Niaspan促进1型糖尿病大鼠脑卒中后神经轴索重塑
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摘要
目的：
探讨Ⅰ型糖尿病大鼠脑梗死后双侧大脑皮层神经轴索的可塑性变化以及长期应用Nispan对其影响。
方法：
应用链脲佐菌素腹腔注射成年Wistar大鼠诱导的1型糖尿病大鼠模型,实施大脑中动脉闭塞手术,形成糖尿病缺血性脑卒中模型,术后24小时给予40mg/kgNiaspan／生理盐水治疗,每日1次,共28天。经健侧大脑皮层注射生物素葡聚糖胺(BDA)顺行性标记神经轴索,评价患侧大脑皮层区域神经轴索芽生；观察卒中后大鼠神经功能恢复情况,以及SMI-31、Bielschowsky silver、突触素和Angl表达水平的改变；在体外实验中原代神经元细胞培养,培养基中加入不同浓度葡萄糖及干预药物,观察神经轴索芽生的长度。
结果：
与对照组相比,Niaspan对脑卒中后1型糖尿病大鼠治疗可以明显改善卒中的神经功能恢复,提高缺血脑组织SMI-3、SMI-31、Bielschowsky silver、突触素的表达水平(p<0.05)。在1型糖尿病卒中大鼠模型中,借助于BDA顺行性标记神经轴索及其终末端方法,显示Niaspan可以显著增加患侧半球运动皮层神经轴索的密度。烟酸可以明显增加高糖环境中培养的初级神经元细胞血管生成素-1的表达水平(p<0.05)；同时,抗-血管生成素-1抗体可以轻微降低高糖环境中培养的初级神经元细胞烟酸诱导的轴突外生(p=0.06)。
结论：
Niaspan对缺血脑组织的治疗能够促进神经轴索的重塑,进而改善大鼠卒中后神经功能的恢复；Ang-1对Niaspan诱导的1型糖尿病大鼠卒中后神经轴索的重塑起到一定作用。
Objective:We investigated axonal plasticity in the bilateral motor cortices and the long term therapeutic effect of Niaspan on axonal remodeling after stroke in type-1diabetic (T1DM) rats.
Methods:T1DM was induced in young adult male Wistar rats via injection of streptozotocin. T1DM rats were subjected to2h transient middle cerebral artery occlusion (MCAo) and were treated with40mg/kg Niaspan or saline starting24h after MCAo daily for28days. Anterograde tracing using biotinylated dextran amine (BDA) injected into the contralateral motor cortex was performed to assess axonal sprouting in the ipsilateral motor cortex area. Functional outcome, SMI-31(a pan-axonal microfilament marker), Bielshowsky silver and Synaptophysin expression were measured.
Results:Niaspan treatment of stroke in TIDM-MCAo rats significantly improved functional outcome after stroke and increased SMI-31, Bielshowsky silver and Synaptophysin expression in the ischemic brain compared to saline treated TIDM-MCAo rats (p<0.05). Using BDA to anterograde label axons and terminals, Niaspan treatment significantly increased axonal density in ipsilateral motor cortex in TIDM-MCAo rats (p<0.05. n=7/group). Using a Primary cortical neuron (PCN) culture, Niacin treatment of PCN significantly increased Ang1expression under high glucose condition. Niacin and Ang1significantly increased neurite outgrowth, and Anti-Angl antibody marginally attenuated Niacin induced neurite outgrowth (p=0.06, n=6/group) in cultured PCN under high glucose condition.
Conclusion:Niaspan treatment increased ischemic brain Ang1expression and promoted axonal remodeling in the ischemic brain as well as improved functional outcome after stroke. Ang1may partially contribute to Niaspan-induced axonal remodeling after stroke in T1DM-rats.
探讨Ⅰ型糖尿病大鼠脑梗死后双侧大脑皮层神经轴索的可塑性变化以及长期应用Nispan对其影响。
方法：
应用链脲佐菌素腹腔注射成年Wistar大鼠诱导的1型糖尿病大鼠模型,实施大脑中动脉闭塞手术,形成糖尿病缺血性脑卒中模型,术后24小时给予40mg/kgNiaspan／生理盐水治疗,每日1次,共28天。经健侧大脑皮层注射生物素葡聚糖胺(BDA)顺行性标记神经轴索,评价患侧大脑皮层区域神经轴索芽生；观察卒中后大鼠神经功能恢复情况,以及SMI-31、Bielschowsky silver、突触素和Angl表达水平的改变；在体外实验中原代神经元细胞培养,培养基中加入不同浓度葡萄糖及干预药物,观察神经轴索芽生的长度。
结果：
与对照组相比,Niaspan对脑卒中后1型糖尿病大鼠治疗可以明显改善卒中的神经功能恢复,提高缺血脑组织SMI-3、SMI-31、Bielschowsky silver、突触素的表达水平(p<0.05)。在1型糖尿病卒中大鼠模型中,借助于BDA顺行性标记神经轴索及其终末端方法,显示Niaspan可以显著增加患侧半球运动皮层神经轴索的密度。烟酸可以明显增加高糖环境中培养的初级神经元细胞血管生成素-1的表达水平(p<0.05)；同时,抗-血管生成素-1抗体可以轻微降低高糖环境中培养的初级神经元细胞烟酸诱导的轴突外生(p=0.06)。
结论：
Niaspan对缺血脑组织的治疗能够促进神经轴索的重塑,进而改善大鼠卒中后神经功能的恢复；Ang-1对Niaspan诱导的1型糖尿病大鼠卒中后神经轴索的重塑起到一定作用。
Objective:We investigated axonal plasticity in the bilateral motor cortices and the long term therapeutic effect of Niaspan on axonal remodeling after stroke in type-1diabetic (T1DM) rats.
Methods:T1DM was induced in young adult male Wistar rats via injection of streptozotocin. T1DM rats were subjected to2h transient middle cerebral artery occlusion (MCAo) and were treated with40mg/kg Niaspan or saline starting24h after MCAo daily for28days. Anterograde tracing using biotinylated dextran amine (BDA) injected into the contralateral motor cortex was performed to assess axonal sprouting in the ipsilateral motor cortex area. Functional outcome, SMI-31(a pan-axonal microfilament marker), Bielshowsky silver and Synaptophysin expression were measured.
Results:Niaspan treatment of stroke in TIDM-MCAo rats significantly improved functional outcome after stroke and increased SMI-31, Bielshowsky silver and Synaptophysin expression in the ischemic brain compared to saline treated TIDM-MCAo rats (p<0.05). Using BDA to anterograde label axons and terminals, Niaspan treatment significantly increased axonal density in ipsilateral motor cortex in TIDM-MCAo rats (p<0.05. n=7/group). Using a Primary cortical neuron (PCN) culture, Niacin treatment of PCN significantly increased Ang1expression under high glucose condition. Niacin and Ang1significantly increased neurite outgrowth, and Anti-Angl antibody marginally attenuated Niacin induced neurite outgrowth (p=0.06, n=6/group) in cultured PCN under high glucose condition.
