CD147在神经病理性疼痛模型大鼠脊髓及背根神经节内的表达变化
摘要
神经病理性疼痛(Neuropathic pain)是指外周或中枢神经系统结构损害、功能障碍或者疾病所致的疼痛,它给患者带来极大的痛苦,但临床缺乏有效的治疗手段。CD147分子是一种广泛表达于人体多种组织的跨膜糖蛋白,属于免疫球蛋白超家族成员。CD147分子在多种肿瘤细胞和组织中高表达,通过诱导基质金属蛋白酶MMPs的分泌促进肿瘤的浸润、转移。同时, CD147与炎症反应如类风湿性关节炎,以及细胞、组织的分化和发育等密切相关。已有研究证明,MMPs通过细胞外基质蛋白的活化和裂解及促炎性细胞因子和趋化因子的作用参与了神经炎症的发生,在神经病理性疼痛的发生机制中起着非常重要的作用。作为MMPs的上游分子,CD147在神经病理性疼痛的发病机制中很可能扮演着重要角色。本研究应用免疫荧光组织化学染色和western blotting方法,观察脊神经选择性结扎(SNL模型)所致神经病理性疼痛条件下,大鼠脊髓(SC)和背根神经节(DRG)中的CD147的表达变化,为进一步研究CD147在神经病理性疼痛发病机制中的作用奠定基础。
1. CD147在神经病理性痛模型大鼠脊髓背角内的表达利用疼痛行为学评估大鼠脊神经选择性结扎模型。雄性SD大鼠80只随机分为2组,假手术组(Sham组)和脊神经选择性结扎组(SNL组)。结果显示:SNL组术后TWL, PWT均明显降低,其中SNL组PWL从术后第1天开始下降,第7天降至最低值,与Sham组相比(P < 0.01)有统计学差异;SNL组TWL从术后1天开始缩短,第3日即缩短到最低值,与Sham组相比(P < 0.01)有统计学差异。
免疫荧光化学染色结果显示:大鼠SNL模型后1、3、7d,术侧和对侧脊髓背角CD147表达均无明显变化,与Sham组相比无明显差异。
2. CD147在神经病理性痛模型大鼠背根神经节内的表达变化免疫荧光化学染色结果显示:大鼠SNL模型后1、3、7d分别观察到术侧背根神经节中CD147表达变化,SNL组从术后第1d即可发现CD147表达开始上调,第3d表达最强。GFAP活化程度同CD147表达相平行,在SNL模型后,背根神经节中GFAP的活化明显增强,在术后3d时活化最为强烈。Sham组各时间点表达无明显差别。
Western blotting结果提示:大鼠SNL模型后1、3、7d,术侧CD147表达明显上调,同免疫荧光组织化学染色结果一致,即术后1d即可出现CD147的表达上调(P < 0.05),术后3d表达最强,与对侧和Sham组相比有统计学意义(P < 0.01)。
结论:
1)大鼠SNL模型后,术侧后肢均产生机械性和热痛敏。机械性痛敏在术后第7d达到高峰,此后略有下降并持续到术后21d。热痛敏在术后第3d达到高峰,此后略有下降并持续到术后21d。
2)正常脊髓背角未见明显CD147表达,SNL模型后连续观察21d,亦未观察到明显表达变化。
3)正常背根神经节内可见少许背景CD147染色,但在SNL模型后,背根神经节中CD147的表达明显上调,且在术后3d时表达最为强烈,术后7天略有下降,但仍维持高水平表达。GFAP活化程度同CD147表达相平行,在SNL模型后,背根神经节中GFAP的活化明显增强,在术后3d时活化最为强烈。
4) CD147在背根神经节中的表达仅局限于细胞间质和神经节被膜,与神经元、星形胶质细胞、内皮细胞及成纤维细胞并无明显重叠。
5)以上结果提示: CD147在背根神经节的表达上调与机械性和热痛敏的产生以及GFAP的活化密切相关,即CD147很可能在神经病理性疼痛的发病机制中起着重要作用。
CD147, a member of the immunoglobulin superfamily, is widely expressed in various tissues, originally identified as a tumor surface protein capable of inducing matrix metalloproteinase (MMPs) expression in fibroblasts. While increased expression of CD147 occurs in many tumors, its expression is not limited to tumor cells. CD147 is a pleiotropic molecule that is critical in fetal development and retinal function and has been shown to play a role in thymic T cell development, as well as many neurological processes ranging from the development of the nervous system to the involvement in spatial learning and plaque formation within Alzheimer?s stricken brains.
