甘草甜素促进小鼠周围神经损伤修复的实验研究
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摘要
目的：探讨甘草甜素对坐骨神经损伤后的Balb/c小鼠免疫功能的影响，及其通过干预免疫反应促进周围神经再生的机制。
方法和结果:
1.甘草甜素对Balb/c小鼠免疫功能的影响
将坐骨神经损伤模型小鼠随机分为甘草甜素高、中、低剂量组和生理盐水对照组，每组各5只，分别按照20mg/kg/d，10mg/kg/d，5mg/kg/d剂量腹腔注射甘草甜素及等体积的生理盐水，于造模前一天开始给药，以后连续给药直至处死。取造模后3天、5天、7天、14天的小鼠，脱颈处死，用MTT法检测各时间点各组小鼠脾T淋巴细胞和B淋巴细胞的增殖能力。同时，用相同方法检测不同浓度甘草甜素对正常Balb/c小鼠脾淋巴细胞增殖的影响，并以环孢素作对照。体内及体外实验结果均表明不同浓度的甘草甜素能抑制小鼠T和B淋巴细胞的增殖，且浓度越高抑制作用越强。
2.甘草甜素对坐骨神经损伤模型小鼠GAP-43、p75NTR等表达的影响
实验小鼠的分组、给药方法同第1部分实验中的方法，每组各10只,分别于给药1d，3d，5d，lw，2w，4w，8w，12w后处死小鼠，以免疫组化、Real-timePCR、 Western-blot方法检测坐骨神经相应脊髓节段GAP-43、P75NTR表达量。实验结果表明：（1）坐骨神经损伤后，相应脊髓节段的生长相关蛋白GAP-43被激活并大量表达，高表达的GAP-43主要存在于脊髓前角运动神经原细胞浆内；（2）甘草甜素高、中剂量组的GAP-43表达明显高于低剂量组及对照组。（3）坐骨神经损伤后1d相应脊髓节段的p75NTR表达量开始增加，2w达到高峰，增高表达的p75NTR主要存在于脊髓前角运动神经元胞浆内；（4）甘草甜素高、中剂量组P75NTR表达量明显低于低剂量组及对照组。
3.甘草甜素对损伤后神经修复和再生的影响
应用改良Marsland法与LFB双重染色检测不同剂量甘草甜素治疗组及生理盐水对照组小鼠有髓神经纤维数目和髓鞘变化；HE染色观察肌纤维的大体形态、肌纤维横截面积和纤维数量；测量坐骨神经功能指数和神经传导速度及波幅，检测神经损伤后功能的恢复；应用TUNEL法检测脊髓神经元凋亡。实验结果表明：（1）各浓度甘草甜素均可减少继发性神经损害及降低神经再生中的脱髓鞘程度；（2）与对照组相比各甘草甜素治疗组有髓神经纤维数目较多，分布均匀，髓鞘变性较少；（3）与对照组相比不同剂量甘草甜素治疗组的肌纤维横截面积较大，肌细胞排列较紧密，结缔组织增生较少；（4）甘草甜素治疗组神经功能恢复情况优于对照组；（5）各浓度甘草甜素均可减少脊髓运动神经元细胞的凋亡。
结论:
1.甘草甜素可以抑制Balb/c小鼠的免疫机能，通过抑制淋巴细胞的转化能力，从而降低了细胞免疫和体液免疫应答的强度，在一定范围内呈现出剂量依赖关系。
2.甘草甜素上调GAP-43表达并下调p75NTR的表达。
3.甘草甜素可促进周围神经损伤后的修复和再生，这一功能与其抑制机体细胞免疫和体液免疫，下调p75NTR的表达，从而减少周围神经的继发免疫损伤及上调GAP-43密切相关。
Objective: To observe the effect of Glycyrrhizin on immune function ofBalb/c mice with sciatic nerve injury, and explore the mechanism of improvedperipheral nerve regeneration induced by Glycyrrhizin.
Methods and Results:
1. The effect of Glycyrrhizin on immune function of Balb/c mice
80mice with sciatic nerve injury were randomly divided into4groups, andthe Glycyrrhizin were injected intraperitioneally according to the dose of20mg/kg/d，10mg/kg/d,5mg/kg/d, respectively. The mice of control group wereinjected with normal saline. The day before the molding, the start ofadministration,Continuous administration to death，After3days,5days,7days,14days administration, respectively, the mice were killed by spinal separation, andthe spleen lymphocytes were isolated and cultured in RPMI1640medium.Thenthe transformation capability of T and B lymphocytes were tested by MTT method.At the same time, the T and B lymphocytes of normal mice were stimulated bydifferent concentrations of Glycyrrhizin and Cyclosporine A in vitro, and thetransformation capability of T and B lymphocyte were also tested by MTT method.The results show that: Glycyrrhizin can significantly inhibit T and B lymphocytes’proliferation and transformation in vitro and in vivo by dose-dependent method.