Conclusion:Niaspan treatment increased ischemic brain Ang1expression and promoted axonal remodeling in the ischemic brain as well as improved functional outcome after stroke. Ang1may partially contribute to Niaspan-induced axonal remodeling after stroke in T1DM-rats.
引文
1. Hou ST, et al. Permissive and repulsive cues and signaling pathways of axonal outgrowth andregeneration. [J] Int Rev Cell Mol Biol.2008; 267:125-181.
2. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. [J] Diabetes Res Clin Pract.2010; 87(1):4-14
3. Li W,Prakash R, Kelly-Cobbs AI, Ogbi S, Kozak A, El-Remessy AB, Schreihofer DA, Fagan SC, Ergul A. Adaptive cerebral neovascularization in a model of type 2 diabetes:relevance to focal cerebral ischemia. [J] Diabetes.2010 59(1):228-35
4. Creager MA, Luscher TF, Cosentino F, Beckman JA. Diabetes and vascular disease:pathophysiology, clinical consequences, and medical therapy:Part Ⅰ. [J] Circulation.2003; 108(12):1527-32.
5. Fox CS, Coady S, Sorlie PD, Trends in cardiovascular complications of diabetes. [J] JAMA.2004 24;292(20):2495-9
6. Yong M, Kaste M. Dynamic of hyperglycemia as a predictor of stroke outcome in the ECASS-Ⅱ trial. [J] Stroke.2008; 39:2749-2755
7. Schmidt RE. Neuropathology and pathogenesis of diabetic autonomic neuropathy. [J] Int Rev Neurobiol.2002; 50:257-292
8. Elam MB, et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease:the ADMIT study: a randomized trial. Arterial Disease Multiple Intervention Trial [J] JAMA. 2000; 284:1263-1270.
9. Rosenson RS. Antiatherothrombotic effects of nicotinic acid. [J] Atherosclerosis. 2003;171:87-96
10. Ye X, Chopp M, Cui X, Zacharek A, Cui Y, Yan T, Shehadah A, Roberts C, Liu X, Lu M, Chen J.Niaspan enhances vascular remodeling after stroke in type 1 diabetic rats. [J] Exp Neurol.2011; 232:299-308
11. Walmsley AR, Mir AK. Targeting the Nogo-A signalling pathway to promote recovery following acute CNS injury. [J] Curr Pharm Des.2007; 13:2470-2484
12. Like, A.A. and A.A. Rossini, Streptozotocin-induced pancreatic insulitis:new model of diabetes mellitus. [J] Science,1976; 193(4251):415-7.
13. Wu, K.K. and Y. Huan, Streptozotocin-induced diabetic models in mice and rats. Curr. Protoc. [J] Pharmacol.,2008; 40:5.47.1-5.47.14.
14. Chen, J., et al., Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. [J] Stroke,2001; 32(4):1005-11.
15. Veenman CL, et al. Biotinylated dextran amine as an anterograde tracer for single-and double-labeling studies. [J] J Neurosci Meth.1992; 41:239-254
16. Ho, T.K., et al., Increased angiogenic response but deficient arteriolization and abnormal microvessel ultrastructure in critical leg ischaemia. [J] Br J Surg,2006; 93(11):1368-76
17. Chen, J., et al., Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. [J] Circ Res,2003; 92(6):692-9.
18. Calza, L., et al., Nerve growth factor control of neuronal expression of angiogenetic and vasoactive factors. [J] Proc Natl Acad Sci U S A,2001; 98(7): 4160-5.
19. Starr, J.M., et al., Increased blood-brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. [J] J Neurol Neurosurg Psychiatry,2003.74(1):p.70-6
20. Xiao J, Monteiro MJ. Identification and characterization of a novel (115 kDa) neurofilament-associated kinase. [J] J Neurosci 1994; 14:1820-33
21. Calhoun ME, Jucker M, Martin LJ, Thinakaran G, Price DL, Mouton PR. Comparative evaluation of synaptophysin-based methods for quantification of synapses. [J] J Neurocytol.1996,25 (12):821-8.
22. Ujike H, et al. Gene expression related to synaptogenesis, neuritogenesis, and MAP kinase in behavioral sensitization to psychostimulants. [J] Ann N Y Acad Sci.2002; 965:55-67
23. Galtrey CM, Fawcett JW. The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. [J] Brain Res Rev.2007; 54:1-18
24. Liu Z, et al. Remodeling of the corticospinal innervation and spontaneous behavioral recovery after ischemic stroke in adult mice. [J] Stroke.2009; 40:2546-2551
25. Liu Z. et al. Bone marrow stromal cells enhance inter-and intracortical axonal connections after ischemic stroke in adult rats. [J] J Cereb Blood Flow Metab. 2010; 30:1288-1295
26. Toth, P.P. High-density lipoprotein as a therapeutic target, clinical evidence and treatment strategies. [J] Am. J. Cardiol.,2005,96 (9A),50K-58K
27. Chapman, M.J.; Assmann, G.; Fruchart, J.C.; Shepherd, J.; Sirtori, C. Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk, the role of nicotinic acid--a position paper developed by the European Consensus Panel on HDL-C. [J] Curr. Med. Res. Opin.,2004,20(8),1253-1268
28. Birimohun, R.S.; Hutten, B.A.; Kastelein, J.J.; Stroes, E.S. Increasing HDL cholesterol with extended-release nicotinic acid, from promise to practice. [J] Neth. J. Med.,2004,62(7),229-234
29. Ito, M.K. Niacin-based therapy for dyslipidemia, past evidence and future advances. [J] Am. J. Manag. Care,2002,8 (12 Suppl), S315-322.
30. Suri C, et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. [J] Cell.1996; 87:1171-1180
31. Sato TN, et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. [J] Nature.1995; 376:70-74
32. Ward NL, et al. Angiopoietin 1 expression levels in the myocardium direct coronary vessel development. [J] Dev Dyn.2004; 229:500-509.