It was documented that MMPs are invovled in the development and mantainance of neuropathic pain. We proposed a hypothesis that CD147, as a inducer of MMPs, may be directly involved in the development of neuropathic pain, and immune therapy targeted at this molecule might provide effictive means for the treatment of neuropathic pain.
To provide evidence that CD147 is invovled in the development of neuropathic pain, immunofluorescence staining and western blotting were used to observe the expression of CD147 in the spinal cord (SC) and dorsal root ganglion (DRG) in a neuropathic pain model --- spinal never ligation model (SNL).
1. The expression of CD147 in the SC of the rats after SNL. Behavioral tests were used to assess the success rate of the SNL models. Male SD rats (n=80) were randomly divided into two groups: sham operation group (Sham group) and SNL group. The results showed that the PWT and TWL in SNL group were significantly lower than that in the sham group after the surgery (P < 0.01). The PWT in SNL group reached a peak at day 7 and mantained at least untill day 21. The TWL in SNL group began to decline after 1d of surgery, reached a peak at day 3 and lasted to day 21. Immunofluoresence staining showed that there were no significant expression changes of CD147 between SNL and Sham group after 1,3,7d of SNL in the dorsal horn of the spinal cord.
2. The expression of CD147 in the DRG of the rats after SNL. Immunofluorescence staining and western blotting showed that the expression of CD147 was significantly upregulated in the DRG of SNL group, comparing with sham group. The upregulaed expression of CD147 in SNL group reached a peak at day 3 and maintained untill day 21. Activation of GFAP is paralleled with CD147 in the dorsal root ganglion in SNL models. The CD147 stauing was mainly located in the stroma. Double-staining indicated that CD147 staining is not overlaped with neurons, satellite cells, fibroblasts and endothelial cells.
Conclusions:
The present study indicated that the expression of CD147 was upregulated in the DRGs, but not in the spinal cord, after SNL. The upregulated expression of CD147 is paralleled with the activation of GFAP and the development of mechanical allodynia and thermal hyperalgesia after SNL, suggesting its potential role in the development of neuropathic pain.
1. CD147在神经病理性痛模型大鼠脊髓背角内的表达利用疼痛行为学评估大鼠脊神经选择性结扎模型。雄性SD大鼠80只随机分为2组,假手术组(Sham组)和脊神经选择性结扎组(SNL组)。结果显示:SNL组术后TWL, PWT均明显降低,其中SNL组PWL从术后第1天开始下降,第7天降至最低值,与Sham组相比(P < 0.01)有统计学差异;SNL组TWL从术后1天开始缩短,第3日即缩短到最低值,与Sham组相比(P < 0.01)有统计学差异。
免疫荧光化学染色结果显示:大鼠SNL模型后1、3、7d,术侧和对侧脊髓背角CD147表达均无明显变化,与Sham组相比无明显差异。
2. CD147在神经病理性痛模型大鼠背根神经节内的表达变化免疫荧光化学染色结果显示:大鼠SNL模型后1、3、7d分别观察到术侧背根神经节中CD147表达变化,SNL组从术后第1d即可发现CD147表达开始上调,第3d表达最强。GFAP活化程度同CD147表达相平行,在SNL模型后,背根神经节中GFAP的活化明显增强,在术后3d时活化最为强烈。Sham组各时间点表达无明显差别。
Western blotting结果提示:大鼠SNL模型后1、3、7d,术侧CD147表达明显上调,同免疫荧光组织化学染色结果一致,即术后1d即可出现CD147的表达上调(P < 0.05),术后3d表达最强,与对侧和Sham组相比有统计学意义(P < 0.01)。
结论:
1)大鼠SNL模型后,术侧后肢均产生机械性和热痛敏。机械性痛敏在术后第7d达到高峰,此后略有下降并持续到术后21d。热痛敏在术后第3d达到高峰,此后略有下降并持续到术后21d。
2)正常脊髓背角未见明显CD147表达,SNL模型后连续观察21d,亦未观察到明显表达变化。
3)正常背根神经节内可见少许背景CD147染色,但在SNL模型后,背根神经节中CD147的表达明显上调,且在术后3d时表达最为强烈,术后7天略有下降,但仍维持高水平表达。GFAP活化程度同CD147表达相平行,在SNL模型后,背根神经节中GFAP的活化明显增强,在术后3d时活化最为强烈。
4) CD147在背根神经节中的表达仅局限于细胞间质和神经节被膜,与神经元、星形胶质细胞、内皮细胞及成纤维细胞并无明显重叠。
5)以上结果提示: CD147在背根神经节的表达上调与机械性和热痛敏的产生以及GFAP的活化密切相关,即CD147很可能在神经病理性疼痛的发病机制中起着重要作用。