2. The effect of Glycyrrhizin on expression of GAP-43and p75NTR in Balb/C mice with sciatic nerve injury
Balb/c mice with sciatic nerve injury were interved by different dose ofGlycyrrhizin for1day,3days,5days,1week,2weeks,4weeks,8weeks,12weeks,respectively, and the expression of GAP-43and in spinal cord were testedby immunohistochemical assay, Real-time PCR and western-blot. The resultsshow that:(1) the expression of GAP-43in the spinal cord segment wasincreased,and GAP-43mainly occur in the cytoplasm of anterior horn cells;(2) theexpression of GAP-43in high and middle dose of Glycyrrhizin groups weresignificantly higher than that of low dose and control groups;(3) the expression ofp75NTR in spinal cord start to increase and reach to peak after1day to2weeks ofsciatic nerve injury, and the expression of p75NTR mainly occur in the cytoplasmof anterior horn cells;(4) the expression of p75NTR in high and middle dose ofGlycyrrhizin groups were significantly lower than that of low dose and controlgroups.
3. The effect of Glycyrrhizin on nerve regeneration after injury
After intervention by different dose of Glycyrrhizin, the spinal cord segmentof Balb/c mice with sciatic nerve injury were stained by HE, double stain ofimproved Marsland and LFB method and observed under the microscope. Theapoptosis of spinal cord segment of mice with sciatic nerve injury were also testedby TUNEL method. And nerve conduction velocity and amplitude were tested byMedtronic Keypoint machine.The results showed that:(1) Glycyrrhizin decreasedthe secondary never injury and demyelination level;(2) the number of myelinated nerve fibers of Glycyrrhizin treated groups with uniform distribution and lessdemyelination level are more than that of control group;(3) Glycyrrhizin canimprove the structure, function, distribution of the muscle cells, and the musclecells treated by Glycyrrhizin arranged closely and has the larger cross-sectionalarea of muscle fibers with low proliferation of connective tissue;(4) the nervefunction improvement of Glycyrrhizin treated groups are better than control group;(5) Glycyrrhizin decreased the apoptosis of spinal cord segment of mice withsciatic nerve injury.
Conclusion:
1. Glycyrrhizin inhibited immune function and decrease the immune responseintensity of Balb/c mice in a dose dependent manner.
2. Glycyrrhizin increased the expression of GAP-43and decreased theexpression of p75NTR.
3. Glycyrrhizin improved the regeneration of injured peripheral nerve, whichis related to the inhibition of immune system and reduction of expression ofp75NTR by decreasing the secondary immune injury and uploading the expressionof GAP-43.
方法和结果:
1.甘草甜素对Balb/c小鼠免疫功能的影响
将坐骨神经损伤模型小鼠随机分为甘草甜素高、中、低剂量组和生理盐水对照组，每组各5只，分别按照20mg/kg/d，10mg/kg/d，5mg/kg/d剂量腹腔注射甘草甜素及等体积的生理盐水，于造模前一天开始给药，以后连续给药直至处死。取造模后3天、5天、7天、14天的小鼠，脱颈处死，用MTT法检测各时间点各组小鼠脾T淋巴细胞和B淋巴细胞的增殖能力。同时，用相同方法检测不同浓度甘草甜素对正常Balb/c小鼠脾淋巴细胞增殖的影响，并以环孢素作对照。体内及体外实验结果均表明不同浓度的甘草甜素能抑制小鼠T和B淋巴细胞的增殖，且浓度越高抑制作用越强。
2.甘草甜素对坐骨神经损伤模型小鼠GAP-43、p75NTR等表达的影响
实验小鼠的分组、给药方法同第1部分实验中的方法，每组各10只,分别于给药1d，3d，5d，lw，2w，4w，8w，12w后处死小鼠，以免疫组化、Real-timePCR、 Western-blot方法检测坐骨神经相应脊髓节段GAP-43、P75NTR表达量。实验结果表明：（1）坐骨神经损伤后，相应脊髓节段的生长相关蛋白GAP-43被激活并大量表达，高表达的GAP-43主要存在于脊髓前角运动神经原细胞浆内；（2）甘草甜素高、中剂量组的GAP-43表达明显高于低剂量组及对照组。（3）坐骨神经损伤后1d相应脊髓节段的p75NTR表达量开始增加，2w达到高峰，增高表达的p75NTR主要存在于脊髓前角运动神经元胞浆内；（4）甘草甜素高、中剂量组P75NTR表达量明显低于低剂量组及对照组。
3.甘草甜素对损伤后神经修复和再生的影响
应用改良Marsland法与LFB双重染色检测不同剂量甘草甜素治疗组及生理盐水对照组小鼠有髓神经纤维数目和髓鞘变化；HE染色观察肌纤维的大体形态、肌纤维横截面积和纤维数量；测量坐骨神经功能指数和神经传导速度及波幅，检测神经损伤后功能的恢复；应用TUNEL法检测脊髓神经元凋亡。实验结果表明：（1）各浓度甘草甜素均可减少继发性神经损害及降低神经再生中的脱髓鞘程度；（2）与对照组相比各甘草甜素治疗组有髓神经纤维数目较多，分布均匀，髓鞘变性较少；（3）与对照组相比不同剂量甘草甜素治疗组的肌纤维横截面积较大，肌细胞排列较紧密，结缔组织增生较少；（4）甘草甜素治疗组神经功能恢复情况优于对照组；（5）各浓度甘草甜素均可减少脊髓运动神经元细胞的凋亡。
结论:
1.甘草甜素可以抑制Balb/c小鼠的免疫机能，通过抑制淋巴细胞的转化能力，从而降低了细胞免疫和体液免疫应答的强度，在一定范围内呈现出剂量依赖关系。
2.甘草甜素上调GAP-43表达并下调p75NTR的表达。
3.甘草甜素可促进周围神经损伤后的修复和再生，这一功能与其抑制机体细胞免疫和体液免疫，下调p75NTR的表达，从而减少周围神经的继发免疫损伤及上调GAP-43密切相关。
Objective: To observe the effect of Glycyrrhizin on immune function ofBalb/c mice with sciatic nerve injury, and explore the mechanism of improvedperipheral nerve regeneration induced by Glycyrrhizin.