33. Bai Y, et al. Ectopic expression of angiopoietin-1 promotes neuronal differentiation in neural progenitor cells through the Akt pathway. [J] Biochem Biophys Res Commun.2009; 378:296-301
34. Chen X, et al. Angiopoietin-1 induces neurite outgrowth of PC 12 cells in a Tie2-independent, betal-integrin-dependent manner. [J] Neurosci Res.2009; 64:348-354
35. Kosacka J, et al. Angiopoietin-1 promotes neurite outgrowth from dorsal root ganglion cells positive for Tie-2 receptor. [J] Cell Tissue Res.2005; 320:11-19
36. Kosacka J, et al. Adipocyte-derived angiopoietin-1 supports neurite outgrowth and synaptogenesis of sensory neurons. [J] J Neurosci Res.2006; 83:1160-1169
37. Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos CD. Isolation of angiopoietin-1,a ligand for the Tie2 receptor, by secretion-trap expression cloning. [J] Cell,1996;87(7):1161-1691
38. Ziegler SF, Bird TA, Schneringer JA, Schooley KA. Baum PR. Molecular cloning and characterization of a novel receptor protein tyrosine kinase from human placenta. [J] Oncogen,1993;8:663
39. Runting AS, Stacker SA, Wiks AF. Tie2, a putative protein tyrosine kinase with extracelluar epidermal growth factor homology domains. [J] Mol Cell Biol.1992:12:1698
40. Loughna S, Sato TN. Angiopoietin and TIE signaling pathway in vascular development. [J] Matrix Biol,2001;20(5-6):319-295
41. Jones N, Master Z, Jones J, Bouchard D, Gunji Y, Sasaki H, Daly R, Alitalo K, Dumont DJ. Identification of Tek/TIE2 binding partners. [J] J Biol Chem,1999;274(43):30896-30905
42. Kim I, Kim HG, So JN, Kim JH, Kwak HJ, Koh GY. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3'-Kinase/Akt signal transduction pathway. [J] Circ Res,2000;86(1):24-29
43. Witzenbichler B, Maisonpierre PC. Jones P, Yancopoulos GD, Isner JM. Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. [J] J Biol Chem,1998;273:18514-18521
44. Cui X, et al. Niacin treatment of stroke increases synaptic plasticity and axon growth in rats. [J] Stroke.2010; 41:2044-2049
45. Chen J, et al. Niaspan increases angiogenesis and improves functional recovery after stroke. [J] Ann Neurol.2007; 62:49-58.
46. Iurlaro M, et al. Rat aorta-derived mural precursor cells express the Tie2 receptor and respond directly to stimulation by angiopoietins. [J] J Cell Sci.2003; 116:3635-3643
47. Ward NL, et al. Vascular-specific growth factor angiopoietin 1 is involved in the organization of neuronal processes. [J] J Comp Neurol.2005; 482:244-256
48. Chen J, et al. White matter damage and the effect of matrix metalloproteinases in type 2 diabetic mice after stroke. [J] Stroke,2011; 42:445-452
49. Arese M, et al. Nervous vascular parallels:axon guidance and beyond. [J] Int J Dev Biol.2011; 55:439-445
30. Serini G, Bussolino F. Common cues in vascular and axon guidance. [J] Physiology (Bethesda).2004; 19:348-354
51. Carmeliet P, Tessier-Lavigne M. Common mechanisms of nerve and blood vessel wiring. [J] Nature.2005; 436:193-200
52. Cui X, et al. Angiopoietin/Tie2 pathway mediates type 2 diabetes induced vascular damage after cerebral stroke. [J] Neurobiol Dis.2011; 43:285-292 激活模式在卒中后也会出现,包括代偿和学习放弃。代偿是试验对象采取一个行为完成任务,但是和未受损伤之前的策略不同,通常这种策略效率较低而且消耗大,易造成长期的肌肉骨骼并发症3。学习放弃是指试验对象仅仅不使用受到影响的功能,例如肢体或语言。对于重组中的大脑,这是一个截然不同的激活模式。因为轴索的芽生和塑形仅仅与其活性相关79,80,适应良好与适应不良均会影响卒中后大脑联系的结构。这需要在将来研究中进一步细致探索,获得-个公认的有效的神经修复治疗方法。
三、研究前景展望
将来的研究应该关注卒中后轴索芽生的基础研究转化到临床脑梗死治疗时存在的问题和其局限性。目前关于卒中后细胞死亡机制以及神经保护的基础研究是相一致的,但是并没有很好的转化到临床应用。关于卒中的临床试验存在很多问题,比如药物剂量不足以产生治疗效果；超出药物使用的时间窗；基于较好的基础研究结果设计的临床试验,因为基础研究的动物模型过于单一而未取得好的临床试验效果4,81。在临床转化过程中关键点,如果缺乏细致问题就会出现问题。关于卒中后轴索的芽生,数据显示可以引起某些系统的改变,但是并没有指出具体是什么部位的变化促进了神经功能的恢复。轴索的芽生可以在卒中病灶的同侧半球、对侧半球投射到脊髓的皮质脊髓束、脑干和纹状体中发生,哪一个或哪些系统真正通过轴索芽生介导了神经功能的恢复还需要去探索。
卒中在临床上的表现呈多样性,病灶位置各异,受累组织不同,而且经常发生在老年人群中。目前的大部分卒中动物模型主要是年轻大鼠,其受累部位通常是皮层和基底节区,在以后实验中的动物模型应多样化,并加强老年动物的研究。
尽管目前的研究还存在诸多缺陷,但是也得到了一些研究结果,卒中后大脑可塑性变化对神经功能的恢复起到了一定的作用,而增强其效果的一些治疗手段在临床上的应用将会有巨大的潜力。
1. Del Zoppo GJ, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator:a science advisory from the American Heart Association/American Stroke Association. [J] Stroke 2009; 40:2945-8
2. Bramlett HM, Dietrich WD. Pathophysiology of cerebral ischemia and brain trauma:similarities and differences. [J] J Cereb Blood Flow Metab 2004; 24:133-50
3. Dobkin, BH. The Clinical Science of Neurologic Rehabilitation. Oxford University Press; New York.NY:2003
4. Ginsberg MD. Neuroprotection for ischemic stroke:Past, present and future. [J] Neuropharmacology 2008; 55:363-389
5. Fisher M, Schaebitz W. An overview of acute stroke therapy:past, present, and future. [J] Arch Intern Med.2000,160 (21):3196-206
6. Floel A, Cohen LG. Recovery of function in humans:cortical stimulation and pharmacological treatments after stroke. [J] Neurobiol Dis.2010; 37(2):243-51.
