鼠脑组织中Olig1mRNA的表达在整个病程中较正常大鼠而言,均没有明显变化。5)治疗组大鼠脑组织中Olig1蛋白位于细胞核的Olig1+细胞的数量明显高于对照组。研究结果提示:黄体酮促进脑组织髓鞘再生的作用机制可能主要在于:1)减少中枢神经系统由于脱髓鞘病变产生的髓鞘碎片,减少髓鞘碎片对髓鞘再生的抑制作用;2)稳定髓鞘膜结构;3)促进少突胶质前体细胞分化,重新形成致密的髓鞘结构;4)黄体酮不能上调实验性变态反应性脑脊髓炎大鼠脑组织中Olig1mRNA的表达。5)促进Olig1蛋白从细胞浆向细胞核移位,发挥对髓鞘再生的调控作用。
因此,黄体酮有望成为治疗中枢神经系统的脱髓鞘疾病的有效药物,影响Olig1蛋白核-浆移位,可能成为治疗脱髓鞘疾病新药物的作用靶点。
Multiple sclerosis is one kind of central nervous system(CNS) demyelinating disearses, which typical example course is release- relapse and aggravation in progress. The pathogenesy is not clear and there is not active treatment. After demyelination of CNS, the spontaneous remyelination is not sufficient. So that there are no myelin to encapselate naked axon. Finaly, the axon are damaged secondary. Above all, it is active treatment to promote the remyelination of MS. Progesterone is one of progestins which are clinically used widely. It is cheap and gained easily. It has been confirmed that progesterone can promote the differentiation of oligodendrocyte, the myelination and the remyelination in CNS.
Myelin basic protein(MBP) protein is a main composition of myelin which is importment for maintaining the membrane layer of myelin. MBP liberates from myelin when myelin has been destoried. The impairment of myelin in CNS can be conclude by detect the MBP protein in blood and cerebrospinal fluid. The PDGF-αR is an early and importment marker of oligodendrocyte precursor cells. With the differentiation, the PDGF-αR disapears. The Olig1 which expresses in oligodendrocyte cells is one of basic helix-loop-helix(bHLH). It can increase the expression of MBP、myelin proteolipid protein(PLP1)、myelin associated glucoprotein (MAG).at same time, it can suppress the expression of GFAP. Perhaps, the Olig1 regulates the remyelination only. Because of the low Olig1 protein, the remyelination of older rats were sufficient by immunohistochemistry(IHC). Resently, the translocation of Olig1 protein in myelination and remyelination was reported. Only in nucleus, the Olig1 protein can be active. In some Olig1+ cell of MS brain, the Olig1 protein located in cytoplasmic. Those cells can’t differentiate to mature oligodendrocyte to remyelinate axon. The translocation of Olig1 protein may be a key factor of remyelination.
The experimental allergic encephalomyelitis(EAE) is a good animal modle. In this study, the EAE rats were treated with progesterone. The therapeutic efficacy was judgement by nerve function score, staining of myelin and electron microscope et al. Meanshile, the machanism was researched initially by IHC,Western Blot, real time RT-PCR, et al. There are some revelations.
Firstly, there was no obvious differention in the nerve function score between treating and control group. The nerve function score was used usually in similar researchs. But it is too rough. So according to the score, it is not concluded that the progesterone can lessen the symptom of EAE rats. But the density of normal myelin in treating group was higher than that in control group by electron microscope. The gray scale of normal myelin in treating group was higher and cataplasis myelin in treating myelin was lower than that in control by LFB and marchi’s staining. So it can be concluded that the progesterone can promote the remyelination of EAE rats.
Secondly, PDGF-αR expressing cells were found in the forebrain and midbrain, but not in the cerebellum and brainstem. Based on the number of cell processes and branches, the main distinction among PDGF-αR expressing cells in different regions, the cells were classified into 3 categories, ie., type I to type III. From type I to type III, number of processes increased gradually. The OB and hippocampus which were I type cells mainly may be the germinal areas of PDGF-αR expressing cells in the adult rat brain. It may be relatively difficult for myelination and remyelination to occur in the cerebellum and brainstem resulting in a high susceptibility of the cerebellum and brainstem to chronic damages.
Thirdly, it is about the mechanism. 1)The gray scale of myelin debris in treating group was lower than that in control. 2)The MBP protein in treating group was lower than that in control also. 3)In early stage, the PDGF-αR protein didn’t change in treating and control groups. After this, it decreased . But in 25th, the PDGF-αR protein came back to the level of normal rats. There was no difference among treating and control groups. 4)The Olig1mRNA of EAE rat was not different than that of normal all course. 5)The quantity of Olig1+ cells in which the olig1 protein located in nucleus in treating group was higher than that in control. Those results suggest that 1)the progesterone can decrease the myelin debris which come from the demyelination. So it can decrease the inhibitory of myelin debris to remyelination. 2)The progesterone can stabilize the structure of myelin’s membrane layer. 3)The progesterone can promote the OPCs differentiating to mature oligodendrocyte to remyelination. 4)The progesterone can not in creasethe Olig1mRNA in EAE rats. 5)But it can promote the Olig1 protein translocating from cytoplasm to nucleus.