CD147, a member of the immunoglobulin superfamily, is widely expressed in various tissues, originally identified as a tumor surface protein capable of inducing matrix metalloproteinase (MMPs) expression in fibroblasts. While increased expression of CD147 occurs in many tumors, its expression is not limited to tumor cells. CD147 is a pleiotropic molecule that is critical in fetal development and retinal function and has been shown to play a role in thymic T cell development, as well as many neurological processes ranging from the development of the nervous system to the involvement in spatial learning and plaque formation within Alzheimer?s stricken brains.
It was documented that MMPs are invovled in the development and mantainance of neuropathic pain. We proposed a hypothesis that CD147, as a inducer of MMPs, may be directly involved in the development of neuropathic pain, and immune therapy targeted at this molecule might provide effictive means for the treatment of neuropathic pain.
To provide evidence that CD147 is invovled in the development of neuropathic pain, immunofluorescence staining and western blotting were used to observe the expression of CD147 in the spinal cord (SC) and dorsal root ganglion (DRG) in a neuropathic pain model --- spinal never ligation model (SNL).
1. The expression of CD147 in the SC of the rats after SNL. Behavioral tests were used to assess the success rate of the SNL models. Male SD rats (n=80) were randomly divided into two groups: sham operation group (Sham group) and SNL group. The results showed that the PWT and TWL in SNL group were significantly lower than that in the sham group after the surgery (P < 0.01). The PWT in SNL group reached a peak at day 7 and mantained at least untill day 21. The TWL in SNL group began to decline after 1d of surgery, reached a peak at day 3 and lasted to day 21. Immunofluoresence staining showed that there were no significant expression changes of CD147 between SNL and Sham group after 1,3,7d of SNL in the dorsal horn of the spinal cord.
2. The expression of CD147 in the DRG of the rats after SNL. Immunofluorescence staining and western blotting showed that the expression of CD147 was significantly upregulated in the DRG of SNL group, comparing with sham group. The upregulaed expression of CD147 in SNL group reached a peak at day 3 and maintained untill day 21. Activation of GFAP is paralleled with CD147 in the dorsal root ganglion in SNL models. The CD147 stauing was mainly located in the stroma. Double-staining indicated that CD147 staining is not overlaped with neurons, satellite cells, fibroblasts and endothelial cells.
Conclusions:
The present study indicated that the expression of CD147 was upregulated in the DRGs, but not in the spinal cord, after SNL. The upregulated expression of CD147 is paralleled with the activation of GFAP and the development of mechanical allodynia and thermal hyperalgesia after SNL, suggesting its potential role in the development of neuropathic pain.
引文
1. Soeren H. Sindrup , Marit Otto. Antidepressants in the Treatment of Neuropathic Pain. Basic&ClinicalPharmacology&Toxicology, 2004. 96:399-409.
2. Crown ED, Ye Z, Johnson KM, Xu GY, McAdoo DJ, Hulsebosch CE. Increases inthe activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with theexpression of at-level mechanical allodynia following spinal cord injury. ExpNeurol ,2006, 199:397–407.
3. Bryan C. Hains and Stephen G. Waxman. Activated Microglia Contribute to the Maintenance of Chronic Pain after Spinal Cord Injury. J Neuroscience, 2006,26(16): 4308-4317.
4. F.Y. Tanga, V. Raghavendra and J.A. DeLeo, Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain, Neurochem Int .2004, pp. 397–407.