7. Wittenberg GF Experience, cortical remapping, and recovery in brain disease. [J]Neurobiol Dis.2010; 37(2):252-8.
8. Cramer SC. Repairing the human brain after stroke:Ⅰ. Mechanisms of spontaneous recovery. [J]Ann Neurol 2008;63:272-87
9. Ward NS, Frackowiak RS. The functional anatomy of cerebral reorganisation after focal brain injury. [J] Physiol Paris 2006;99:425-36
10. Calautti C, et al. Displacement of primary sensorimotor cortex activation after subcortical stroke:a longitudinal PET study with clinical correlation. [J] Neuroimage 2003; 19:1650-4
11. Cramer SC, Crafton KR. Somatotopy and movement representation sites following cortical stroke. [J] Exp Brain Res 2006; 168:25-32
12. Johansen-Berg H, et al. The role of ipsilateral premotor cortex in hand movement after stroke. [J] Proc Natl Acad Sci U S A 2002;99:14518-23
13. Winhuisen L, et al. Role of the contralateral inferior frontal gyrus in recovery of language function in poststroke aphasia:a combined repetitive transcranial magnetic stimulation and positron emission tomography study. [J] Stroke 2005;36:1759-63
14. Murase N, et al. Influence of interhemispheric interactions on motor function in chronic stroke. [J] Ann Neurol 2004;55:400-9
15. Brown CE, et al. Rapid morphologic plasticity of peri-infarct dendritic spines after focal ischemic stroke. [J] Stroke 2008;39:] 286-91
16. Brown CE, et al. In vivo voltage-sensitive dye imaging in adult mice reveals that somatosensory maps lost to stroke are replaced over weeks by new structural and functional circuits with prolonged modes of activation within both the peri-infarct zone and distant sites. [J] Neurosci 2009;29:1719-34
17. Winship IR, Murphy TH. In vivo calcium imaging reveals functional rewiring of single somatosensory neurons after stroke. [J] Neurosci 2008;28:6592-606
18. Kolb B, Gibb R. Environmental enrichment and cortical injury:behavioral and anatomical consequences of frontal cortex lesions. [J] Cereb Cortex 1991;1:189-98
19. Jones TA, et al. Synaptogenesis and dendritic growth in the cortex opposite unilateral sensorimotor cortex damage in adult rats:a quantitative electron microscopic examination. [J] Brain Res 1996;733:142-8
20. Jones TA, Schallert T. Use-dependent growth of pyramidal neurons after neocortical damage. [J] Neurosci 1994; 14:2140-52
21. Jones TA, et al. Motor skills training enhances lesion-induced structural plasticity in the motor cortex of adult rats. [J] Neurosci 1999; 19:10153-63
22. Biernaskie J, Corbett D. Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. [JJNeurosci 2001;21:5272-80
23. Papadopoulos CM, et al. Dendritic plasticity in the adult rat following middle cerebral artery occlusion and Nogo-a neutralization. [J] Cereb Cortex 2006; 16:529-36
24. Raisman G, Field PM. A quantitative investigation of the development of collateral reinnervation after partial deafferentation of the septal nuclei. [J] Brain Res 1973;50:241-64
25. Lynch G, et al. Postlesion axonal growth produces permanent functional connections. [J] Science 1973; 180:1364-6
26. Carmichael ST. et al. New patterns of intracortical projections after focal cortical stroke. [J] Neurobiol Dis 2001:8:910-22
27. Dancause N, et al. Extensive cortical rewiring after brain injury. [J] Neurosci 2005;25:10167-79
28. Nudo RJ. Mechanisms for recovery of motor function following cortical damage. [J] Curr Opin Neurobiol 2006; 16:638-44
29. Conner JM, et al. The basal forebrain cholinergic system is essential for cortical plasticity and functional recovery following brain injury. [J] Neuron 2005;46:173-9
30. Weidner N, et al. Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury. [J] Proc Natl Acad Sci U S A 2001;98:3513-8
31. Lee JK, et al. Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. [J] Neurosci 2004;24:6209-17
32. Zai L, et al. Inosine alters gene expression and axonal projections in neurons contralateral to a cortical infarct and improves skilled use of the impaired limb. [J] Neurosci 2009;29:8187-97
33. Filbin MT. Myelin-associated inhibitors of axonal regeneration in the adult mammalian.CNS [J] Nat Rev Neurosci 2003;4:703-13
34. Atwal JK, et al. PirB is a functional receptor for myelin inhibitors of axonal regeneration. [J] Science 2008;322:967-70
35. Goh EL, et al. betal-integrin mediates myelin-associated glycoprotein signaling in neuronal growth cones. [J] Mol Brain 2008; 1:10
36. Hu F, Strittmatter SM. The N-terminal domain of Nogo-A inhibits cell adhesion and axonal outgrowth by an integrin-specific mechanism. [J] Neurosci 2008;28:1262-9
37. Fujitani M, et al. Binding of soluble myelin-associated glycoprotein to specific gangliosides induces the association of p75NTR to lipid rafts and signal transduction. [J] Neurochem 2005;94:15-21
38. Venkatesh K, et al. The Nogo-66 receptor homolog NgR2 is a sialic acid-dependent receptor selective for myelin-associated glycoprotein. [J] Neurosci 2005;25:808-22
39. Benson MD, et al. Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth. [J] Proc Natl Acad Sci USA 2005; 102:10694-9
40. Goldberg JL, et al. An oligodendrocyte lineage-specific semaphorin, Sema5A, inhibits axon growth by retinal ganglion cells. [J] Neurosci 2004;24:4989-99
41. Silver J, Miller JH. Regeneration beyond the glial scar. [J] Nat Rev Neurosci 2004;5:146-56
42. Liu BP, et al. Extracellular regulators of axonal growth in the adult central nervous system. [J] Philos Trans R Soc Lond B Biol Sci 2006;361:1593-610
43. Papadopoulos CM, et al. Functional recovery and neuroanatomical plasticity following middle cerebral artery occlusion and IN-1 antibody treatment in the adult rat. [J] Ann Neurol 2002;51:433-41
44. McGee AW, et al. Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. [J] Science 2005;309:2222-6
45. Bradbury EJ, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. [J] Nature 2002;416:636-40
46. Galtrey CM, et al. Promoting plasticity in the spinal cord with chondroitinase improves functional recovery after peripheral nerve repair. [J] Brain 2007; 130:926-39
47. Pizzorusso T, et al. Reactivation of ocular dominance plasticity in the adult visual cortex. [J] Science 2002;298:1248-52
48. Carmichael ST, et al. Growth-associated gene expression after stroke:evidence for a growth-promoting region in peri-infarct cortex. [J] Exp Neurol 2005;193:291-311
49. Goldberg JL, et al. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. [J] Science 2002;296:1860-4
50. Benowitz LI, Routtenberg A. GAP-43:an intrinsic determinant of neuronal development and plasticity. [J] Trends in Neurosciences 1997;20:84-91
51. Fischer D, et al. Switching mature retinal ganglion cells to a robust growth state in vivo:gene expression and synergy with RhoA inactivation. [J] Neurosci 2004;24:8726-8740
52. Skene JH. Axonal growth-associated proteins. [J] Annu Rev Neurosci 1989; 12:127-56
53. Stroemer RP, et al. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. [J] Stroke 1998; 29:2381-93
54. Kawamata T, et al. Intracistemal basic fibroblast growth factor enhances functional recovery and up-regulates the expression of a molecular marker of neuronal sprouting following focal cerebral infarction. [J] Proc Natl Acad Sci U S A 1997;94:8179-84
55. Kawamata T, et al. Intracisternal antisense oligonucleotide to growth associated protein-43 blocks the recovery-promoting effects of basic fibroblast growth factor after focal stroke. [J] Exp Neurol 1999; 158:89-96
56. Lu P, et al. Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. [J] Neurosci 2004;24:6402-9
57. Ramer MS, et al. Functional regeneration of sensory axons into the adult spinal cord. [J] Nature 2000;403:312-6
58. Vavrek R, et al. BDNF promotes connections of corticospinal neurons onto spared descending interneurons in spinal cord injured rats. [J] Brain 2006; 129:1534-45
