P_0蛋白在正己烷致周围神经损伤中的作用
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摘要
近年来,职业性慢性正己烷中毒,因其发病率高,危害严重,且缺乏用于早期筛检的生物标志物,逐渐成为我国倍受关注的一类职业病。2,5-己二酮(2,5-hexanedione,2,5-HD)是正己烷在体内的最终代谢产物,是正己烷的毒物形式之一。正己烷引起的慢性中毒性周围神经病的病理学特征主要是沃勒尔变性和脱髓鞘反应,其发病机制尚有很多不清楚之处。P0是周围神经髓鞘上的一种主要结构蛋白,对维持髓鞘结构的稳定性发挥了极其重要的作用,因此,在正己烷引起的周围神经脱髓鞘病变过程中,P0可能起着重要作用。
在本实验室前期工作的基础上,本文重点探讨了在慢性正己烷中毒性周围神经损伤所引起的脱髓鞘性病变中,坐骨神经P0的改变,并研究了因脱髓鞘进入外周血液中的P0作为慢性正己烷中毒性周围神经病效应标志物的可能性；由于周围神经髓鞘组织属于免疫豁免区(immunologically privileged site),在周围神经损伤过程中,伴随着血-神经屏障的损坏,机体对髓鞘组织蛋白(如P0)可能产生免疫应答,本研究对免疫作用在正己烷中毒致脱髓鞘病变过程中的机制进行了初步研究。针对正己烷产生的氧化损伤等作用机制,本研究利用临床药品银杏叶提取物(Extract of ginkgo biloba leaves, Egb761)对2,5-HD致大鼠周围神经损伤进行干预研究,根据Egb761的药理学机理对2,5-HD的毒作用机制进行探讨。
1.正已烷对坐骨神经P0表达的影响
为观察正己烷对P0表达的影响,选用Wistar大鼠,用不同剂量(50,100,200,400mg/kg.d)的正己烷代谢产物2,5-HD染毒4周,制成中毒性周围神经病模型,利用Evans-blue(EB)的渗透量研究血-神经屏障通透性的改变,并重点观察P0表达及其mRNA的转录水平变化。结果显示,随着2,5-HD染毒剂量的增高,大鼠体重增重显著减缓,逐渐出现如共济失调、鸭步及瘫痪等各种毒性症状,大鼠的周围神经损伤逐渐严重；荧光显微镜观察发现,各2,5-HD染毒组大鼠坐骨神经内有含量不等的EB存在,甲酰胺法定量测定各组大鼠坐骨神经中EB含量后发现,随着染毒剂量加大,坐骨神经中EB含量越多,表明血-神经屏障通透性随着2,5-HD染毒剂量的加大而增高；同时检测发现,P0表达降低,P0 mRNA转录水平减少,并呈现一定的量效关系。将体重、神经通透性、P0表达及P0mRNA转录的变化与代表周围神经损伤的步态评分值分别进行关联性分析,结果表明体重、神经屏障通透性及P0含量与神经损伤等级程度关联性较高,且具有统计学意义(P<0.05),P0可指示2,5-HD引起周围神经损伤。
2.血清中P0作为慢性正己烷中毒性周围神经病生物标志物的探讨
为了研究血清中P0能否作为2,5-HD引起的慢性正己烷中毒的生物标志物,采用蛋白质印记技术检测13名工人血清中P0的表达情况,检测结果显示7份患者血清中有6份呈阳性,而6份对照血清有2份呈阳性；采用酶联免疫法分别对来自不同地区的工人血清中P0含量进行检测,并与同区域的对照人群均值相比后取相对值进行分析,结果显示：从事正己烷接触作业6个月以上的10名工人,其血清中P0相对含量明显增高(P<0.05),23名慢性正己烷中毒患者血清中P0相对含量值达到1.58,与对照人群相比,差异具有统计学意义(P<0.01)；并对其中9名患者进行随访观察,结果表明,经过一段时间的治疗后,P0含量明显降低(P<0.01),因此治疗可以减少患者血清中P0的含量。
3.免疫作用在正己烷中毒性周围神经病中的初步机制探讨
为了探讨免疫作用在正己烷中毒引起的脱髓鞘性损伤中的作用,本研究分别用提纯的髓鞘组织和2,5-HD致毒的大鼠阳性血清注射Wistar大鼠,观察引起的毒性反应。结果显示,髓鞘处理组大鼠无任何明显的毒性反应症状,而阳性血清处理组大鼠体重虽有下降,但趋势不明显(P>0.05)。
4.银杏叶提取物(Egb761)对2,5-HD致周围神经损伤的保护作用
为了研究Egb761对2,5-HD引起的周围神经损伤的保护作用,本研究用100mg/kg.d Egb761预处理一小时后,再给予400 mg/kg.d的2,5-HD,观察其对2,5-HD引起的周围神经损伤是否具有保护作用以及对P0表达的影响。结果显示,Egb761预处理大鼠步态评分值显著降低(P<0.01),Egb761明显的减轻了大鼠的中毒症状；同时检测发现Egb761预处理后,坐骨神经中EB含量降低,Egb761减少了2,5-HD对血-神经屏障通透性的破坏,对P0的表达及其mRNA的转录均起到了保护作用。作为髓鞘组织的主要组成成分,P0发挥着重要的作用,结合本部分的研究结果,可认为P0的改变在2,5-HD引起的周围神经损伤中发挥了重要作用,Egb761保护了P0的表达,并可能通过此途径减轻了2,5-HD引起的周围神经损伤。
结论(1)P0的改变在正己烷中毒性周围神经病中发挥了重要,2,5-HD可能通过损伤P0的表达导致了脱髓鞘病变。(2)血清中的P0可作为正己烷中毒性周围神经病的良好效应标志物。(3)Egb761能够减轻2,5-HD对血神经屏障和P0表达的破坏,并降低了2,5-HD对大鼠的周围神经毒性。
In recent sereval years, there has been an increasing number of reported cases of n-hexane-induced peripheral neuropathy in China. Because of high incidence, serious harm, and lack of early screening biomarker, n-hexane neuropathy has drawn greater attention by both public and workers. N-hexane is metabolized to a number of compounds, including 2,5-hexanedione (2,5-HD), which is reconigized to be the ultimate neurotoxic agent of it. The pathological alterations of n-hexane-induced chronic peripheral neuropathy including Wallerian-type degeneration and segmental demyelination, but its mechanisms are still not clear. Myelin protein zero (P0) is the major structural element of peripheral myelin that plays a very important role in maintaining the stability of myelin.
