FK506治疗急性脊髓损伤的实验研究
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摘要
急性脊髓损伤(Acute Spinal Cord Injury,ASCI)是一种严重的神经系统损伤,给个人、家庭和社会带来巨大经济负担,且我国的发病率又较发达国家高。因此,治疗急性脊髓损伤,恢复或者减少神经损害具有重要的意义。但是脊髓损伤的治疗至今仍是医学界的难题之一。
急性脊髓损伤目前分为原发性脊髓损伤和继发性脊髓损伤。原发性脊髓损伤为机械性损伤,受伤程度由受伤当时决定,损伤不可逆,因此无法对其损伤机制进行有效的治疗;继发性脊髓损伤是发生于原发性脊髓损伤之后的一系列损伤,可被控制,具有可逆性,决定了脊髓损伤后的愈后,因此急性脊髓损伤的治疗关键切入点在于继发性脊髓损伤的治疗。目前关于治疗急性脊髓损伤的策略主要是保护神经元,防止其继发性损伤和凋亡;促进神经轴突生长。研究表明某些药物可以影响和干扰继发损伤的过程。目前治疗脊髓继发性损伤的药物主要分为西药和中药两大类。
FK506又名他克莫司,属于大环内酯类抗生素,具有极强的免疫抑制作用。近年的研究表明FK506不但具有免疫抑制作用,还具有神经保护和神经营养作用。FK506的神经保护机制与抑制钙调神经磷酸酶(CaN)有关。FK506作为CaN抑制剂,主要的副作用之一就是神经毒性。有研究表明,FK506的神经毒性发生率与药物浓度存在显著的相关性。因此通过观察不同浓度下FK506对背根神经元生长的影响,寻找促进神经元生长的最佳药物浓度,避免出现该药物的神经毒性副作用,可为该药物治疗急性脊髓损伤提供理论依据。
由于FK506易穿透血脑屏障,有效血药浓度低,在使用过程中往往有很大的副作用,神经毒性是其主要副作用之一。在治疗急性脊髓损伤时,如何既达到治疗效果,又同时减小毒副作用是面临解决的问题。调整药物给药方式和给药速度是解决这一问题的方法之一。局部药膜应用可以减少药物剂量,使局部达到一个较高的药物浓度;持续缓释药物可以减少血药浓度波动进而减少药物的毒副作用。本实验通过局部应用FK506缓释药膜治疗大鼠急性脊髓损伤,观察神经恢复情况,进而研究该方法的可行性。
滋补脾阴方药由人参、丹参、山药、白芍等组成。目前研究表明滋补脾阴方药具有神经保护作用。但是与FK506联合应用是否具有对神经元的保护和促进突起生长目前没有相关研究。通过观察两种药物以及联合应用的情况下对背根神经元生长的影响,可进一步研究两种药物的神经保护作用及该两种药物联合应用治疗急性脊髓损伤的可行性。
第一部分不同浓度FK506对新生大鼠脊髓背根神经元生长的影响
目的:观察并寻找促进新生大鼠脊髓背根神经元生长的最佳FK506浓度。
方法:取8只新生24h SD大鼠的背根神经节,剥除神经外膜,剪成约1mm~3大小的碎块,用0.25%胰蛋白酶消化后进行纯化培养,建立体外新生大鼠脊髓背根神经元培养体系。培养96h后,将背根神经元分为:空白对照组(A组)、100pmol/LFK506组(B组)、1nmol/LFK506组(C组)和10nmol/LFK506组(D组)。继续培养48h后,通过NF200免疫荧光法观察神经元生长情况,四甲基偶氮唑盐比色法(MTT法)检测细胞活力及逆转录聚合酶链式反应法(RT-PCR)检测生长相关蛋白—43信使核糖核酸(GAP-43 mRNA)的表达情况。
结果:免疫荧光结果显示C组的背根神经元数量和突起的长度生长明显优于A组、B组和D组,B组神经元生长情况优于A组,D组的神经元生长情况明显差于A组。B组的MTT吸光度OD值及GAP-43mRNA的相对表达量高于A组,没有统计学差异差异(P＞0.01),C组的MTT吸光度OD值及GAP-43mRNA的相对表达量高于A组和B组,差异有统计学意义(P＜0.0 1),D组MTT吸光度OD值及GAP-43mRNA的相对表达量明显低于A组,差异有统计学意义(P＜0.01)。
结论:1nmol/L浓度的FK506对大鼠脊髓背根神经元生长的促进和保护作用最好;100pmol/L浓度的FK506对大鼠脊髓背根神经元生长具有促进和保护作用;10nmol/L浓度的FK506对神经元的生长具有抑制作用。
第二部分FK506缓释药膜治疗大鼠急性脊髓损伤的实验研究
目的:观察FK506缓释药膜对大鼠急性脊髓损伤后神经再生的影响。
方法:采用Allen's法制成大鼠急性脊髓损伤动物实验模型。将动物随机分成:假手术组(A组,n=20):单纯切除椎板,不损伤脊髓;损伤组(B组,n=20):单纯损伤脊髓;壳聚糖组(C组,n=20):在损伤脊髓节段放置不含药物的壳聚糖膜;FK506缓释膜片组(D组,n=20):在损伤脊髓节段放置复合FK506的壳聚糖缓释膜,分别与1w、2w、3w和4w进行脊髓功能评分(BBB评分)、脊髓组织HE染色观察病理变化和免疫组化染色后用图像分析系统检测NF200的表达。