Above all, the progesterone may be an active drug. The translocation of Olig1 protein from cytoplasm to nucleus may be a action point of new drugs for demyelination diseases.
MBP蛋白是髓鞘的重要组成部分,对维持髓鞘的膜状板层结构有重要作用。当髓鞘结构被破坏时,MBP从髓鞘上游离。检测脑脊液、血液中MBP蛋白的含量,可以间接了解中枢神经系统髓鞘的情况。而PDGF-αR是少突胶质前体细胞发育过程早期表达的蛋白之一,是少突胶质前体细胞的重要标记。随着少突胶质前体细胞逐渐分化成熟,PDGF-αR消失。另外,Olig1作为碱性螺旋-环-螺旋结构的重要成员,在少突胶质细胞系细胞表达。它是MBP、PLP1、MAG等髓鞘特异蛋白基因的上游基因,可以促进髓鞘特异蛋白基因的表达,同时抑制星形胶质细胞特异蛋白基因GFAP的表达。Olig1因子在神经系统的发育过程中可能不发挥作用,而对髓鞘修复有重要作用。既往通过免疫组化的研究证实,在老年大鼠脑组织中,由于Olig1蛋白低水平表达,髓鞘再生不完全。新近研究发现,Olig1蛋白在髓鞘生成和髓鞘再生过程中发生细胞核与细胞浆之间的移位。Olig1蛋白只有定位于细胞核时才能发挥调控作用。多发性硬化患者脑组织病理研究也证实,Olig1蛋白位于细胞浆的Olig1+细胞的分化停留在幼稚阶段,不能分化成成熟的少突胶质细胞,重新形成髓鞘,完成髓鞘再生的过程。Olig1蛋白在髓鞘再生过程中发生核-浆移位,可能是髓鞘再生是否完全的关键因素。
实验性变态反应性脑脊髓炎是研究多发性硬化的成熟的动物模型。因此,本研究采用黄体酮治疗实验性变态反应性脑脊髓炎,运用神经功能评分、髓鞘染色、电镜等多种方法观察黄体酮的治疗效果。同时运用免疫组化、Western Blot、实时RT-PCR等技术,就其作用机制进行初步探讨。研究结果如下:
1.黄体酮治疗组和对照组大鼠的神经功能评分没有明显区别。实验中采用的神经功能评分方法是相似研究中常用的评分方法,但是比较粗糙,不能精确表现出大鼠的神经功能状况。因此,根据评分结果,还不能定论黄体酮可以减轻实验性变态反应性脑脊髓炎大鼠的神经症状。但是电镜检查见黄体酮治疗组的髓鞘密度高于对照组,LFB染色后黄体酮治疗组的正常髓鞘的光密度值也高于对照组,而且Marchi’s染色后黄体酮治疗组退变髓鞘的光密度值低于对照组,提示黄体酮可以明显促进EAE大鼠脑组织的髓鞘再生。
2.PDGF-αR在少突胶质前体细胞的发育早期表达。壮年大鼠脑组织中PDGF-αR+细胞根据细胞的突起数量和突起的分支数量不同,可以分为I、II、III型。突起的数量越少,突起分支的数量越少,细胞越幼稚。在嗅球和海马,幼稚的I型细胞密度最高,提示其可能是髓鞘再生时少突胶质前体细胞的生发中心。在小脑和脑干未见明确的PDGF-αR+细胞。提示在髓鞘再生时,少突胶质前体细胞需要移行更远的距离到达小脑和脑干,或者由于少突胶质前体细胞已经分化到比较成熟的阶段,PDGF-αR消失,其增殖能力受限,以至于这些部位的髓鞘再生困难,因此对慢性损伤也更加敏感。
3.黄体酮1)治疗组脑组织中髓鞘碎片的光密度值低于对照组。2)治疗组MBP蛋白含量也低于对照组。3)治疗组和对照组的PDGF-αR蛋白在病程早期没有明显变化,在病程中一过性降低,后又逐渐恢复至正常大鼠水平。治疗组和对照组之间没有明显区别。4)治疗组和对照组大鼠脑组织中Olig1mRNA的表达在整个病程中较正常大鼠而言,均没有明显变化。5)治疗组大鼠脑组织中Olig1蛋白位于细胞核的Olig1+细胞的数量明显高于对照组。研究结果提示:黄体酮促进脑组织髓鞘再生的作用机制可能主要在于:1)减少中枢神经系统由于脱髓鞘病变产生的髓鞘碎片,减少髓鞘碎片对髓鞘再生的抑制作用;2)稳定髓鞘膜结构;3)促进少突胶质前体细胞分化,重新形成致密的髓鞘结构;4)黄体酮不能上调实验性变态反应性脑脊髓炎大鼠脑组织中Olig1mRNA的表达。5)促进Olig1蛋白从细胞浆向细胞核移位,发挥对髓鞘再生的调控作用。
因此,黄体酮有望成为治疗中枢神经系统的脱髓鞘疾病的有效药物,影响Olig1蛋白核-浆移位,可能成为治疗脱髓鞘疾病新药物的作用靶点。
Multiple sclerosis is one kind of central nervous system(CNS) demyelinating disearses, which typical example course is release- relapse and aggravation in progress. The pathogenesy is not clear and there is not active treatment. After demyelination of CNS, the spontaneous remyelination is not sufficient. So that there are no myelin to encapselate naked axon. Finaly, the axon are damaged secondary. Above all, it is active treatment to promote the remyelination of MS. Progesterone is one of progestins which are clinically used widely. It is cheap and gained easily. It has been confirmed that progesterone can promote the differentiation of oligodendrocyte, the myelination and the remyelination in CNS.