Methods and Results:
1. The effect of Glycyrrhizin on immune function of Balb/c mice
80mice with sciatic nerve injury were randomly divided into4groups, andthe Glycyrrhizin were injected intraperitioneally according to the dose of20mg/kg/d，10mg/kg/d,5mg/kg/d, respectively. The mice of control group wereinjected with normal saline. The day before the molding, the start ofadministration,Continuous administration to death，After3days,5days,7days,14days administration, respectively, the mice were killed by spinal separation, andthe spleen lymphocytes were isolated and cultured in RPMI1640medium.Thenthe transformation capability of T and B lymphocytes were tested by MTT method.At the same time, the T and B lymphocytes of normal mice were stimulated bydifferent concentrations of Glycyrrhizin and Cyclosporine A in vitro, and thetransformation capability of T and B lymphocyte were also tested by MTT method.The results show that: Glycyrrhizin can significantly inhibit T and B lymphocytes’proliferation and transformation in vitro and in vivo by dose-dependent method.
2. The effect of Glycyrrhizin on expression of GAP-43and p75NTR in Balb/C mice with sciatic nerve injury
Balb/c mice with sciatic nerve injury were interved by different dose ofGlycyrrhizin for1day,3days,5days,1week,2weeks,4weeks,8weeks,12weeks,respectively, and the expression of GAP-43and in spinal cord were testedby immunohistochemical assay, Real-time PCR and western-blot. The resultsshow that:(1) the expression of GAP-43in the spinal cord segment wasincreased,and GAP-43mainly occur in the cytoplasm of anterior horn cells;(2) theexpression of GAP-43in high and middle dose of Glycyrrhizin groups weresignificantly higher than that of low dose and control groups;(3) the expression ofp75NTR in spinal cord start to increase and reach to peak after1day to2weeks ofsciatic nerve injury, and the expression of p75NTR mainly occur in the cytoplasmof anterior horn cells;(4) the expression of p75NTR in high and middle dose ofGlycyrrhizin groups were significantly lower than that of low dose and controlgroups.
3. The effect of Glycyrrhizin on nerve regeneration after injury
After intervention by different dose of Glycyrrhizin, the spinal cord segmentof Balb/c mice with sciatic nerve injury were stained by HE, double stain ofimproved Marsland and LFB method and observed under the microscope. Theapoptosis of spinal cord segment of mice with sciatic nerve injury were also testedby TUNEL method. And nerve conduction velocity and amplitude were tested byMedtronic Keypoint machine.The results showed that:(1) Glycyrrhizin decreasedthe secondary never injury and demyelination level;(2) the number of myelinated nerve fibers of Glycyrrhizin treated groups with uniform distribution and lessdemyelination level are more than that of control group;(3) Glycyrrhizin canimprove the structure, function, distribution of the muscle cells, and the musclecells treated by Glycyrrhizin arranged closely and has the larger cross-sectionalarea of muscle fibers with low proliferation of connective tissue;(4) the nervefunction improvement of Glycyrrhizin treated groups are better than control group;(5) Glycyrrhizin decreased the apoptosis of spinal cord segment of mice withsciatic nerve injury.
Conclusion:
1. Glycyrrhizin inhibited immune function and decrease the immune responseintensity of Balb/c mice in a dose dependent manner.
2. Glycyrrhizin increased the expression of GAP-43and decreased theexpression of p75NTR.
3. Glycyrrhizin improved the regeneration of injured peripheral nerve, whichis related to the inhibition of immune system and reduction of expression ofp75NTR by decreasing the secondary immune injury and uploading the expressionof GAP-43.
引文
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