结果:脊髓功能评分A组优于B组、C组和D组(P＜0.05),B组和C组比较没有统计学差异(P＞0.05),D组优于B组和C组(P＜0.05);组织病理学观察发现脊髓损伤后神经元大量坏死,组织内形成大量空洞。D组的神经元坏死和组织内空洞形成均少于B组和C组。免疫组化染色观察NF200表达的结果:A组的NF200免疫荧光灰度值结果明显高于B组、C组和D组(P＜0.05),B组NF200免疫荧光灰度值与C组比较没有统计学差异(P＞0.05),D组NF200免疫荧光灰度值结果优于B组和C组(P＜0.05)。
结论:局部应用壳聚糖复合FK506缓释膜片可以保护神经细胞骨架,促进轴突生长,对急性脊髓损伤后神经再生具有促进作用。
第三部分滋补脾阴方药血清、FK506及其联合应用对大鼠背根神经元生长的影响
目的:观察滋补脾阴方药血清、他克莫司(FK506)及两者联合应用对大鼠背根神经元生长的影响,探讨两种药物对神经细胞生长的作用。
方法:取8只新生24h SD大鼠的背根神经节,剥除神经外膜,剪成约1mm~3大小的碎块,用0.25%胰蛋白酶消化后进行纯化培养,建立体外新生大鼠背根神经元培养体系。培养96h后,将背根神经元分为空白对照组(A组)、空白血清对照组(B组)、滋补脾阴方药血清组(1%)(C组)、FK506(1nmol/l)组(D组)和联合用药组(E组)。继续培养48h后,通过NF200免疫荧光法观察神经元生长情况,四甲基偶氮唑盐比色法(MTT法)检测细胞活力及逆转录聚合酶链式反应法(RT-PCR)检测生长相关蛋白—43信使核糖核酸(GAP-43 mRNA)的表达情况。
结果:免疫荧光结果显示C组、D组、E组神经元突起生长的情况优于A组和B组,E组神经元生长的情况差于C组和D组;B组的MTT吸光度(OD)值及GAP-43 mRNA的相对表达量与A组比较无统计学差异(P＞0.05),C组、D组和E组的MTT OD值及GAP-43 mRNA的相对表达量均较A组显著增高(P＜0.05);C组和D组的MTT OD值及GAP-43 mRNA的相对表达量均较B组显著增高(P＜0.05),E组与B组比较无统计学差异(P＞0.05):D组、E组与C组比较无统计学差异(P＞0.05),E组与D组比较有统计学差异(P＜0.05)。
结论:1%浓度的滋补脾阴方药具有保护神经元和促进突起生长的作用;1nmol/L的FK506对体外培养的大鼠背根神经元具有神经保护和促神经再生作用;1%滋补脾阴方药和1nmol/L FK506联合应用时作用减弱。
综上所述,通过对FK506在治疗急性脊髓损伤方面的实验的研究,获得了以下成果:
1.进一步验证了FK506的神经营养作用和神经保护作用,提示在治疗急性脊髓损伤时FK506是通过保护神经元,促进突起生长来发挥作用。
2.不同浓度FK506对大鼠脊髓背根神经元生长表现出不同的作用,神经损伤时应该合理应用FK506,避免出现该药物的神经毒性副作用。本实验结果发现,1nmol/L浓度FK506对大鼠脊髓背根神经元生长的促进和保护作用最好;当FK506浓度达到10nmol/L时,神经元的生长受到明显抑制。
3.壳聚糖复合FK506缓释膜片可以降低给药剂量,减少血药浓度,在治疗脊髓损伤方面表现出良好的结果同时,可以减少神经毒性的可能性。局部应用壳聚糖复合FK506缓释膜片可以保护神经细胞骨架,促进轴突生长,对急性脊髓损伤具有治疗作用。
4.FK506和滋补脾阴方药不但可以提高背根神经元的存活率,还可以促进神经突起的生长,具有神经保护和神经营养作用。但二者联合用药虽然具有神经细胞保护作用和促进神经突起生长作用,但是效果低于单一用药组。
5.如何进一步探求急性脊髓损伤治疗中FK506的作用及使用(包括药物的剂量、方法等),并最大限度地抑制其神经毒性,还有待今后的实验研究与完善。
Acute spinal cord injury(ASCI) was a kind of serious damage of nervous system,it brought huge burden to the individuals,the families and the society.The morbidity of ASCI in our country was higher than those of the developed countries.So,it was important to treat ASCI so that to recover or reduce the damage of nervous system.However,the treatment of ASCI was still a difficult problem.