59. Yin Y, et al. Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. [J] Nat Neurosci 2006;9:843-52
60. Song H, et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. [J] Science 1998; 281:1515-8.
61. Neumann S, et al. Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. [J] Neuron 2002;34:885-93
62. MacDonald E, et al. A novel phosphodiesterase type 4 inhibitor, HT-0712, enhances rehabilitation-dependent motor recovery and cortical reorganization after focal cortical ischemia. [J] Neurorehabil Neural Repair 2007:21:486-496
63. Langley B, et al. Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke. [J] Stroke 2009;40:2899-905
64. Irwin N, et al. Mst3b, a purine-sensitive Ste20-like protein kinase, regulates axon outgrowth. [J] Proc Natl Acad Sci U S A 2006; 103:18320-5
65. Lorber B, et al. Mst3b, an Ste20-like kinase, regulates axon regeneration in the mature. CNS and PNS [J] Nature Neurosci 2009; 12:1403-1409
66. Hasko G, et al. Immunomodulatory and neuroprotective effects of inosine. T [J] rends Pharmacol Sci 2004;25:152-7
67. Shen H, et al. Inosine reduces ischemic brain injury in rats. [J] Stroke 2005;36:654-9
68. Scott GS, et al. Uric acid protects against secondary damage after spinal cord injury. [J] Proc Nat] Acad Sci U S A 2005;102:3483-8
69. Chen P, et al. Inosine induces axonal rewiring and improves behavioral outcome after stroke. [J] Proc Natl Acad Sci U S A 2002;99:9031-6
70. Zai L, et al. Inosine augments the effects of a Nogo receptor blocker and of environmental enrichment to restore skilled forelimb use after stroke. [J] Neurosci.2011;31(16):5977-88.
71. Czamecki W, Czarnecki A. Haemodynamic effects of inosine. A new drug for failing human heart? [J] Pharmacol Res 1989;21:587-94
72. Starling RD, et al. Effect of inosine supplementation on aerobic and anaerobic cycling performance. [J] Med Sci Sports Exerc 1996:28:1193-8
73. Katz LC, Shatz CJ. Synaptic activity and the construction of cortical circuits. [J] Science 1996;274:1133-8
74. Martin JH. The corticospinal system:from development to motor control. [J] Neuroscientist 2005; 11:161-73
75. Brus-Ramer M, et al. Electrical stimulation of spared corticospinal axons augments connections with ipsilateral spinal motor circuits after injury. [J] Neurosci 2007;27:13793-801
76. Yozbatiran N, et al. Safety and behavioral effects of high-frequency repetitive transcranial magnetic stimulation in stroke. [J] Stroke 2009;40:309-12
77. Wolf SL, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke:the EXCITE randomized clinical trial. [J] JAMA 2006;296:2095-104
78. Maier IC, et al. Constraint-induced movement therapy in the adult rat after unilateral corticospinal tract injury. [J] Neurosci 2008;28:9386-403
79. Kleim JA, et al. Cortical synaptogenesis and motor map reorganization occur during late, but not early, phase of motor skill learning. [J]Neurosci 2004;24:628-633
80. Harms KJ, et al. Transient spine expansion and learning-induced plasticity in layer 1 primary motor cortex. [J] Neurosci 2008;28:5686-5690
81. Carmichael ST. Translating the frontiers of brain repair to treatments:Starting not to break the rules. [J] Neurobiol Dis.2010 Sep 18; 2009
2. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. [J] Diabetes Res Clin Pract.2010; 87(1):4-14
3. Li W,Prakash R, Kelly-Cobbs AI, Ogbi S, Kozak A, El-Remessy AB, Schreihofer DA, Fagan SC, Ergul A. Adaptive cerebral neovascularization in a model of type 2 diabetes:relevance to focal cerebral ischemia. [J] Diabetes.2010 59(1):228-35
4. Creager MA, Luscher TF, Cosentino F, Beckman JA. Diabetes and vascular disease:pathophysiology, clinical consequences, and medical therapy:Part Ⅰ. [J] Circulation.2003; 108(12):1527-32.
5. Fox CS, Coady S, Sorlie PD, Trends in cardiovascular complications of diabetes. [J] JAMA.2004 24;292(20):2495-9
6. Yong M, Kaste M. Dynamic of hyperglycemia as a predictor of stroke outcome in the ECASS-Ⅱ trial. [J] Stroke.2008; 39:2749-2755
7. Schmidt RE. Neuropathology and pathogenesis of diabetic autonomic neuropathy. [J] Int Rev Neurobiol.2002; 50:257-292
8. Elam MB, et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease:the ADMIT study: a randomized trial. Arterial Disease Multiple Intervention Trial [J] JAMA. 2000; 284:1263-1270.
9. Rosenson RS. Antiatherothrombotic effects of nicotinic acid. [J] Atherosclerosis. 2003;171:87-96
10. Ye X, Chopp M, Cui X, Zacharek A, Cui Y, Yan T, Shehadah A, Roberts C, Liu X, Lu M, Chen J.Niaspan enhances vascular remodeling after stroke in type 1 diabetic rats. [J] Exp Neurol.2011; 232:299-308
11. Walmsley AR, Mir AK. Targeting the Nogo-A signalling pathway to promote recovery following acute CNS injury. [J] Curr Pharm Des.2007; 13:2470-2484
12. Like, A.A. and A.A. Rossini, Streptozotocin-induced pancreatic insulitis:new model of diabetes mellitus. [J] Science,1976; 193(4251):415-7.
13. Wu, K.K. and Y. Huan, Streptozotocin-induced diabetic models in mice and rats. Curr. Protoc. [J] Pharmacol.,2008; 40:5.47.1-5.47.14.
14. Chen, J., et al., Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. [J] Stroke,2001; 32(4):1005-11.
15. Veenman CL, et al. Biotinylated dextran amine as an anterograde tracer for single-and double-labeling studies. [J] J Neurosci Meth.1992; 41:239-254
16. Ho, T.K., et al., Increased angiogenic response but deficient arteriolization and abnormal microvessel ultrastructure in critical leg ischaemia. [J] Br J Surg,2006; 93(11):1368-76
17. Chen, J., et al., Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. [J] Circ Res,2003; 92(6):692-9.
18. Calza, L., et al., Nerve growth factor control of neuronal expression of angiogenetic and vasoactive factors. [J] Proc Natl Acad Sci U S A,2001; 98(7): 4160-5.
