硫酸軟骨素酶ABC對大鼠脊髓損傷后軸突髓鞘化和膠質瘢痕的影響_《中國修復重建外科雜志》

作者：

張濤 , 沈憶新 , 蘆磊磊 , 范志海 , 霍偉偉

蘇州大學附屬第二醫院骨科（江蘇蘇州，215004）;

關鍵詞：

脊髓損傷硫酸軟骨素酶ABC 髓鞘堿性蛋白生長相關蛋白43 膠質纖維酸性蛋白大鼠

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目的探討硫酸軟骨素酶ABC（chondroitinase ABC，ChABC）對大鼠脊髓損傷后軸突再生、髓鞘化和膠質瘢痕形成的影響。方法將72只雄性SD大鼠隨機分為ChABC治療組（A組）、生理鹽水治療組（B組）和假手術組（C組），每組24只。A、B組采用改良Allen撞擊法制作大鼠T9中度脊髓損傷模型，分別在傷后1 h和之后連續7 d每天1次經蛛網膜下腔注射6 μL濃度為1 U/mL ChABC和生理鹽水；C組僅打開椎管，不損傷脊髓。術后1、7、14、28 d，采用BBB評分評定大鼠后肢運動功能恢復情況；取出損傷段脊髓組織，行HE染色和Nissl染色，并采用免疫組織化學染色檢測髓鞘堿性蛋白（myelin basic protein，MBP）、生長相關蛋白43（growth associated protein 43，GAP-43）和膠質纖維酸性蛋白（glial fibrillary acidic protein，GFAP）的變化情況。結果術后各時間點C組BBB評分均明顯高于A、B組（P lt; 0.05）；術后隨時間延長A、B組BBB評分逐漸增加，14、28 d時A組BBB評分明顯優于B組（P lt; 0.05）。HE和Nissl染色顯示術后各時間點A組脊髓組織形態和神經元數量均優于B組。術后各時間點A、B組MBP和GAP-43的積分吸光度（IA）值及GFAP染色陽性面積均高于C組（P lt; 0.05），術后7、14、28 d時A組MBP和GAP-43的IA值明顯高于B組（P lt; 0.05），GFAP染色陽性面積明顯小于B組（P lt; 0.05）。結論ChABC能有效改善大鼠脊髓損傷區域微環境，提高MBP和GAP-43表達并抑制GFAP表達，促進軸突再生與髓鞘化，抑制膠質瘢痕形成，促進神經功能恢復。

引用本文： 張濤,沈憶新,蘆磊磊,范志海,霍偉偉. 硫酸軟骨素酶ABC對大鼠脊髓損傷后軸突髓鞘化和膠質瘢痕的影響. 中國修復重建外科雜志, 2013, 27(2): 145-150. doi: 復制