ASCI can be divided into primary ASCI and secondary ASCI.Primary ASCI was a mechanical damage.The degree of damage were determined when damage happened.Primary ASCI was non-reversible,and no effective method can be used to treat it;Secondary ASCI happened after the primary ASCI,it was reversible and could be controlled.Secondary ASCI determined the results of ASCI,so the key to treat ASCI was the treatment of secondary ASCI.Now the strategies of treating ASCI were protecting neurons and preventing neurons' apoptosis;promoting the growth of the neurites.Some drugs can influence and interfere the process of secondary damage.The drugs were divided into two groups:Western medicine and Chinese medicine.
FK506 named tacrolimus belonged to macrolides antibiotics with strong immunosuppressive action.Recent research showed that FK506 had both immunosuppressive action and neuroprotection,neurotrophy.The mechanism of neuroprotection associated with inhibiting calcineurin(CaN).As a CaN inhibitor,one of the main side effect was neurotoxity.It showed that the notable relativity existed between the incidence rate of neurotoxity and the concentration of FK506.Therefore observing the growth of dorsal root ganglion with different concentration of FK506 to find the best drug's concentration can avoide the neurotoxity and provide a theoretical basis to treat ASCI.
FK506 had great side-effect for its easily penetrating blood-brain barrier and low effective plasma concentration.Neurotoxity is one of the main side-effect of FK506.When treating ASCI with FK506,how to achieve the therapeutic effect and reduce the toxic side effect at the same time is the problem faced.One of the ways solved the problem was adjusting the delivery method and speed of FK506.Drug-membrane used locally can provide higher concentration of drugs in the region, sustain-release can reduce the wave of the plasm concentration of FK506. The experiment that using Chitosan sustained-release FK506 incorporated membrane to treat ASCI was carry out to observe the recovery of spinal cord and research the possibility of this method.
Ginseng,Salvia miltiorrhiza,Yam,Radix Paeoniae Alba and other drugs composed Zi-Bu-Pi-Yin recipe.Recent research showed that Zi-Bu-Pi-Yin recipe had neuroprotection.But whether the neuroprotection and promoting neurite existed,when Zi-Bu-Pi-Yin recipe combined used with FK506,were unknown.By observing the growth of neurons treated with the two drugs and combined use,the two drugs' neuroprotection and the possibility of combined used to treat the ASCI were researched.
Part 1
Effects of different concentrations of FK506 on the growth of the new-born rat's dorsal root ganglia neuron
Objective:To find the best concentration of FK506 suitable to the growth of the dorsal root ganglia neuron(DRGn)
Method:The dorsal root ganglia(DRG) of eight newborn SD rats (within 24 hours) were collected and the epineurium of the DRG was separated.After dissected into about 1mm~3 size,the DRG were digested by 0.25%trypsin.Then DRGn were purified and cultured.Cultured after 96 hours,the neuron was divided into 100pmol/L FK506(Group B)、1nmol/L FK506(Group C) and 10nmol/L FK506(Group D),the blank-control group (Group A) was established at the same time.Keep on culturing the DRGn for 48 hours,examine the growth of neurons by NF200 immunofluore-scence, the vitality of the DRGn by MTT method and the expression of GAP-43's mRNA by RT-PCR method.
Results:The immunofluorescence results showed that the growth of neurons of Group C were better than Group A、B、D,the growth of neurons of Group B were better than those of Group A,the growth of neurons of Group D were lower than Group A;the OD value of MTT and the expression of GAP-43's mRNA of group B were higher than those of Group A with no statistical significance(P>0.01),the OD value of MTT and the expression of GAP-43's mRNA of group C were significantly better than those of Group A and B(P<0.01),the OD value of MTT and the expression of GAP-43's mRNA of group D were lower than those of Group A(P<0.01).
Conclusion:The concentration of FK506(1nmol/L) was the best concentration which having neurotrophy and neuroprotection on the growth of DRGn;100pmol/LFK506 also had neurotrophy and neuroprotection on the growth of DRGn;but 10nmol/L FK506 showed inhibitory action on the neurons.