Based on our previous studies, this paper emphatically discusses the role of P0 in 2,5-HD-induced peripheral nerve demyelination, and the possibility of Po in serum owing to demyelination as a potential marker of n-hexane-induced peripheral neuropathy. Peripheral nerve myelin does not elicit an immune response because of isolation by blood-nerve barrier (BNB), but as the BNB destroyed during the peripheral nerve injury, it can induce immunity response against myelin protein including Po. The effect of immunization participated in pathogenesis of peripheral nerve demyelination was preliminary investigated. For the oxidative damage and other effects induced by m-hexane, extract of ginkgo biloba leaves (Egb761) was also used for intervention study on m-hexane-induced peripheral neuropathy, and the mechanism of 2,5-HD-induced peripheral neuropathy was investigated according to the mechanism of pharmacological actions of Egb761.
1. The effect of n-hexane on the level of Po in sciatic nerve To examine the effect of 2,5-HD on the levels of Po in sciatic nerve, Wistar rats were treated with different doses of 2,5-HD (50,100,200,400 mg/kg.d) for 4 weeks, to establish the toxicity model for peripheral nerve injury. Evans-blue (EB),the fluorescent penetrant, was used to study the the blood-nerve barrier (BNB) permeability of the sciatic nerve. Especially the changes in the levels of Po and P0 mRNA in rat sciatic nerves was investigated. The result showed that after given 2,5-HD, the rats weight gain reduced, showed tip-toe walking、foot spay with limb abduction and inability to support body weight. Correspondingly, the peripheral nerve injury was more seriously. There were more EB fluorescence observed in sciatic-tibial nerves of rats treated by 2,5-HD. The level of EB extracted in formamide was determined by fluorimetric spectrophotometry. As the dosage of 2,5-HD increased, the higher level of EB in sciatic-tibial nerves was observed, the permeability of BNB was augmented. The results also showed that the expression of Po mRNA and P0 protein decreased in a dose-dependent manner after treatment with 2,5-HD for 4 weeks. Correlation analysis showed significantly correlation between gait score and body weight, as well as BNB permeability and the level of P0 (P<0.05), and they can indicate the peripheral nerve injury.