Myelin basic protein(MBP) protein is a main composition of myelin which is importment for maintaining the membrane layer of myelin. MBP liberates from myelin when myelin has been destoried. The impairment of myelin in CNS can be conclude by detect the MBP protein in blood and cerebrospinal fluid. The PDGF-αR is an early and importment marker of oligodendrocyte precursor cells. With the differentiation, the PDGF-αR disapears. The Olig1 which expresses in oligodendrocyte cells is one of basic helix-loop-helix(bHLH). It can increase the expression of MBP、myelin proteolipid protein(PLP1)、myelin associated glucoprotein (MAG).at same time, it can suppress the expression of GFAP. Perhaps, the Olig1 regulates the remyelination only. Because of the low Olig1 protein, the remyelination of older rats were sufficient by immunohistochemistry(IHC). Resently, the translocation of Olig1 protein in myelination and remyelination was reported. Only in nucleus, the Olig1 protein can be active. In some Olig1+ cell of MS brain, the Olig1 protein located in cytoplasmic. Those cells can’t differentiate to mature oligodendrocyte to remyelinate axon. The translocation of Olig1 protein may be a key factor of remyelination.
The experimental allergic encephalomyelitis(EAE) is a good animal modle. In this study, the EAE rats were treated with progesterone. The therapeutic efficacy was judgement by nerve function score, staining of myelin and electron microscope et al. Meanshile, the machanism was researched initially by IHC,Western Blot, real time RT-PCR, et al. There are some revelations.
Firstly, there was no obvious differention in the nerve function score between treating and control group. The nerve function score was used usually in similar researchs. But it is too rough. So according to the score, it is not concluded that the progesterone can lessen the symptom of EAE rats. But the density of normal myelin in treating group was higher than that in control group by electron microscope. The gray scale of normal myelin in treating group was higher and cataplasis myelin in treating myelin was lower than that in control by LFB and marchi’s staining. So it can be concluded that the progesterone can promote the remyelination of EAE rats.
Secondly, PDGF-αR expressing cells were found in the forebrain and midbrain, but not in the cerebellum and brainstem. Based on the number of cell processes and branches, the main distinction among PDGF-αR expressing cells in different regions, the cells were classified into 3 categories, ie., type I to type III. From type I to type III, number of processes increased gradually. The OB and hippocampus which were I type cells mainly may be the germinal areas of PDGF-αR expressing cells in the adult rat brain. It may be relatively difficult for myelination and remyelination to occur in the cerebellum and brainstem resulting in a high susceptibility of the cerebellum and brainstem to chronic damages.
Thirdly, it is about the mechanism. 1)The gray scale of myelin debris in treating group was lower than that in control. 2)The MBP protein in treating group was lower than that in control also. 3)In early stage, the PDGF-αR protein didn’t change in treating and control groups. After this, it decreased . But in 25th, the PDGF-αR protein came back to the level of normal rats. There was no difference among treating and control groups. 4)The Olig1mRNA of EAE rat was not different than that of normal all course. 5)The quantity of Olig1+ cells in which the olig1 protein located in nucleus in treating group was higher than that in control. Those results suggest that 1)the progesterone can decrease the myelin debris which come from the demyelination. So it can decrease the inhibitory of myelin debris to remyelination. 2)The progesterone can stabilize the structure of myelin’s membrane layer. 3)The progesterone can promote the OPCs differentiating to mature oligodendrocyte to remyelination. 4)The progesterone can not in creasethe Olig1mRNA in EAE rats. 5)But it can promote the Olig1 protein translocating from cytoplasm to nucleus.
Above all, the progesterone may be an active drug. The translocation of Olig1 protein from cytoplasm to nucleus may be a action point of new drugs for demyelination diseases.
引文
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