Part 2
The experiment of using Chitosan sustained-release FK506 incorporated membrane to treat ASCI
Objective:To observe the effects of Chitosan sustained-release FK506 incorporated membrane on the neuroregeneration of the rats after acute spinal cord injury.
Method:Allen's method was used to make actue spinal cord injury of the rats.The rats were divided into four groups:sham-operation group(group A,n=20):only cut off vertebral lamina.Damage group(group B,n=20):after cut off vertebral lamina,only damage spinal cord.Chitosan membrane group without drug(group C,n=20):after damage the spinal cord,the chitosan membrane without drug were put up on the damaged spinal cord. Chitosan membrane group with drug(group D,n=20):after damage the spinal cord,the chitosan membrane with FK506 were put up on the damaged spinal cord.BBB judgement were used to observe the rats locomotive function.At the same time,HE staining was used to observe the spinal cord histopathology;immunofluorescence were used to judge the intensity of NF200.
Result:BBB judgement showed that group A was better than group B、group C and group D(P<0.05).There was no statistical difference between group B and group C(P>0.05).Group D was significantly better than group B and group C(P<0.05);The histopathology of spinal cord showed that many neurons died and many cavities formed after spinal cord injuried,the number of neurons died and cavities formed of Group D were lower than those of Group B and C;immunofluorescence analysis of NF200 showed that group A was significantly better than group B,C and D(P<0.05).There was no statistical difference between the results of group B and group C (P>0.05).The results of group D was better than group B and group C (P<0.05)
Conclusion:Chitosan sustained-release FK506 incorporated membrane used local application can protect the framework of neuron and promote the growth of the neurite,promote the recovery of the spinal cord injury.
Part 3
The effects of Zi-Bu-Pi-Yin recipe、Tacrolimus(FK506) and combined use on the growth of the dorsal root ganglia neuron of newborn rats
Objective:To observe the effects of Zi-Bu-Pi-Yin recipe、Tacrolimus (FK506) and combined use on the growth of the dorsal root ganglia neuron (DRGn) of newborn rats,discuss the effect of the two drugs on the growth of neuron.
Method:The dorsal root ganglia(DRG) of eight newborn SD rats (within 24 hours) were collected and the epineurium of the DRG was separated.After dissected into about 1mm~3 size,the DRG were digested by 0.25%trypsin.Then DRGn were purified and cultured.Cultured after 96 hours,the DRGn were separated into:blank-control group(group A),blankserum control group(group B),Zi-Bu-Pi-Yin recipe group(1%)(group C), FK506 group(1nmol/1)(group D) and combined use group(group E).Keep on culturing the DRGn for 48 hours,examinethe growth of neurons by NF200 immunofluorescence,the vitality of the DRGn by MTT method and examine the expression of GAP-43's mRNA by RT-PCR method.
Result:The immunofluorescence results showed that the growth of neurons of Group C,D and E were better than those of Group A and B,the growth of neurons of Group E were lower than Group C and D;There was no statistical difference in the OD value of MTT and the expression of GAP-43's mRNA between group B and group A(P>0.05),the OD value of MTT and the expression of GAP-43's mRNA of group C,D and E were significantly better than those of group A(P<0.05);The OD value of MTT and the expression of GAP-43's mRNA of group C and D were significantly better than those of group B(P<0.05).There was no statistical difference between group E and group B(P>0.05);Compared with group C,group D and E had no significant difference(P>0.05),significant difference was observed between group E and D(P<0.05).
Conclusion:1%Zi-Bu-Pi-Yin recipe had neuroprotection and neuroregeneration on the DRGn of newborn rats cultured in vitro;1nmol/l FK506 had neuroprotection and neuroregeneration on the DRGn of newborn rats cultured in vitro;the effect was weakened when1%Zi-Bu-Pi-Yin recipe combined ueded with 1nmol/l FK506.
From the above,we conclude that:
1.Proving the neuroprotection and neurotrophy of FK506,suggesting that the effects of FK506 were protecting neurons and promoting neurites when treating ASCI.
2.Different influence were found on the growth of dorsal root ganglion with different concentration of FK506.When the concentration of FK506 was 1nmol/L,the growth of neurons were significantly better(P<0.01) When the concentration of FK506 was 10nmol/L,the drug inhibit the growth of neurons.
3.Chitosan sustained-release FK506 incorporated membrane can reduce the dose of using FK506 and the plasma congcentration.This method can gain good results with low possibility of neurotoxity.Chitosan sustained-release FK506 incorporated membrane using locally can protect neuroframe and promote the neurites so that treating the ASCI of rats.
4.Both Zi-Bu-Pi-Yin recipe and FK506 had neuroprotection and neurotrophy,but when the two drugs combined used,the effects were weakened.