2. The study of n-hexane on the level of Po protein in serum
To examine the possibility of Po in serum as a potential marker of n-hexane-induced peripheral neuropathy, the serum Po protein of 13 workers were detected by Western blotting. The result demonstrated that 6 of 7 patients were positive, while 2 of 6 control were positive. The level of P0 in serum from different cities was also detected by ELISA. All relative value were expressed as the percentage of control of same city, and the ratios were analyzed. The result showed after exposed to n-hexane more than 6 months, the relative amout of Po protein in workers'serum increased (P<0.05),and the relative level of P0 in 23 n-hexane-induced peripheral neuropathy patients was 1.58, significantly higher (P<0.01)than the control group. And 9 patients were followed up, the result demonstrated that the P0 level could decreased markedly (P<0.05)in the recovery phase after months of treatment.
3. The mechanism discussion of immunization in n-hexane induced peripheral neuropathy
To explore the effect of immunization in n-hexane induced peripheral neuropathy, the peripheral nerve myelin and the positive serum taken from the 2,5-HD induced peripheral nerve injury in rats, were respectively injected to the Wistar rats. The result displayed that treatment with myelin could not producing any toxic effects, and positive serum could slightly reduced the rats' body weight gain, but the statistical analysis gave a negative result (P>0.05).
4. The protective effect of Ginkgo biloba extract (Egb761) on 2,5-HD-induced toxic peripheral neuropathy
To investigate the role of Egb761 on 2,5-HD-induced peripheral nerve injury, one hour before 400 mg/kg.d 2,5-HD treated, Egb761 (100 mg/kg.d) was pretreated. The signs of neurotoxic symptom induced by 2,5-HD, and the effect of P0 level in sciatic nerve was investigated. The result showed the gait score decreased (P<0.01), and the EB level in sciatic-tibial nerves was reduced. These indicated that pretreatment with Egb761 significantly reduced the signs of neurotoxicity induced by 2,5-HD, and protected the BNB interruption. Egb761 could also inhibited the decreasing tendency of Po and mRNA (P<0.05). P0 constitutes more than 50% of the total peripheral myelin protein, and it is the major adhesive and structural element of peripheral myelin. Combining the above results, it can be concluded that the change of P0 expression may play an important role in the toxic peripheral neuropathy induced by 2,5-HD, Egb761 has protective effects on P0 expression, and by which Egb761 reduce the 2,5-HD-induced peripheral neurotoxicity in rats.
Conclusions (1) The alteration of Po may be an important mechanism of the toxic peripheral neuropathy induced by n-hexane, and by damaging the expression of Po, n-hexane induced demyelination.(2) The serum Po level may be a good biomarker of peripheral neuropathy induced n-hexane. (3) Egb761 reduced the damage of BNB permeability and Po expression induced by 2,5-HD, and has a protective effect against 2,5-HD-induced peripheral neurotoxicity in rats.