5. Kawasaki, Y. et al. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat. Med. 2008, 14, 331–336
6. Biswas, C. Tumor cell stimulation of collagenase production by fibroblasts. Biochem. Biophys. Res. Commun , 1982, 109, 1026–1034.
7. Biswas, C., 1984. Collagenase stimulation in cocultures of human fibroblasts and human tumor cells. Cancer Lett. 24, 201–207.
8. M. Zimmermann, Pathobiology of neuropathic pain, Eur J Pharmacol 429 2001, pp. 23–37.
9. AttalN, Bouhassira D. Neuropathic pain: experimental advances and clinicalapplications. Rev Neurol (Paris), 2004, 160: 199~203.
10. Planjar-PrvanM, Bielen I, BarabaR, eta.l Pathophysiologic basis of the treatment of neurogenic pain. ActaMed Croatica, 2004, 58: 197~205.
11. Baron R. Neuropathic pain. The long path from mechanisms to mechanism-based treatmen.t Anaesthesist. 2000, 49: 373~386.
12. Baron R. Peripheralneuropathic pain: from mechanisms to symptoms. Clin JPain, 2000, 16: S12~20.
13. Julius, D. and Basbaum, A.I. Molecular mechanisms of nociception. Nature. 2001, 413, 203–210
14. Woolf, C.J. and Salter, M.W. Neuronal plasticity: increasing the gain in pain. Science. 2000,288, 1765–1769
15. Ji, R.R. et al. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci.2003,26, 696–705
16. Sommer, C. and Kress, M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci. Lett. 2004, 361,184–187
17. Schafers, M. et al. Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-a after spinal nerve ligation. J. Neurosci. 2003, 23, 3028–3038.
18. Kawasaki, Y. et al. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat. Med. 2008,14, 331–336.
19. Jin, X. and Gereau, R.W., IV. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-a. J. Neurosci. 2006, 26, 246–255.
20. Binshtok, A.M. et al. Nociceptors are interleukin-1b sensors. J. Neurosci.2008, 28, 14062–14073.
21. Coull, J.A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature.2005, 438, 1017–1021
22. Kawasaki, Y. et al. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1b, interleukin-6, and tumor necrosis factor-a in regulating synaptic and neuronal activity in the superficial spinal cord. J. Neurosci. 2008,28, 5189–5194
23. Watkins, L.R. et al. Glial activation: a driving force for pathological pain. Trends Neurosci. 2001,24, 450–455
24. Scholz, J. and Woolf, C.J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci. 2007, 10, 1361–1368
25. Milligan, E.D. and Watkins, L.R. Pathological and protective roles of glia in chronic pain. Nat. Rev. Neurosci. 2009,10, 23–36
26. Tsuda, M. et al. Neuropathic pain and spinal microglia: a big problem from molecules in ??small?? glia. Trends Neurosci. 2005,28, 101–107
27. Ji, R.R. et al. Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol. 2006,2, 259–269
28. Raghavendra, V. et al. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J. Pharmacol. Exp. Ther.2003,306, 624–630
29. Zhuang, Z.Y. et al. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance.J. Neurosci. 2006,26, 3551–3560
30. DeLeo, J.A. and Yezierski, R.P. The role of neuroinflammation and neuroimmune activation in persistent pain. Pain.2001,90, 1–6
31. Milligan, E.D. et al. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J. Neurosci. 2003, 23, 1026–1040
32. Sweitzer, S. et al. Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience 2001,103, 529–539
33. Guo, W. et al. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J. Neurosci. 2007, 27, 6006–6018
34. Jin, S.X. et al. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J. Neurosci. 2003,23, 4017–4022
35. Zhuang, Z.Y. et al. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic painmodel. Pain.2005,114, 149–159
36. Woolf, C.J. and Mannion, R.J. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet .1999, 353, 1959–1964