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2.	Cakir E, Usul H, Peksoylu B, et al. Effect of citicoline on experimental spinal cord injury. J Clin Neurosci, 2005, 12(8): 923-926.
3.	Yaksh TL, Kohl RL, Rudy TA. Induction of tolerance and withdrawal in rats receiving morp- hine in the spinal subarachnoid space. Eur J Pharmacol, 1977, 42(3): 275-284.
4.	Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma, 1995, 12(1): 1-21.
5.	Siebert JR, Osterhout DJ. The inhibitory effects of chondroitin sulfate proteog- lycans on oligodendrocytes. J Neurochem, 2011, 119(1): 176-188.
6.	Monnier PP, Sierra A, Schwab JM, et al. The Rho/ROCK pathway mediates neurite growth- inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar. Mol Cell Neurosci, 2003, 22(3): 319-330.
7.	Ughrin YM, Chen ZJ, Levine JM. Multiple regions of the NG2 proteoglycan inhibit neurite growth and induce growth cone collapse. J Neurosci, 2003, 23(1): 175-186.
8.	Caggiano AO, Zimber MP, Ganguly A, et al. Chondroitinase ABC improves locomotion and bladder function following contusion injury of the rat spinal cord. J Neurotrauma, 2005, 22(2): 226-239.
9.	Tester NJ, Howland DR. Chondroitinase ABC improves basic and skilled locomotion in spinal cord injured cats. Exp Neurol, 2008, 209(2): 483-496.
10.	Lee H, McKeon RJ, Bellamkonda RV. Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury. Proc Natl Acad Sci U S A, 2010, 107(8): 3340-3345.
11.	Bradbury EJ, Carter LM. Manipulating the glial scar: Chondroitinase ABC as a therapy for spinal cord injury. Brain Res Bull, 2011, 84(4-5): 306-316.
12.	Harauz G, Ishiyama N, Hill CM, et al. Myelin basic protein-diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis. Micron, 2004, 35(7): 503-542.
13.	吳波, 孫磊, 任先軍. 少突膠質前體細胞移植治療對大鼠脊髓損傷軸突髓鞘化的影響. 中華創傷雜志, 2010, 26(11): 1035-1039.
14.	Atkinson S, Li YQ, Wong CS. Changes in oligodendrocytes and myelin gene expression after radiation in the rodent spinal cord. Int J Radiat Oncol Biol Phys, 2003, 57(4): 1093-1100．.
15.	Fukuda A, Fukuda H, Swanpalmer J, et al. Age-dependent sensitivity of the developing brain to irradiation is correlated with the number and Vulnerability of progenitor cells. J Neurochem, 2005, 92(3): 569-584.
16.	Kotter MR, Li WW, Zhao C, et al. Myelin impairs CNS remyelination by inhibiting oligoden- drocyte precursor cell differentiation. J Neurosci, 2006, 26(1): 328-332.
17.	徐紀偉, 孫丹華, 劉喜民, 等. 硫酸軟骨素酶ABC對大鼠脊髓損傷后生長相關蛋白43和神經膠質纖維酸性蛋白的影響. 中國修復重建外科雜志, 2010, 24(10): 1212-1216.
18.	Metz GA, Schwab ME. Behavioral characterization in a comprehensive mouse test battery reveals motor and sensory impairments in growth-associated protein-43 null mutant mice. Neuroscience, 2004, 129(3): 563-574.
19.	Shen Y, Mani S, Donovan SL, et al. Growth-associated protein-43 is required for commissural axon guidance in the developing vertebrate nervous system. J Neurosci, 2002, 22(1): 239-247.
20.	Horner PJ, Gage FH. Regenerating the damaged central nervous system. Nature, 2000, 407(6807): 963-970.
21.	Rhodes KE, Moon LD, Fawcett JW. Inhibiting cell proliferation during formation of the glial scar: effect on axon regeneration in the CNS. Neuroscience, 2003, 120(1): 41-56.
22.	Tang X, Davies JE, Davies SJ. Changes in distribution, cell associations, and protein expression levels of NG2, neurocan, phosphacan, brevican, verslcan V2, and tenascin-C during acute to chronic maturation of spinal cord scar tissue . J Neurosci Res, 2003, 71 (3): 427-444.
23.	Wang XX, Hasan O, Arzeno A, et al. Axonal regeneration induced by blockade of glial inhibitors coupled with activation of intrinsic neuronal growth pathways. Exp Neurol, 2012, 237 (1): 55-69.
24.	Starkey ML, Bartus K, Barritt AW, et al. Chondroitinase ABC promotes compensatory sprouting of the intact corticospinal tract and recovery of forelimb function following unilateral pyramidotomy in adult mice. Eur J Neurosci, 2012. [Epub ahead of print].
25.	Bosch KD, Bradbury EJ, Verhaagen J, et al. Chondroitinase ABC promotes plasticity of spinal reflexes following peripheral nerve injury. Exp Neurol, 2012, 238 (1): 64-78.