19. Starr, J.M., et al., Increased blood-brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. [J] J Neurol Neurosurg Psychiatry,2003.74(1):p.70-6
20. Xiao J, Monteiro MJ. Identification and characterization of a novel (115 kDa) neurofilament-associated kinase. [J] J Neurosci 1994; 14:1820-33
21. Calhoun ME, Jucker M, Martin LJ, Thinakaran G, Price DL, Mouton PR. Comparative evaluation of synaptophysin-based methods for quantification of synapses. [J] J Neurocytol.1996,25 (12):821-8.
22. Ujike H, et al. Gene expression related to synaptogenesis, neuritogenesis, and MAP kinase in behavioral sensitization to psychostimulants. [J] Ann N Y Acad Sci.2002; 965:55-67
23. Galtrey CM, Fawcett JW. The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. [J] Brain Res Rev.2007; 54:1-18
24. Liu Z, et al. Remodeling of the corticospinal innervation and spontaneous behavioral recovery after ischemic stroke in adult mice. [J] Stroke.2009; 40:2546-2551
25. Liu Z. et al. Bone marrow stromal cells enhance inter-and intracortical axonal connections after ischemic stroke in adult rats. [J] J Cereb Blood Flow Metab. 2010; 30:1288-1295
26. Toth, P.P. High-density lipoprotein as a therapeutic target, clinical evidence and treatment strategies. [J] Am. J. Cardiol.,2005,96 (9A),50K-58K
27. Chapman, M.J.; Assmann, G.; Fruchart, J.C.; Shepherd, J.; Sirtori, C. Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk, the role of nicotinic acid--a position paper developed by the European Consensus Panel on HDL-C. [J] Curr. Med. Res. Opin.,2004,20(8),1253-1268
28. Birimohun, R.S.; Hutten, B.A.; Kastelein, J.J.; Stroes, E.S. Increasing HDL cholesterol with extended-release nicotinic acid, from promise to practice. [J] Neth. J. Med.,2004,62(7),229-234
29. Ito, M.K. Niacin-based therapy for dyslipidemia, past evidence and future advances. [J] Am. J. Manag. Care,2002,8 (12 Suppl), S315-322.
30. Suri C, et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. [J] Cell.1996; 87:1171-1180
31. Sato TN, et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. [J] Nature.1995; 376:70-74
32. Ward NL, et al. Angiopoietin 1 expression levels in the myocardium direct coronary vessel development. [J] Dev Dyn.2004; 229:500-509.
33. Bai Y, et al. Ectopic expression of angiopoietin-1 promotes neuronal differentiation in neural progenitor cells through the Akt pathway. [J] Biochem Biophys Res Commun.2009; 378:296-301
34. Chen X, et al. Angiopoietin-1 induces neurite outgrowth of PC 12 cells in a Tie2-independent, betal-integrin-dependent manner. [J] Neurosci Res.2009; 64:348-354
35. Kosacka J, et al. Angiopoietin-1 promotes neurite outgrowth from dorsal root ganglion cells positive for Tie-2 receptor. [J] Cell Tissue Res.2005; 320:11-19
36. Kosacka J, et al. Adipocyte-derived angiopoietin-1 supports neurite outgrowth and synaptogenesis of sensory neurons. [J] J Neurosci Res.2006; 83:1160-1169
37. Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos CD. Isolation of angiopoietin-1,a ligand for the Tie2 receptor, by secretion-trap expression cloning. [J] Cell,1996;87(7):1161-1691
38. Ziegler SF, Bird TA, Schneringer JA, Schooley KA. Baum PR. Molecular cloning and characterization of a novel receptor protein tyrosine kinase from human placenta. [J] Oncogen,1993;8:663
39. Runting AS, Stacker SA, Wiks AF. Tie2, a putative protein tyrosine kinase with extracelluar epidermal growth factor homology domains. [J] Mol Cell Biol.1992:12:1698
40. Loughna S, Sato TN. Angiopoietin and TIE signaling pathway in vascular development. [J] Matrix Biol,2001;20(5-6):319-295
41. Jones N, Master Z, Jones J, Bouchard D, Gunji Y, Sasaki H, Daly R, Alitalo K, Dumont DJ. Identification of Tek/TIE2 binding partners. [J] J Biol Chem,1999;274(43):30896-30905
42. Kim I, Kim HG, So JN, Kim JH, Kwak HJ, Koh GY. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3'-Kinase/Akt signal transduction pathway. [J] Circ Res,2000;86(1):24-29
43. Witzenbichler B, Maisonpierre PC. Jones P, Yancopoulos GD, Isner JM. Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. [J] J Biol Chem,1998;273:18514-18521
44. Cui X, et al. Niacin treatment of stroke increases synaptic plasticity and axon growth in rats. [J] Stroke.2010; 41:2044-2049
45. Chen J, et al. Niaspan increases angiogenesis and improves functional recovery after stroke. [J] Ann Neurol.2007; 62:49-58.