5.How to use Fk506 including dilivery methods and speed when treat ASCI and how to prevent the neurotoxity of FK506 still need to be investigated.
急性脊髓损伤目前分为原发性脊髓损伤和继发性脊髓损伤。原发性脊髓损伤为机械性损伤,受伤程度由受伤当时决定,损伤不可逆,因此无法对其损伤机制进行有效的治疗;继发性脊髓损伤是发生于原发性脊髓损伤之后的一系列损伤,可被控制,具有可逆性,决定了脊髓损伤后的愈后,因此急性脊髓损伤的治疗关键切入点在于继发性脊髓损伤的治疗。目前关于治疗急性脊髓损伤的策略主要是保护神经元,防止其继发性损伤和凋亡;促进神经轴突生长。研究表明某些药物可以影响和干扰继发损伤的过程。目前治疗脊髓继发性损伤的药物主要分为西药和中药两大类。
FK506又名他克莫司,属于大环内酯类抗生素,具有极强的免疫抑制作用。近年的研究表明FK506不但具有免疫抑制作用,还具有神经保护和神经营养作用。FK506的神经保护机制与抑制钙调神经磷酸酶(CaN)有关。FK506作为CaN抑制剂,主要的副作用之一就是神经毒性。有研究表明,FK506的神经毒性发生率与药物浓度存在显著的相关性。因此通过观察不同浓度下FK506对背根神经元生长的影响,寻找促进神经元生长的最佳药物浓度,避免出现该药物的神经毒性副作用,可为该药物治疗急性脊髓损伤提供理论依据。
由于FK506易穿透血脑屏障,有效血药浓度低,在使用过程中往往有很大的副作用,神经毒性是其主要副作用之一。在治疗急性脊髓损伤时,如何既达到治疗效果,又同时减小毒副作用是面临解决的问题。调整药物给药方式和给药速度是解决这一问题的方法之一。局部药膜应用可以减少药物剂量,使局部达到一个较高的药物浓度;持续缓释药物可以减少血药浓度波动进而减少药物的毒副作用。本实验通过局部应用FK506缓释药膜治疗大鼠急性脊髓损伤,观察神经恢复情况,进而研究该方法的可行性。
滋补脾阴方药由人参、丹参、山药、白芍等组成。目前研究表明滋补脾阴方药具有神经保护作用。但是与FK506联合应用是否具有对神经元的保护和促进突起生长目前没有相关研究。通过观察两种药物以及联合应用的情况下对背根神经元生长的影响,可进一步研究两种药物的神经保护作用及该两种药物联合应用治疗急性脊髓损伤的可行性。
第一部分不同浓度FK506对新生大鼠脊髓背根神经元生长的影响
目的:观察并寻找促进新生大鼠脊髓背根神经元生长的最佳FK506浓度。
方法:取8只新生24h SD大鼠的背根神经节,剥除神经外膜,剪成约1mm~3大小的碎块,用0.25%胰蛋白酶消化后进行纯化培养,建立体外新生大鼠脊髓背根神经元培养体系。培养96h后,将背根神经元分为:空白对照组(A组)、100pmol/LFK506组(B组)、1nmol/LFK506组(C组)和10nmol/LFK506组(D组)。继续培养48h后,通过NF200免疫荧光法观察神经元生长情况,四甲基偶氮唑盐比色法(MTT法)检测细胞活力及逆转录聚合酶链式反应法(RT-PCR)检测生长相关蛋白—43信使核糖核酸(GAP-43 mRNA)的表达情况。
结果:免疫荧光结果显示C组的背根神经元数量和突起的长度生长明显优于A组、B组和D组,B组神经元生长情况优于A组,D组的神经元生长情况明显差于A组。B组的MTT吸光度OD值及GAP-43mRNA的相对表达量高于A组,没有统计学差异差异(P＞0.01),C组的MTT吸光度OD值及GAP-43mRNA的相对表达量高于A组和B组,差异有统计学意义(P＜0.0 1),D组MTT吸光度OD值及GAP-43mRNA的相对表达量明显低于A组,差异有统计学意义(P＜0.01)。
结论:1nmol/L浓度的FK506对大鼠脊髓背根神经元生长的促进和保护作用最好;100pmol/L浓度的FK506对大鼠脊髓背根神经元生长具有促进和保护作用;10nmol/L浓度的FK506对神经元的生长具有抑制作用。
第二部分FK506缓释药膜治疗大鼠急性脊髓损伤的实验研究
目的:观察FK506缓释药膜对大鼠急性脊髓损伤后神经再生的影响。
方法:采用Allen's法制成大鼠急性脊髓损伤动物实验模型。将动物随机分成:假手术组(A组,n=20):单纯切除椎板,不损伤脊髓;损伤组(B组,n=20):单纯损伤脊髓;壳聚糖组(C组,n=20):在损伤脊髓节段放置不含药物的壳聚糖膜;FK506缓释膜片组(D组,n=20):在损伤脊髓节段放置复合FK506的壳聚糖缓释膜,分别与1w、2w、3w和4w进行脊髓功能评分(BBB评分)、脊髓组织HE染色观察病理变化和免疫组化染色后用图像分析系统检测NF200的表达。