在本实验室前期工作的基础上,本文重点探讨了在慢性正己烷中毒性周围神经损伤所引起的脱髓鞘性病变中,坐骨神经P0的改变,并研究了因脱髓鞘进入外周血液中的P0作为慢性正己烷中毒性周围神经病效应标志物的可能性；由于周围神经髓鞘组织属于免疫豁免区(immunologically privileged site),在周围神经损伤过程中,伴随着血-神经屏障的损坏,机体对髓鞘组织蛋白(如P0)可能产生免疫应答,本研究对免疫作用在正己烷中毒致脱髓鞘病变过程中的机制进行了初步研究。针对正己烷产生的氧化损伤等作用机制,本研究利用临床药品银杏叶提取物(Extract of ginkgo biloba leaves, Egb761)对2,5-HD致大鼠周围神经损伤进行干预研究,根据Egb761的药理学机理对2,5-HD的毒作用机制进行探讨。
1.正已烷对坐骨神经P0表达的影响
为观察正己烷对P0表达的影响,选用Wistar大鼠,用不同剂量(50,100,200,400mg/kg.d)的正己烷代谢产物2,5-HD染毒4周,制成中毒性周围神经病模型,利用Evans-blue(EB)的渗透量研究血-神经屏障通透性的改变,并重点观察P0表达及其mRNA的转录水平变化。结果显示,随着2,5-HD染毒剂量的增高,大鼠体重增重显著减缓,逐渐出现如共济失调、鸭步及瘫痪等各种毒性症状,大鼠的周围神经损伤逐渐严重；荧光显微镜观察发现,各2,5-HD染毒组大鼠坐骨神经内有含量不等的EB存在,甲酰胺法定量测定各组大鼠坐骨神经中EB含量后发现,随着染毒剂量加大,坐骨神经中EB含量越多,表明血-神经屏障通透性随着2,5-HD染毒剂量的加大而增高；同时检测发现,P0表达降低,P0 mRNA转录水平减少,并呈现一定的量效关系。将体重、神经通透性、P0表达及P0mRNA转录的变化与代表周围神经损伤的步态评分值分别进行关联性分析,结果表明体重、神经屏障通透性及P0含量与神经损伤等级程度关联性较高,且具有统计学意义(P<0.05),P0可指示2,5-HD引起周围神经损伤。
2.血清中P0作为慢性正己烷中毒性周围神经病生物标志物的探讨
为了研究血清中P0能否作为2,5-HD引起的慢性正己烷中毒的生物标志物,采用蛋白质印记技术检测13名工人血清中P0的表达情况,检测结果显示7份患者血清中有6份呈阳性,而6份对照血清有2份呈阳性；采用酶联免疫法分别对来自不同地区的工人血清中P0含量进行检测,并与同区域的对照人群均值相比后取相对值进行分析,结果显示：从事正己烷接触作业6个月以上的10名工人,其血清中P0相对含量明显增高(P<0.05),23名慢性正己烷中毒患者血清中P0相对含量值达到1.58,与对照人群相比,差异具有统计学意义(P<0.01)；并对其中9名患者进行随访观察,结果表明,经过一段时间的治疗后,P0含量明显降低(P<0.01),因此治疗可以减少患者血清中P0的含量。
3.免疫作用在正己烷中毒性周围神经病中的初步机制探讨
为了探讨免疫作用在正己烷中毒引起的脱髓鞘性损伤中的作用,本研究分别用提纯的髓鞘组织和2,5-HD致毒的大鼠阳性血清注射Wistar大鼠,观察引起的毒性反应。结果显示,髓鞘处理组大鼠无任何明显的毒性反应症状,而阳性血清处理组大鼠体重虽有下降,但趋势不明显(P>0.05)。
4.银杏叶提取物(Egb761)对2,5-HD致周围神经损伤的保护作用
为了研究Egb761对2,5-HD引起的周围神经损伤的保护作用,本研究用100mg/kg.d Egb761预处理一小时后,再给予400 mg/kg.d的2,5-HD,观察其对2,5-HD引起的周围神经损伤是否具有保护作用以及对P0表达的影响。结果显示,Egb761预处理大鼠步态评分值显著降低(P<0.01),Egb761明显的减轻了大鼠的中毒症状；同时检测发现Egb761预处理后,坐骨神经中EB含量降低,Egb761减少了2,5-HD对血-神经屏障通透性的破坏,对P0的表达及其mRNA的转录均起到了保护作用。作为髓鞘组织的主要组成成分,P0发挥着重要的作用,结合本部分的研究结果,可认为P0的改变在2,5-HD引起的周围神经损伤中发挥了重要作用,Egb761保护了P0的表达,并可能通过此途径减轻了2,5-HD引起的周围神经损伤。
结论(1)P0的改变在正己烷中毒性周围神经病中发挥了重要,2,5-HD可能通过损伤P0的表达导致了脱髓鞘病变。(2)血清中的P0可作为正己烷中毒性周围神经病的良好效应标志物。(3)Egb761能够减轻2,5-HD对血神经屏障和P0表达的破坏,并降低了2,5-HD对大鼠的周围神经毒性。
In recent sereval years, there has been an increasing number of reported cases of n-hexane-induced peripheral neuropathy in China. Because of high incidence, serious harm, and lack of early screening biomarker, n-hexane neuropathy has drawn greater attention by both public and workers. N-hexane is metabolized to a number of compounds, including 2,5-hexanedione (2,5-HD), which is reconigized to be the ultimate neurotoxic agent of it. The pathological alterations of n-hexane-induced chronic peripheral neuropathy including Wallerian-type degeneration and segmental demyelination, but its mechanisms are still not clear. Myelin protein zero (P0) is the major structural element of peripheral myelin that plays a very important role in maintaining the stability of myelin.