37. Dworkin, R.H. et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch.Neurol. 2003,60, 1524–1534
38. Ji, R.R. and Strichartz, G. Cell signaling and the genesis of neuropathic pain. Sci. STKE 2004, reE14
39. Kehlet, H. et al. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006, 367, 1618–1625
40. Polomano, R.C. and Bennett, G.J. Chemotherapy-evoked painful peripheralneuropathy. Pain Med. 2001, 2, 8–14
41. Bennett, G.J. and Xie, Y.K. A peripheralmononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain ,1988, 33, 87–107
42. Seltzer, Z. et al. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain.1990, 43, 205–218
43. Kim, S.H. and Chung, J.M. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain. 1992,50, 355–363
44. Decosterd, I. and Woolf, C.J. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain.2000, 87, 149–158
45. Hu, J. et al. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat. Rev. Drug Discov. 2007, 6, 480–498
46. Yong, V.W. et al. The promise of minocycline in neurology. Lancet Neurol. 2004 ,3, 744–751
47. Murata, Y. et al. Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke. 2008,39, 3372–3377
48. Murphy, G. and Willenbrock, F. Tissue inhibitors of matrix metalloendopeptidases. Methods Enzymol. 1995,248, 496–510
49. Rosenberg, G.A. Matrix metalloproteinases in neuroinflammation. Glia. 2002,39, 279–291
50. Parks, W.C. et al. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 2004, 4, 617–629
51. Wang, X. et al. Effects of matrix metalloproteinase-9 gene knockout onmorphological and motor outcomes after traumatic brain injury.J. Neurosci. 2000,20, 7037–7042
52. Zhao, B.Q. et al. Role of matrix metalloproteinases in delayed corticalresponses after stroke. Nat. Med. 2006,12, 441–445
53. Clark, A.K. et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl. Acad. Sci. U. S. A. 2007,104,10655–10660
54. Komori, K. et al. Absence of mechanical allodynia and Ab-fiber sprouting after sciatic nerve injury in mice lacking membrane-type 5 matrix metalloproteinase. FEBS Lett. 2004 ,557, 125–128
55. Igakura T, Kadomatsu K, Taguchi O, et al. Roles of basigin, a member of the immunoglobulin superfamily, in behavior as to an irritating odor, lymphocyte response, and blood- brain barrier.Biochem Biophys Res Commun, 1996,224:33.
56. Saxena DK, Oh- Oka T, Kadomatsu K, et al. Behaviour of a sperm surface transmembrane glycoprotein basigin during epididymal maturation and its role in fertilization in mice. Reproduction, 2002, 123:435.
57. Naruhashi K, Kadomatsu K, Igakura T, et al. Abnormalities of sensory and memory functions in mice lacking Bsg gene. Biochem Biophys Res Commun, 1997,236:733.
58. Kaname T, Miyauchi T, Kuwano A, et al. Mapping basigin(BSG), a member of the immunoglobulin superfamily, to 19p13.3. Cytogenet Cell Genet, 1993,64:195
59. Ellis SM, Nabeshima K, Biswas C. Monoclonal antibody preparation and purification of a tumor cell collagenase- stimulatory factor. Cancer Res, 1989,49:3385
60. Guo H, Majmudar G, Jensen TC, et al. Characterization of the human EMMPR IN, a tumor cell surface inducer of matrix metalloproteinases. Gene, 1998,220(122):99
61. Sun J, Hemler ME. Regulation of MMP- 1 and MMP- 2 production throughCD147 /extracellular matrix metalloproteinase inducer interactions. Cancer Res, 2001,61:2276
62. Nehme CL, Fayos BE,Bartles JR. Distribution of the integral plasma membrane glycoprotein CE9 (MRC OX- 47) among rat tissues and its induction by diverse stimuli of metabolic activation.Biochem J, 1995,310:693
63. Papoutsi M, Kurz H, Schachtelec C, et al. Induction of the blood brain barrier marker neurothelin /HT7 in endothelial cell by a variety of tumors in chick embryos. Histochem Cell Biol, 2000,113 (2):105.