结果:脊髓功能评分A组优于B组、C组和D组(P＜0.05),B组和C组比较没有统计学差异(P＞0.05),D组优于B组和C组(P＜0.05);组织病理学观察发现脊髓损伤后神经元大量坏死,组织内形成大量空洞。D组的神经元坏死和组织内空洞形成均少于B组和C组。免疫组化染色观察NF200表达的结果:A组的NF200免疫荧光灰度值结果明显高于B组、C组和D组(P＜0.05),B组NF200免疫荧光灰度值与C组比较没有统计学差异(P＞0.05),D组NF200免疫荧光灰度值结果优于B组和C组(P＜0.05)。
结论:局部应用壳聚糖复合FK506缓释膜片可以保护神经细胞骨架,促进轴突生长,对急性脊髓损伤后神经再生具有促进作用。
第三部分滋补脾阴方药血清、FK506及其联合应用对大鼠背根神经元生长的影响
目的:观察滋补脾阴方药血清、他克莫司(FK506)及两者联合应用对大鼠背根神经元生长的影响,探讨两种药物对神经细胞生长的作用。
方法:取8只新生24h SD大鼠的背根神经节,剥除神经外膜,剪成约1mm~3大小的碎块,用0.25%胰蛋白酶消化后进行纯化培养,建立体外新生大鼠背根神经元培养体系。培养96h后,将背根神经元分为空白对照组(A组)、空白血清对照组(B组)、滋补脾阴方药血清组(1%)(C组)、FK506(1nmol/l)组(D组)和联合用药组(E组)。继续培养48h后,通过NF200免疫荧光法观察神经元生长情况,四甲基偶氮唑盐比色法(MTT法)检测细胞活力及逆转录聚合酶链式反应法(RT-PCR)检测生长相关蛋白—43信使核糖核酸(GAP-43 mRNA)的表达情况。
结果:免疫荧光结果显示C组、D组、E组神经元突起生长的情况优于A组和B组,E组神经元生长的情况差于C组和D组;B组的MTT吸光度(OD)值及GAP-43 mRNA的相对表达量与A组比较无统计学差异(P＞0.05),C组、D组和E组的MTT OD值及GAP-43 mRNA的相对表达量均较A组显著增高(P＜0.05);C组和D组的MTT OD值及GAP-43 mRNA的相对表达量均较B组显著增高(P＜0.05),E组与B组比较无统计学差异(P＞0.05):D组、E组与C组比较无统计学差异(P＞0.05),E组与D组比较有统计学差异(P＜0.05)。
结论:1%浓度的滋补脾阴方药具有保护神经元和促进突起生长的作用;1nmol/L的FK506对体外培养的大鼠背根神经元具有神经保护和促神经再生作用;1%滋补脾阴方药和1nmol/L FK506联合应用时作用减弱。
综上所述,通过对FK506在治疗急性脊髓损伤方面的实验的研究,获得了以下成果:
1.进一步验证了FK506的神经营养作用和神经保护作用,提示在治疗急性脊髓损伤时FK506是通过保护神经元,促进突起生长来发挥作用。
2.不同浓度FK506对大鼠脊髓背根神经元生长表现出不同的作用,神经损伤时应该合理应用FK506,避免出现该药物的神经毒性副作用。本实验结果发现,1nmol/L浓度FK506对大鼠脊髓背根神经元生长的促进和保护作用最好;当FK506浓度达到10nmol/L时,神经元的生长受到明显抑制。
3.壳聚糖复合FK506缓释膜片可以降低给药剂量,减少血药浓度,在治疗脊髓损伤方面表现出良好的结果同时,可以减少神经毒性的可能性。局部应用壳聚糖复合FK506缓释膜片可以保护神经细胞骨架,促进轴突生长,对急性脊髓损伤具有治疗作用。
4.FK506和滋补脾阴方药不但可以提高背根神经元的存活率,还可以促进神经突起的生长,具有神经保护和神经营养作用。但二者联合用药虽然具有神经细胞保护作用和促进神经突起生长作用,但是效果低于单一用药组。
5.如何进一步探求急性脊髓损伤治疗中FK506的作用及使用(包括药物的剂量、方法等),并最大限度地抑制其神经毒性,还有待今后的实验研究与完善。
Acute spinal cord injury(ASCI) was a kind of serious damage of nervous system,it brought huge burden to the individuals,the families and the society.The morbidity of ASCI in our country was higher than those of the developed countries.So,it was important to treat ASCI so that to recover or reduce the damage of nervous system.However,the treatment of ASCI was still a difficult problem.