Based on our previous studies, this paper emphatically discusses the role of P0 in 2,5-HD-induced peripheral nerve demyelination, and the possibility of Po in serum owing to demyelination as a potential marker of n-hexane-induced peripheral neuropathy. Peripheral nerve myelin does not elicit an immune response because of isolation by blood-nerve barrier (BNB), but as the BNB destroyed during the peripheral nerve injury, it can induce immunity response against myelin protein including Po. The effect of immunization participated in pathogenesis of peripheral nerve demyelination was preliminary investigated. For the oxidative damage and other effects induced by m-hexane, extract of ginkgo biloba leaves (Egb761) was also used for intervention study on m-hexane-induced peripheral neuropathy, and the mechanism of 2,5-HD-induced peripheral neuropathy was investigated according to the mechanism of pharmacological actions of Egb761.
1. The effect of n-hexane on the level of Po in sciatic nerve To examine the effect of 2,5-HD on the levels of Po in sciatic nerve, Wistar rats were treated with different doses of 2,5-HD (50,100,200,400 mg/kg.d) for 4 weeks, to establish the toxicity model for peripheral nerve injury. Evans-blue (EB),the fluorescent penetrant, was used to study the the blood-nerve barrier (BNB) permeability of the sciatic nerve. Especially the changes in the levels of Po and P0 mRNA in rat sciatic nerves was investigated. The result showed that after given 2,5-HD, the rats weight gain reduced, showed tip-toe walking、foot spay with limb abduction and inability to support body weight. Correspondingly, the peripheral nerve injury was more seriously. There were more EB fluorescence observed in sciatic-tibial nerves of rats treated by 2,5-HD. The level of EB extracted in formamide was determined by fluorimetric spectrophotometry. As the dosage of 2,5-HD increased, the higher level of EB in sciatic-tibial nerves was observed, the permeability of BNB was augmented. The results also showed that the expression of Po mRNA and P0 protein decreased in a dose-dependent manner after treatment with 2,5-HD for 4 weeks. Correlation analysis showed significantly correlation between gait score and body weight, as well as BNB permeability and the level of P0 (P<0.05), and they can indicate the peripheral nerve injury.
2. The study of n-hexane on the level of Po protein in serum
To examine the possibility of Po in serum as a potential marker of n-hexane-induced peripheral neuropathy, the serum Po protein of 13 workers were detected by Western blotting. The result demonstrated that 6 of 7 patients were positive, while 2 of 6 control were positive. The level of P0 in serum from different cities was also detected by ELISA. All relative value were expressed as the percentage of control of same city, and the ratios were analyzed. The result showed after exposed to n-hexane more than 6 months, the relative amout of Po protein in workers'serum increased (P<0.05),and the relative level of P0 in 23 n-hexane-induced peripheral neuropathy patients was 1.58, significantly higher (P<0.01)than the control group. And 9 patients were followed up, the result demonstrated that the P0 level could decreased markedly (P<0.05)in the recovery phase after months of treatment.
3. The mechanism discussion of immunization in n-hexane induced peripheral neuropathy
To explore the effect of immunization in n-hexane induced peripheral neuropathy, the peripheral nerve myelin and the positive serum taken from the 2,5-HD induced peripheral nerve injury in rats, were respectively injected to the Wistar rats. The result displayed that treatment with myelin could not producing any toxic effects, and positive serum could slightly reduced the rats' body weight gain, but the statistical analysis gave a negative result (P>0.05).
4. The protective effect of Ginkgo biloba extract (Egb761) on 2,5-HD-induced toxic peripheral neuropathy
To investigate the role of Egb761 on 2,5-HD-induced peripheral nerve injury, one hour before 400 mg/kg.d 2,5-HD treated, Egb761 (100 mg/kg.d) was pretreated. The signs of neurotoxic symptom induced by 2,5-HD, and the effect of P0 level in sciatic nerve was investigated. The result showed the gait score decreased (P<0.01), and the EB level in sciatic-tibial nerves was reduced. These indicated that pretreatment with Egb761 significantly reduced the signs of neurotoxicity induced by 2,5-HD, and protected the BNB interruption. Egb761 could also inhibited the decreasing tendency of Po and mRNA (P<0.05). P0 constitutes more than 50% of the total peripheral myelin protein, and it is the major adhesive and structural element of peripheral myelin. Combining the above results, it can be concluded that the change of P0 expression may play an important role in the toxic peripheral neuropathy induced by 2,5-HD, Egb761 has protective effects on P0 expression, and by which Egb761 reduce the 2,5-HD-induced peripheral neurotoxicity in rats.
Conclusions (1) The alteration of Po may be an important mechanism of the toxic peripheral neuropathy induced by n-hexane, and by damaging the expression of Po, n-hexane induced demyelination.(2) The serum Po level may be a good biomarker of peripheral neuropathy induced n-hexane. (3) Egb761 reduced the damage of BNB permeability and Po expression induced by 2,5-HD, and has a protective effect against 2,5-HD-induced peripheral neurotoxicity in rats.