64. Kanekura T, Chen X, Kanzaki T. Basigin(CD147) is expressed on melanoma cells and induces tumor cell invasion by stimulating production of matrix metalloproteinases by fibroblasts. Int J Cancer, 2002,99(4):520
65. Dalberg K, Eriksson E, Eaberg U, et al. Gelatinase A, membrane type- matrix metalloproteinase, and extracellular matrix metalloproteinase inducer mRNA expression: correlation with invasive growth of breast cancer. World J Surg, 2000,24(3):334
66. Zucker S, Hymowitz M, Rollo EE, et al. Tumorigenic potential of extracellular matrix metalloproteinase inducer. Am J Pathol, 2001,158:1921
67. Caudroy S, Polette M, Tournier JM, et al. Expression of the extracellular matrix metalloproteinase inducer(EMMPRIN) and the matrix metalloproteinase- 2 in broncho pulmonary and breast lesions. J Histochem. Cytochem, 1999,47:1575
68. Thorns C, Feller AC, Merz H. EMMPRIN(CD147) is expressed in Hodgkin' s lymphoma and anaplastic large cell lymphoma. Anticancer Res, 2002,22:1983
69. Polette M, Gilles C, Marchand V, et al. Tumor collagenase stimulatory factor(TCSF) expression and localization in human lung and breast cancers. J Histochem Cytochem, 1997,45:703
70. Kanekura T, Chen X, Kanzaki T. Basigin(CD147) is expressed on melanoma cells and induces tumor cell invasion by stimulating production of matrix metalloproteinases by fibroblasts. Int J Cancer, 2002,99:520
71. Bordador LC, Li X, Toole B, et al. Expression of EMMPRIN by oral squamous cell carcinoma. Int J Cancer, 2000,85:347.
72. Caudroy S, Polette M, Nawrocki- Raby B, et al. EMMPRIN- mediated MMP regulation in tumor and endothelial cells. Clin Exp Metastasis, 2002,19:697
73. Menashi S, Serova M, Ma L, et al. Regulation of extracellular matrix metalloproteinase inducer and matrix metalloproteinase expression by amphiregulin in transformed human breast epithelial cells. Cancer Res, 2003,63:7575
74. Li R, Huang L, Guo H, et al. Basigin(murine EMMPRIN) stimulates matrix metalloproteinase production by fibroblasts. J CellPhysiol, 2001,186:371.
2. Crown ED, Ye Z, Johnson KM, Xu GY, McAdoo DJ, Hulsebosch CE. Increases inthe activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with theexpression of at-level mechanical allodynia following spinal cord injury. ExpNeurol ,2006, 199:397–407.
3. Bryan C. Hains and Stephen G. Waxman. Activated Microglia Contribute to the Maintenance of Chronic Pain after Spinal Cord Injury. J Neuroscience, 2006,26(16): 4308-4317.
4. F.Y. Tanga, V. Raghavendra and J.A. DeLeo, Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain, Neurochem Int .2004, pp. 397–407.
5. Kawasaki, Y. et al. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat. Med. 2008, 14, 331–336
6. Biswas, C. Tumor cell stimulation of collagenase production by fibroblasts. Biochem. Biophys. Res. Commun , 1982, 109, 1026–1034.
7. Biswas, C., 1984. Collagenase stimulation in cocultures of human fibroblasts and human tumor cells. Cancer Lett. 24, 201–207.
8. M. Zimmermann, Pathobiology of neuropathic pain, Eur J Pharmacol 429 2001, pp. 23–37.
9. AttalN, Bouhassira D. Neuropathic pain: experimental advances and clinicalapplications. Rev Neurol (Paris), 2004, 160: 199~203.
10. Planjar-PrvanM, Bielen I, BarabaR, eta.l Pathophysiologic basis of the treatment of neurogenic pain. ActaMed Croatica, 2004, 58: 197~205.
11. Baron R. Neuropathic pain. The long path from mechanisms to mechanism-based treatmen.t Anaesthesist. 2000, 49: 373~386.
12. Baron R. Peripheralneuropathic pain: from mechanisms to symptoms. Clin JPain, 2000, 16: S12~20.
13. Julius, D. and Basbaum, A.I. Molecular mechanisms of nociception. Nature. 2001, 413, 203–210
14. Woolf, C.J. and Salter, M.W. Neuronal plasticity: increasing the gain in pain. Science. 2000,288, 1765–1769
15. Ji, R.R. et al. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci.2003,26, 696–705
16. Sommer, C. and Kress, M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci. Lett. 2004, 361,184–187
17. Schafers, M. et al. Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-a after spinal nerve ligation. J. Neurosci. 2003, 23, 3028–3038.
18. Kawasaki, Y. et al. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat. Med. 2008,14, 331–336.
19. Jin, X. and Gereau, R.W., IV. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-a. J. Neurosci. 2006, 26, 246–255.