46. Iurlaro M, et al. Rat aorta-derived mural precursor cells express the Tie2 receptor and respond directly to stimulation by angiopoietins. [J] J Cell Sci.2003; 116:3635-3643
47. Ward NL, et al. Vascular-specific growth factor angiopoietin 1 is involved in the organization of neuronal processes. [J] J Comp Neurol.2005; 482:244-256
48. Chen J, et al. White matter damage and the effect of matrix metalloproteinases in type 2 diabetic mice after stroke. [J] Stroke,2011; 42:445-452
49. Arese M, et al. Nervous vascular parallels:axon guidance and beyond. [J] Int J Dev Biol.2011; 55:439-445
30. Serini G, Bussolino F. Common cues in vascular and axon guidance. [J] Physiology (Bethesda).2004; 19:348-354
51. Carmeliet P, Tessier-Lavigne M. Common mechanisms of nerve and blood vessel wiring. [J] Nature.2005; 436:193-200
52. Cui X, et al. Angiopoietin/Tie2 pathway mediates type 2 diabetes induced vascular damage after cerebral stroke. [J] Neurobiol Dis.2011; 43:285-292 激活模式在卒中后也会出现,包括代偿和学习放弃。代偿是试验对象采取一个行为完成任务,但是和未受损伤之前的策略不同,通常这种策略效率较低而且消耗大,易造成长期的肌肉骨骼并发症3。学习放弃是指试验对象仅仅不使用受到影响的功能,例如肢体或语言。对于重组中的大脑,这是一个截然不同的激活模式。因为轴索的芽生和塑形仅仅与其活性相关79,80,适应良好与适应不良均会影响卒中后大脑联系的结构。这需要在将来研究中进一步细致探索,获得-个公认的有效的神经修复治疗方法。
三、研究前景展望
将来的研究应该关注卒中后轴索芽生的基础研究转化到临床脑梗死治疗时存在的问题和其局限性。目前关于卒中后细胞死亡机制以及神经保护的基础研究是相一致的,但是并没有很好的转化到临床应用。关于卒中的临床试验存在很多问题,比如药物剂量不足以产生治疗效果；超出药物使用的时间窗；基于较好的基础研究结果设计的临床试验,因为基础研究的动物模型过于单一而未取得好的临床试验效果4,81。在临床转化过程中关键点,如果缺乏细致问题就会出现问题。关于卒中后轴索的芽生,数据显示可以引起某些系统的改变,但是并没有指出具体是什么部位的变化促进了神经功能的恢复。轴索的芽生可以在卒中病灶的同侧半球、对侧半球投射到脊髓的皮质脊髓束、脑干和纹状体中发生,哪一个或哪些系统真正通过轴索芽生介导了神经功能的恢复还需要去探索。
卒中在临床上的表现呈多样性,病灶位置各异,受累组织不同,而且经常发生在老年人群中。目前的大部分卒中动物模型主要是年轻大鼠,其受累部位通常是皮层和基底节区,在以后实验中的动物模型应多样化,并加强老年动物的研究。
尽管目前的研究还存在诸多缺陷,但是也得到了一些研究结果,卒中后大脑可塑性变化对神经功能的恢复起到了一定的作用,而增强其效果的一些治疗手段在临床上的应用将会有巨大的潜力。
1. Del Zoppo GJ, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator:a science advisory from the American Heart Association/American Stroke Association. [J] Stroke 2009; 40:2945-8
2. Bramlett HM, Dietrich WD. Pathophysiology of cerebral ischemia and brain trauma:similarities and differences. [J] J Cereb Blood Flow Metab 2004; 24:133-50
3. Dobkin, BH. The Clinical Science of Neurologic Rehabilitation. Oxford University Press; New York.NY:2003
4. Ginsberg MD. Neuroprotection for ischemic stroke:Past, present and future. [J] Neuropharmacology 2008; 55:363-389
5. Fisher M, Schaebitz W. An overview of acute stroke therapy:past, present, and future. [J] Arch Intern Med.2000,160 (21):3196-206
6. Floel A, Cohen LG. Recovery of function in humans:cortical stimulation and pharmacological treatments after stroke. [J] Neurobiol Dis.2010; 37(2):243-51.
7. Wittenberg GF Experience, cortical remapping, and recovery in brain disease. [J]Neurobiol Dis.2010; 37(2):252-8.
8. Cramer SC. Repairing the human brain after stroke:Ⅰ. Mechanisms of spontaneous recovery. [J]Ann Neurol 2008;63:272-87
9. Ward NS, Frackowiak RS. The functional anatomy of cerebral reorganisation after focal brain injury. [J] Physiol Paris 2006;99:425-36
10. Calautti C, et al. Displacement of primary sensorimotor cortex activation after subcortical stroke:a longitudinal PET study with clinical correlation. [J] Neuroimage 2003; 19:1650-4
11. Cramer SC, Crafton KR. Somatotopy and movement representation sites following cortical stroke. [J] Exp Brain Res 2006; 168:25-32
12. Johansen-Berg H, et al. The role of ipsilateral premotor cortex in hand movement after stroke. [J] Proc Natl Acad Sci U S A 2002;99:14518-23
13. Winhuisen L, et al. Role of the contralateral inferior frontal gyrus in recovery of language function in poststroke aphasia:a combined repetitive transcranial magnetic stimulation and positron emission tomography study. [J] Stroke 2005;36:1759-63
14. Murase N, et al. Influence of interhemispheric interactions on motor function in chronic stroke. [J] Ann Neurol 2004;55:400-9
15. Brown CE, et al. Rapid morphologic plasticity of peri-infarct dendritic spines after focal ischemic stroke. [J] Stroke 2008;39:] 286-91
16. Brown CE, et al. In vivo voltage-sensitive dye imaging in adult mice reveals that somatosensory maps lost to stroke are replaced over weeks by new structural and functional circuits with prolonged modes of activation within both the peri-infarct zone and distant sites. [J] Neurosci 2009;29:1719-34
17. Winship IR, Murphy TH. In vivo calcium imaging reveals functional rewiring of single somatosensory neurons after stroke. [J] Neurosci 2008;28:6592-606
18. Kolb B, Gibb R. Environmental enrichment and cortical injury:behavioral and anatomical consequences of frontal cortex lesions. [J] Cereb Cortex 1991;1:189-98
19. Jones TA, et al. Synaptogenesis and dendritic growth in the cortex opposite unilateral sensorimotor cortex damage in adult rats:a quantitative electron microscopic examination. [J] Brain Res 1996;733:142-8
20. Jones TA, Schallert T. Use-dependent growth of pyramidal neurons after neocortical damage. [J] Neurosci 1994; 14:2140-52
21. Jones TA, et al. Motor skills training enhances lesion-induced structural plasticity in the motor cortex of adult rats. [J] Neurosci 1999; 19:10153-63
22. Biernaskie J, Corbett D. Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. [JJNeurosci 2001;21:5272-80
23. Papadopoulos CM, et al. Dendritic plasticity in the adult rat following middle cerebral artery occlusion and Nogo-a neutralization. [J] Cereb Cortex 2006; 16:529-36
24. Raisman G, Field PM. A quantitative investigation of the development of collateral reinnervation after partial deafferentation of the septal nuclei. [J] Brain Res 1973;50:241-64
25. Lynch G, et al. Postlesion axonal growth produces permanent functional connections. [J] Science 1973; 180:1364-6
26. Carmichael ST. et al. New patterns of intracortical projections after focal cortical stroke. [J] Neurobiol Dis 2001:8:910-22
27. Dancause N, et al. Extensive cortical rewiring after brain injury. [J] Neurosci 2005;25:10167-79
28. Nudo RJ. Mechanisms for recovery of motor function following cortical damage. [J] Curr Opin Neurobiol 2006; 16:638-44
29. Conner JM, et al. The basal forebrain cholinergic system is essential for cortical plasticity and functional recovery following brain injury. [J] Neuron 2005;46:173-9
30. Weidner N, et al. Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury. [J] Proc Natl Acad Sci U S A 2001;98:3513-8
31. Lee JK, et al. Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. [J] Neurosci 2004;24:6209-17
32. Zai L, et al. Inosine alters gene expression and axonal projections in neurons contralateral to a cortical infarct and improves skilled use of the impaired limb. [J] Neurosci 2009;29:8187-97
33. Filbin MT. Myelin-associated inhibitors of axonal regeneration in the adult mammalian.CNS [J] Nat Rev Neurosci 2003;4:703-13