ASCI can be divided into primary ASCI and secondary ASCI.Primary ASCI was a mechanical damage.The degree of damage were determined when damage happened.Primary ASCI was non-reversible,and no effective method can be used to treat it;Secondary ASCI happened after the primary ASCI,it was reversible and could be controlled.Secondary ASCI determined the results of ASCI,so the key to treat ASCI was the treatment of secondary ASCI.Now the strategies of treating ASCI were protecting neurons and preventing neurons' apoptosis;promoting the growth of the neurites.Some drugs can influence and interfere the process of secondary damage.The drugs were divided into two groups:Western medicine and Chinese medicine.
FK506 named tacrolimus belonged to macrolides antibiotics with strong immunosuppressive action.Recent research showed that FK506 had both immunosuppressive action and neuroprotection,neurotrophy.The mechanism of neuroprotection associated with inhibiting calcineurin(CaN).As a CaN inhibitor,one of the main side effect was neurotoxity.It showed that the notable relativity existed between the incidence rate of neurotoxity and the concentration of FK506.Therefore observing the growth of dorsal root ganglion with different concentration of FK506 to find the best drug's concentration can avoide the neurotoxity and provide a theoretical basis to treat ASCI.
FK506 had great side-effect for its easily penetrating blood-brain barrier and low effective plasma concentration.Neurotoxity is one of the main side-effect of FK506.When treating ASCI with FK506,how to achieve the therapeutic effect and reduce the toxic side effect at the same time is the problem faced.One of the ways solved the problem was adjusting the delivery method and speed of FK506.Drug-membrane used locally can provide higher concentration of drugs in the region, sustain-release can reduce the wave of the plasm concentration of FK506. The experiment that using Chitosan sustained-release FK506 incorporated membrane to treat ASCI was carry out to observe the recovery of spinal cord and research the possibility of this method.
Ginseng,Salvia miltiorrhiza,Yam,Radix Paeoniae Alba and other drugs composed Zi-Bu-Pi-Yin recipe.Recent research showed that Zi-Bu-Pi-Yin recipe had neuroprotection.But whether the neuroprotection and promoting neurite existed,when Zi-Bu-Pi-Yin recipe combined used with FK506,were unknown.By observing the growth of neurons treated with the two drugs and combined use,the two drugs' neuroprotection and the possibility of combined used to treat the ASCI were researched.
Part 1
Effects of different concentrations of FK506 on the growth of the new-born rat's dorsal root ganglia neuron
Objective:To find the best concentration of FK506 suitable to the growth of the dorsal root ganglia neuron(DRGn)
Method:The dorsal root ganglia(DRG) of eight newborn SD rats (within 24 hours) were collected and the epineurium of the DRG was separated.After dissected into about 1mm~3 size,the DRG were digested by 0.25%trypsin.Then DRGn were purified and cultured.Cultured after 96 hours,the neuron was divided into 100pmol/L FK506(Group B)、1nmol/L FK506(Group C) and 10nmol/L FK506(Group D),the blank-control group (Group A) was established at the same time.Keep on culturing the DRGn for 48 hours,examine the growth of neurons by NF200 immunofluore-scence, the vitality of the DRGn by MTT method and the expression of GAP-43's mRNA by RT-PCR method.
Results:The immunofluorescence results showed that the growth of neurons of Group C were better than Group A、B、D,the growth of neurons of Group B were better than those of Group A,the growth of neurons of Group D were lower than Group A;the OD value of MTT and the expression of GAP-43's mRNA of group B were higher than those of Group A with no statistical significance(P>0.01),the OD value of MTT and the expression of GAP-43's mRNA of group C were significantly better than those of Group A and B(P<0.01),the OD value of MTT and the expression of GAP-43's mRNA of group D were lower than those of Group A(P<0.01).
Conclusion:The concentration of FK506(1nmol/L) was the best concentration which having neurotrophy and neuroprotection on the growth of DRGn;100pmol/LFK506 also had neurotrophy and neuroprotection on the growth of DRGn;but 10nmol/L FK506 showed inhibitory action on the neurons.
Part 2
The experiment of using Chitosan sustained-release FK506 incorporated membrane to treat ASCI
Objective:To observe the effects of Chitosan sustained-release FK506 incorporated membrane on the neuroregeneration of the rats after acute spinal cord injury.