20. Binshtok, A.M. et al. Nociceptors are interleukin-1b sensors. J. Neurosci.2008, 28, 14062–14073.
21. Coull, J.A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature.2005, 438, 1017–1021
22. Kawasaki, Y. et al. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1b, interleukin-6, and tumor necrosis factor-a in regulating synaptic and neuronal activity in the superficial spinal cord. J. Neurosci. 2008,28, 5189–5194
23. Watkins, L.R. et al. Glial activation: a driving force for pathological pain. Trends Neurosci. 2001,24, 450–455
24. Scholz, J. and Woolf, C.J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci. 2007, 10, 1361–1368
25. Milligan, E.D. and Watkins, L.R. Pathological and protective roles of glia in chronic pain. Nat. Rev. Neurosci. 2009,10, 23–36
26. Tsuda, M. et al. Neuropathic pain and spinal microglia: a big problem from molecules in ??small?? glia. Trends Neurosci. 2005,28, 101–107
27. Ji, R.R. et al. Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol. 2006,2, 259–269
28. Raghavendra, V. et al. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J. Pharmacol. Exp. Ther.2003,306, 624–630
29. Zhuang, Z.Y. et al. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance.J. Neurosci. 2006,26, 3551–3560
30. DeLeo, J.A. and Yezierski, R.P. The role of neuroinflammation and neuroimmune activation in persistent pain. Pain.2001,90, 1–6
31. Milligan, E.D. et al. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J. Neurosci. 2003, 23, 1026–1040
32. Sweitzer, S. et al. Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience 2001,103, 529–539
33. Guo, W. et al. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J. Neurosci. 2007, 27, 6006–6018
34. Jin, S.X. et al. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J. Neurosci. 2003,23, 4017–4022
35. Zhuang, Z.Y. et al. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic painmodel. Pain.2005,114, 149–159
36. Woolf, C.J. and Mannion, R.J. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet .1999, 353, 1959–1964
37. Dworkin, R.H. et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch.Neurol. 2003,60, 1524–1534
38. Ji, R.R. and Strichartz, G. Cell signaling and the genesis of neuropathic pain. Sci. STKE 2004, reE14
39. Kehlet, H. et al. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006, 367, 1618–1625
40. Polomano, R.C. and Bennett, G.J. Chemotherapy-evoked painful peripheralneuropathy. Pain Med. 2001, 2, 8–14
41. Bennett, G.J. and Xie, Y.K. A peripheralmononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain ,1988, 33, 87–107
42. Seltzer, Z. et al. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain.1990, 43, 205–218
43. Kim, S.H. and Chung, J.M. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain. 1992,50, 355–363
44. Decosterd, I. and Woolf, C.J. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain.2000, 87, 149–158
45. Hu, J. et al. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat. Rev. Drug Discov. 2007, 6, 480–498
46. Yong, V.W. et al. The promise of minocycline in neurology. Lancet Neurol. 2004 ,3, 744–751
47. Murata, Y. et al. Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke. 2008,39, 3372–3377
48. Murphy, G. and Willenbrock, F. Tissue inhibitors of matrix metalloendopeptidases. Methods Enzymol. 1995,248, 496–510
49. Rosenberg, G.A. Matrix metalloproteinases in neuroinflammation. Glia. 2002,39, 279–291
50. Parks, W.C. et al. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 2004, 4, 617–629
51. Wang, X. et al. Effects of matrix metalloproteinase-9 gene knockout onmorphological and motor outcomes after traumatic brain injury.J. Neurosci. 2000,20, 7037–7042
52. Zhao, B.Q. et al. Role of matrix metalloproteinases in delayed corticalresponses after stroke. Nat. Med. 2006,12, 441–445
53. Clark, A.K. et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl. Acad. Sci. U. S. A. 2007,104,10655–10660
54. Komori, K. et al. Absence of mechanical allodynia and Ab-fiber sprouting after sciatic nerve injury in mice lacking membrane-type 5 matrix metalloproteinase. FEBS Lett. 2004 ,557, 125–128
55. Igakura T, Kadomatsu K, Taguchi O, et al. Roles of basigin, a member of the immunoglobulin superfamily, in behavior as to an irritating odor, lymphocyte response, and blood- brain barrier.Biochem Biophys Res Commun, 1996,224:33.