34. Atwal JK, et al. PirB is a functional receptor for myelin inhibitors of axonal regeneration. [J] Science 2008;322:967-70
35. Goh EL, et al. betal-integrin mediates myelin-associated glycoprotein signaling in neuronal growth cones. [J] Mol Brain 2008; 1:10
36. Hu F, Strittmatter SM. The N-terminal domain of Nogo-A inhibits cell adhesion and axonal outgrowth by an integrin-specific mechanism. [J] Neurosci 2008;28:1262-9
37. Fujitani M, et al. Binding of soluble myelin-associated glycoprotein to specific gangliosides induces the association of p75NTR to lipid rafts and signal transduction. [J] Neurochem 2005;94:15-21
38. Venkatesh K, et al. The Nogo-66 receptor homolog NgR2 is a sialic acid-dependent receptor selective for myelin-associated glycoprotein. [J] Neurosci 2005;25:808-22
39. Benson MD, et al. Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth. [J] Proc Natl Acad Sci USA 2005; 102:10694-9
40. Goldberg JL, et al. An oligodendrocyte lineage-specific semaphorin, Sema5A, inhibits axon growth by retinal ganglion cells. [J] Neurosci 2004;24:4989-99
41. Silver J, Miller JH. Regeneration beyond the glial scar. [J] Nat Rev Neurosci 2004;5:146-56
42. Liu BP, et al. Extracellular regulators of axonal growth in the adult central nervous system. [J] Philos Trans R Soc Lond B Biol Sci 2006;361:1593-610
43. Papadopoulos CM, et al. Functional recovery and neuroanatomical plasticity following middle cerebral artery occlusion and IN-1 antibody treatment in the adult rat. [J] Ann Neurol 2002;51:433-41
44. McGee AW, et al. Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. [J] Science 2005;309:2222-6
45. Bradbury EJ, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. [J] Nature 2002;416:636-40
46. Galtrey CM, et al. Promoting plasticity in the spinal cord with chondroitinase improves functional recovery after peripheral nerve repair. [J] Brain 2007; 130:926-39
47. Pizzorusso T, et al. Reactivation of ocular dominance plasticity in the adult visual cortex. [J] Science 2002;298:1248-52
48. Carmichael ST, et al. Growth-associated gene expression after stroke:evidence for a growth-promoting region in peri-infarct cortex. [J] Exp Neurol 2005;193:291-311
49. Goldberg JL, et al. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. [J] Science 2002;296:1860-4
50. Benowitz LI, Routtenberg A. GAP-43:an intrinsic determinant of neuronal development and plasticity. [J] Trends in Neurosciences 1997;20:84-91
51. Fischer D, et al. Switching mature retinal ganglion cells to a robust growth state in vivo:gene expression and synergy with RhoA inactivation. [J] Neurosci 2004;24:8726-8740
52. Skene JH. Axonal growth-associated proteins. [J] Annu Rev Neurosci 1989; 12:127-56
53. Stroemer RP, et al. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. [J] Stroke 1998; 29:2381-93
54. Kawamata T, et al. Intracistemal basic fibroblast growth factor enhances functional recovery and up-regulates the expression of a molecular marker of neuronal sprouting following focal cerebral infarction. [J] Proc Natl Acad Sci U S A 1997;94:8179-84
55. Kawamata T, et al. Intracisternal antisense oligonucleotide to growth associated protein-43 blocks the recovery-promoting effects of basic fibroblast growth factor after focal stroke. [J] Exp Neurol 1999; 158:89-96
56. Lu P, et al. Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. [J] Neurosci 2004;24:6402-9
57. Ramer MS, et al. Functional regeneration of sensory axons into the adult spinal cord. [J] Nature 2000;403:312-6
58. Vavrek R, et al. BDNF promotes connections of corticospinal neurons onto spared descending interneurons in spinal cord injured rats. [J] Brain 2006; 129:1534-45
59. Yin Y, et al. Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. [J] Nat Neurosci 2006;9:843-52
60. Song H, et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. [J] Science 1998; 281:1515-8.
61. Neumann S, et al. Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. [J] Neuron 2002;34:885-93
62. MacDonald E, et al. A novel phosphodiesterase type 4 inhibitor, HT-0712, enhances rehabilitation-dependent motor recovery and cortical reorganization after focal cortical ischemia. [J] Neurorehabil Neural Repair 2007:21:486-496
63. Langley B, et al. Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke. [J] Stroke 2009;40:2899-905
64. Irwin N, et al. Mst3b, a purine-sensitive Ste20-like protein kinase, regulates axon outgrowth. [J] Proc Natl Acad Sci U S A 2006; 103:18320-5
65. Lorber B, et al. Mst3b, an Ste20-like kinase, regulates axon regeneration in the mature. CNS and PNS [J] Nature Neurosci 2009; 12:1403-1409
66. Hasko G, et al. Immunomodulatory and neuroprotective effects of inosine. T [J] rends Pharmacol Sci 2004;25:152-7
67. Shen H, et al. Inosine reduces ischemic brain injury in rats. [J] Stroke 2005;36:654-9
68. Scott GS, et al. Uric acid protects against secondary damage after spinal cord injury. [J] Proc Nat] Acad Sci U S A 2005;102:3483-8
69. Chen P, et al. Inosine induces axonal rewiring and improves behavioral outcome after stroke. [J] Proc Natl Acad Sci U S A 2002;99:9031-6
70. Zai L, et al. Inosine augments the effects of a Nogo receptor blocker and of environmental enrichment to restore skilled forelimb use after stroke. [J] Neurosci.2011;31(16):5977-88.
71. Czamecki W, Czarnecki A. Haemodynamic effects of inosine. A new drug for failing human heart? [J] Pharmacol Res 1989;21:587-94
72. Starling RD, et al. Effect of inosine supplementation on aerobic and anaerobic cycling performance. [J] Med Sci Sports Exerc 1996:28:1193-8
73. Katz LC, Shatz CJ. Synaptic activity and the construction of cortical circuits. [J] Science 1996;274:1133-8
74. Martin JH. The corticospinal system:from development to motor control. [J] Neuroscientist 2005; 11:161-73
75. Brus-Ramer M, et al. Electrical stimulation of spared corticospinal axons augments connections with ipsilateral spinal motor circuits after injury. [J] Neurosci 2007;27:13793-801
76. Yozbatiran N, et al. Safety and behavioral effects of high-frequency repetitive transcranial magnetic stimulation in stroke. [J] Stroke 2009;40:309-12
77. Wolf SL, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke:the EXCITE randomized clinical trial. [J] JAMA 2006;296:2095-104
78. Maier IC, et al. Constraint-induced movement therapy in the adult rat after unilateral corticospinal tract injury. [J] Neurosci 2008;28:9386-403
79. Kleim JA, et al. Cortical synaptogenesis and motor map reorganization occur during late, but not early, phase of motor skill learning. [J]Neurosci 2004;24:628-633
80. Harms KJ, et al. Transient spine expansion and learning-induced plasticity in layer 1 primary motor cortex. [J] Neurosci 2008;28:5686-5690
81. Carmichael ST. Translating the frontiers of brain repair to treatments:Starting not to break the rules. [J] Neurobiol Dis.2010 Sep 18; 2009