引文
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2.何凤生.中华职业医学.北京：人民卫生出版社；1999,437-439.
3.苏胜华,刘新霞,甘德秀,等.正己烷接触对血清神经元特异烯醇化酶及髓鞘碱性蛋白的影响中国职业医学,2006；33(1)：22-26.
4.何坚,马争,赖关朝.正己烷对制鞋业工人白细胞趋化性影响的研究.中国职业医学,2006；33(2)：103-105.
5.黄建勋,马争,唐小江,等.正己烷诱发红细胞血影蛋白共价交联的研究.中国职业医学,2004；31(4)：4-7.
6. Spiryda LB. Myelin protein zero and membrane adhesion. J Neurosci Res,1998; 54(2):137-46.
7. Shapiro L, Doyle JP, Hensley P, et al. Crystal structure of the extracellular domain from P0, the major structural protein of peripheral nerve myelin. Neuron,1996;17(3): 435-49.
8. Filbin MT, Tennekoon GI. The role of complex carbohydrates in adhesion of the myelin protein, PO. Neuron,1991;7(5):845-55.
9. Xu M, Zhao R, Sui X, et al. Tyrosine phosphorylation of myelin P(0) and its implication in signal transduction. Biochem Biophys Res Commun,2000;267(3): 820-5.
10.刘清君,赵磊,段化伟,等.2,5-己二酮不同作用时间对大鼠坐骨神经Po蛋白及血清P0蛋白抗体的水平的影响.卫生研究,2010；39(3)：275-278.
11. Spencer PS, Schaumburg HH, Ludolph AC. Experimental and clinical neurotoxicology.2nd ed. New York:Oxford University Press;2000,
12. Zhang T, Zhao X, Zhu Z, et al.2,5-Hexanedione induced decrease in cytoskeletal proteins of rat sciatic-tibial nerve. Neurochem Res,2005;30(2):177-83.
13. Csurhes PA, Sullivan AA, Green K, et al. T cell reactivity to P0, P2, PMP-22,and myelin basic protein in patients with Guillain-Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol Neurosurg Psychiatry, 2005;76(10):1431-9.
14. Hughes RA, Hadden RD, Gregson NA, et al. Pathogenesis of Guillain-Barre syndrome. J Neuroimmunol,1999;100(1-2):74-97.
15.赵磊,郑玉新.P0蛋白与周围神经相关疾病及其毒理学意义.卫生研究,2010；39(5)：635-638.
16. Doyle JP, Colman DR. Glial-neuron interactions and the regulation of myelin formation. Curr Opin Cell Biol,1993;5(5):779-85.
17. Lemke G, Axel R. Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin. Cell,1985; 40(3):501-8.
18. Yazaki T, Miura M, Asou H, et al. Peripheral myelin P0 protein mediates neurite outgrowth of cortical neurons in vitro and axonal regeneration in vivo. Neurosci Lett, 1994; 176(1):13-6.
19. Eggers SD, Keswani SC, Melli G, et al. Clinical and genetic description of a family with Charcot-Marie-Tooth disease type 1B from a transmembrane MPZ mutation. Muscle Nerve,2004;29(6):867-9.
20. Mandich P, Mancardi GL, Varese A, et al. Congenital hypomyelination due to myelin protein zero Q215X mutation. Ann Neurol,1999;45(5):676-8.
21. LoPachin RM, Ross JF, Reid ML, et al. Neurological evaluation of toxic axonopathies in rats:acrylamide and 2,5-hexanedione. Neurotoxicology,2002;23(1): 95-110.
22. Liu Q, Duan H, Dai Y, et al. The effect of 2,5-hexanedione on permeability of blood-nerve barrier in rats. Hum Exp Toxicol,2010;29(6):497-506.
23. Sirois MG, Plante GE, Braquet P, et al. Role of eicosanoids in PAF-induced increases of the vascular permeability in rat airways. Br J Pharmacol,1990;101(4): 896-900.
24. Norton WT, Poduslo SE. Myelination in rat brain:method of myelin isolation. J Neurochem,1973;21(4):749-57.
25. D'Urso D, Ehrhardt P, Muller HW. Peripheral myelin protein 22 and protein zero: a novel association in peripheral nervous system myelin. J Neurosci,1999;19(9): 3396-403.
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