56. Saxena DK, Oh- Oka T, Kadomatsu K, et al. Behaviour of a sperm surface transmembrane glycoprotein basigin during epididymal maturation and its role in fertilization in mice. Reproduction, 2002, 123:435.
57. Naruhashi K, Kadomatsu K, Igakura T, et al. Abnormalities of sensory and memory functions in mice lacking Bsg gene. Biochem Biophys Res Commun, 1997,236:733.
58. Kaname T, Miyauchi T, Kuwano A, et al. Mapping basigin(BSG), a member of the immunoglobulin superfamily, to 19p13.3. Cytogenet Cell Genet, 1993,64:195
59. Ellis SM, Nabeshima K, Biswas C. Monoclonal antibody preparation and purification of a tumor cell collagenase- stimulatory factor. Cancer Res, 1989,49:3385
60. Guo H, Majmudar G, Jensen TC, et al. Characterization of the human EMMPR IN, a tumor cell surface inducer of matrix metalloproteinases. Gene, 1998,220(122):99
61. Sun J, Hemler ME. Regulation of MMP- 1 and MMP- 2 production throughCD147 /extracellular matrix metalloproteinase inducer interactions. Cancer Res, 2001,61:2276
62. Nehme CL, Fayos BE,Bartles JR. Distribution of the integral plasma membrane glycoprotein CE9 (MRC OX- 47) among rat tissues and its induction by diverse stimuli of metabolic activation.Biochem J, 1995,310:693
63. Papoutsi M, Kurz H, Schachtelec C, et al. Induction of the blood brain barrier marker neurothelin /HT7 in endothelial cell by a variety of tumors in chick embryos. Histochem Cell Biol, 2000,113 (2):105.
64. Kanekura T, Chen X, Kanzaki T. Basigin(CD147) is expressed on melanoma cells and induces tumor cell invasion by stimulating production of matrix metalloproteinases by fibroblasts. Int J Cancer, 2002,99(4):520
65. Dalberg K, Eriksson E, Eaberg U, et al. Gelatinase A, membrane type- matrix metalloproteinase, and extracellular matrix metalloproteinase inducer mRNA expression: correlation with invasive growth of breast cancer. World J Surg, 2000,24(3):334
66. Zucker S, Hymowitz M, Rollo EE, et al. Tumorigenic potential of extracellular matrix metalloproteinase inducer. Am J Pathol, 2001,158:1921
67. Caudroy S, Polette M, Tournier JM, et al. Expression of the extracellular matrix metalloproteinase inducer(EMMPRIN) and the matrix metalloproteinase- 2 in broncho pulmonary and breast lesions. J Histochem. Cytochem, 1999,47:1575
68. Thorns C, Feller AC, Merz H. EMMPRIN(CD147) is expressed in Hodgkin' s lymphoma and anaplastic large cell lymphoma. Anticancer Res, 2002,22:1983
69. Polette M, Gilles C, Marchand V, et al. Tumor collagenase stimulatory factor(TCSF) expression and localization in human lung and breast cancers. J Histochem Cytochem, 1997,45:703
70. Kanekura T, Chen X, Kanzaki T. Basigin(CD147) is expressed on melanoma cells and induces tumor cell invasion by stimulating production of matrix metalloproteinases by fibroblasts. Int J Cancer, 2002,99:520
71. Bordador LC, Li X, Toole B, et al. Expression of EMMPRIN by oral squamous cell carcinoma. Int J Cancer, 2000,85:347.
72. Caudroy S, Polette M, Nawrocki- Raby B, et al. EMMPRIN- mediated MMP regulation in tumor and endothelial cells. Clin Exp Metastasis, 2002,19:697
73. Menashi S, Serova M, Ma L, et al. Regulation of extracellular matrix metalloproteinase inducer and matrix metalloproteinase expression by amphiregulin in transformed human breast epithelial cells. Cancer Res, 2003,63:7575
74. Li R, Huang L, Guo H, et al. Basigin(murine EMMPRIN) stimulates matrix metalloproteinase production by fibroblasts. J CellPhysiol, 2001,186:371.