1. Cafferty WB, Yang SH, Duffy PJ, et al. Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans. J Neurosci, 2007, 27(9): 2176-2185.
2. Cakir E, Usul H, Peksoylu B, et al. Effect of citicoline on experimental spinal cord injury. J Clin Neurosci, 2005, 12(8): 923-926.
3. Yaksh TL, Kohl RL, Rudy TA. Induction of tolerance and withdrawal in rats receiving morp- hine in the spinal subarachnoid space. Eur J Pharmacol, 1977, 42(3): 275-284.
4. Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma, 1995, 12(1): 1-21.
5. Siebert JR, Osterhout DJ. The inhibitory effects of chondroitin sulfate proteog- lycans on oligodendrocytes. J Neurochem, 2011, 119(1): 176-188.
6. Monnier PP, Sierra A, Schwab JM, et al. The Rho/ROCK pathway mediates neurite growth- inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar. Mol Cell Neurosci, 2003, 22(3): 319-330.
7. Ughrin YM, Chen ZJ, Levine JM. Multiple regions of the NG2 proteoglycan inhibit neurite growth and induce growth cone collapse. J Neurosci, 2003, 23(1): 175-186.
8. Caggiano AO, Zimber MP, Ganguly A, et al. Chondroitinase ABC improves locomotion and bladder function following contusion injury of the rat spinal cord. J Neurotrauma, 2005, 22(2): 226-239.
9. Tester NJ, Howland DR. Chondroitinase ABC improves basic and skilled locomotion in spinal cord injured cats. Exp Neurol, 2008, 209(2): 483-496.
10. Lee H, McKeon RJ, Bellamkonda RV. Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury. Proc Natl Acad Sci U S A, 2010, 107(8): 3340-3345.
11. Bradbury EJ, Carter LM. Manipulating the glial scar: Chondroitinase ABC as a therapy for spinal cord injury. Brain Res Bull, 2011, 84(4-5): 306-316.
12. Harauz G, Ishiyama N, Hill CM, et al. Myelin basic protein-diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis. Micron, 2004, 35(7): 503-542.
13. 吳波, 孫磊, 任先軍. 少突膠質前體細胞移植治療對大鼠脊髓損傷軸突髓鞘化的影響. 中華創傷雜志, 2010, 26(11): 1035-1039.
14. Atkinson S, Li YQ, Wong CS. Changes in oligodendrocytes and myelin gene expression after radiation in the rodent spinal cord. Int J Radiat Oncol Biol Phys, 2003, 57(4): 1093-1100．.
15. Fukuda A, Fukuda H, Swanpalmer J, et al. Age-dependent sensitivity of the developing brain to irradiation is correlated with the number and Vulnerability of progenitor cells. J Neurochem, 2005, 92(3): 569-584.
16. Kotter MR, Li WW, Zhao C, et al. Myelin impairs CNS remyelination by inhibiting oligoden- drocyte precursor cell differentiation. J Neurosci, 2006, 26(1): 328-332.
17. 徐紀偉, 孫丹華, 劉喜民, 等. 硫酸軟骨素酶ABC對大鼠脊髓損傷后生長相關蛋白43和神經膠質纖維酸性蛋白的影響. 中國修復重建外科雜志, 2010, 24(10): 1212-1216.
18. Metz GA, Schwab ME. Behavioral characterization in a comprehensive mouse test battery reveals motor and sensory impairments in growth-associated protein-43 null mutant mice. Neuroscience, 2004, 129(3): 563-574.
19. Shen Y, Mani S, Donovan SL, et al. Growth-associated protein-43 is required for commissural axon guidance in the developing vertebrate nervous system. J Neurosci, 2002, 22(1): 239-247.
20. Horner PJ, Gage FH. Regenerating the damaged central nervous system. Nature, 2000, 407(6807): 963-970.
21. Rhodes KE, Moon LD, Fawcett JW. Inhibiting cell proliferation during formation of the glial scar: effect on axon regeneration in the CNS. Neuroscience, 2003, 120(1): 41-56.
22. Tang X, Davies JE, Davies SJ. Changes in distribution, cell associations, and protein expression levels of NG2, neurocan, phosphacan, brevican, verslcan V2, and tenascin-C during acute to chronic maturation of spinal cord scar tissue . J Neurosci Res, 2003, 71 (3): 427-444.
23. Wang XX, Hasan O, Arzeno A, et al. Axonal regeneration induced by blockade of glial inhibitors coupled with activation of intrinsic neuronal growth pathways. Exp Neurol, 2012, 237 (1): 55-69.
24. Starkey ML, Bartus K, Barritt AW, et al. Chondroitinase ABC promotes compensatory sprouting of the intact corticospinal tract and recovery of forelimb function following unilateral pyramidotomy in adult mice. Eur J Neurosci, 2012. [Epub ahead of print].
25. Bosch KD, Bradbury EJ, Verhaagen J, et al. Chondroitinase ABC promotes plasticity of spinal reflexes following peripheral nerve injury. Exp Neurol, 2012, 238 (1): 64-78.

《中國修復重建外科雜志》

硫酸軟骨素酶ABC對大鼠脊髓損傷后軸突髓鞘化和膠質瘢痕的影響

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《中國修復重建外科雜志》

硫酸軟骨素酶ABC對大鼠脊髓損傷后軸突髓鞘化和膠質瘢痕的影響

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