Method:Allen's method was used to make actue spinal cord injury of the rats.The rats were divided into four groups:sham-operation group(group A,n=20):only cut off vertebral lamina.Damage group(group B,n=20):after cut off vertebral lamina,only damage spinal cord.Chitosan membrane group without drug(group C,n=20):after damage the spinal cord,the chitosan membrane without drug were put up on the damaged spinal cord. Chitosan membrane group with drug(group D,n=20):after damage the spinal cord,the chitosan membrane with FK506 were put up on the damaged spinal cord.BBB judgement were used to observe the rats locomotive function.At the same time,HE staining was used to observe the spinal cord histopathology;immunofluorescence were used to judge the intensity of NF200.
Result:BBB judgement showed that group A was better than group B、group C and group D(P<0.05).There was no statistical difference between group B and group C(P>0.05).Group D was significantly better than group B and group C(P<0.05);The histopathology of spinal cord showed that many neurons died and many cavities formed after spinal cord injuried,the number of neurons died and cavities formed of Group D were lower than those of Group B and C;immunofluorescence analysis of NF200 showed that group A was significantly better than group B,C and D(P<0.05).There was no statistical difference between the results of group B and group C (P>0.05).The results of group D was better than group B and group C (P<0.05)
Conclusion:Chitosan sustained-release FK506 incorporated membrane used local application can protect the framework of neuron and promote the growth of the neurite,promote the recovery of the spinal cord injury.
Part 3
The effects of Zi-Bu-Pi-Yin recipe、Tacrolimus(FK506) and combined use on the growth of the dorsal root ganglia neuron of newborn rats
Objective:To observe the effects of Zi-Bu-Pi-Yin recipe、Tacrolimus (FK506) and combined use on the growth of the dorsal root ganglia neuron (DRGn) of newborn rats,discuss the effect of the two drugs on the growth of neuron.
Method:The dorsal root ganglia(DRG) of eight newborn SD rats (within 24 hours) were collected and the epineurium of the DRG was separated.After dissected into about 1mm~3 size,the DRG were digested by 0.25%trypsin.Then DRGn were purified and cultured.Cultured after 96 hours,the DRGn were separated into:blank-control group(group A),blankserum control group(group B),Zi-Bu-Pi-Yin recipe group(1%)(group C), FK506 group(1nmol/1)(group D) and combined use group(group E).Keep on culturing the DRGn for 48 hours,examinethe growth of neurons by NF200 immunofluorescence,the vitality of the DRGn by MTT method and examine the expression of GAP-43's mRNA by RT-PCR method.
Result:The immunofluorescence results showed that the growth of neurons of Group C,D and E were better than those of Group A and B,the growth of neurons of Group E were lower than Group C and D;There was no statistical difference in the OD value of MTT and the expression of GAP-43's mRNA between group B and group A(P>0.05),the OD value of MTT and the expression of GAP-43's mRNA of group C,D and E were significantly better than those of group A(P<0.05);The OD value of MTT and the expression of GAP-43's mRNA of group C and D were significantly better than those of group B(P<0.05).There was no statistical difference between group E and group B(P>0.05);Compared with group C,group D and E had no significant difference(P>0.05),significant difference was observed between group E and D(P<0.05).
Conclusion:1%Zi-Bu-Pi-Yin recipe had neuroprotection and neuroregeneration on the DRGn of newborn rats cultured in vitro;1nmol/l FK506 had neuroprotection and neuroregeneration on the DRGn of newborn rats cultured in vitro;the effect was weakened when1%Zi-Bu-Pi-Yin recipe combined ueded with 1nmol/l FK506.
From the above,we conclude that:
1.Proving the neuroprotection and neurotrophy of FK506,suggesting that the effects of FK506 were protecting neurons and promoting neurites when treating ASCI.
2.Different influence were found on the growth of dorsal root ganglion with different concentration of FK506.When the concentration of FK506 was 1nmol/L,the growth of neurons were significantly better(P<0.01) When the concentration of FK506 was 10nmol/L,the drug inhibit the growth of neurons.
3.Chitosan sustained-release FK506 incorporated membrane can reduce the dose of using FK506 and the plasma congcentration.This method can gain good results with low possibility of neurotoxity.Chitosan sustained-release FK506 incorporated membrane using locally can protect neuroframe and promote the neurites so that treating the ASCI of rats.
4.Both Zi-Bu-Pi-Yin recipe and FK506 had neuroprotection and neurotrophy,but when the two drugs combined used,the effects were weakened.
5.How to use Fk506 including dilivery methods and speed when treat ASCI and how to prevent the neurotoxity of FK506 still need to be investigated.
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