翟志永，馮娟

神經(jīng)元在傳統(tǒng)意義上被看作哺乳動(dòng)物中樞神經(jīng)系統(tǒng)最重要的細(xì)胞，因?yàn)樗巧窠?jīng)傳導(dǎo)的基本單位，神經(jīng)元的死亡或功能障礙都會(huì)引起腦功能的缺失[1]。因此，神經(jīng)保護(hù)在邏輯上成為治療的目的。然而，目前幾乎所有卒中后神經(jīng)保護(hù)3期臨床試驗(yàn)沒(méi)有證實(shí)對(duì)患者有益，提示單純拯救神經(jīng)元是不夠的[2]。近年來(lái)提出的“神經(jīng)血管單元（neurovascular unit，NVU）”的概念強(qiáng)調(diào)神經(jīng)與血管之間的相互作用，突出血管再生在神經(jīng)修復(fù)中的重要作用[3-4]。

1 神經(jīng)再生與血管再生

成年人中樞神經(jīng)系統(tǒng)中存在兩個(gè)神經(jīng)再生功能的腦區(qū)[5]：室管膜下（subvenricular zone，SVZ）和海馬齒狀回的顆粒下層（subgramilar zone，SGZ）。Arvidsson等[6]研究發(fā)現(xiàn)，缺血性卒中能刺激SVZ和SGZ的神經(jīng)細(xì)胞再生。這些成神經(jīng)細(xì)胞不斷生成直到卒中后4個(gè)月，它們可以發(fā)育成成熟的神經(jīng)元并通過(guò)釋放神經(jīng)營(yíng)養(yǎng)激素和其他因子來(lái)維持神經(jīng)元存活[7]。

成年腦血管系統(tǒng)在正常條件下是穩(wěn)定的，在病理情況下（如卒中）可以反應(yīng)性激活重構(gòu)[8]。成年血管重構(gòu)包括由成熟內(nèi)皮細(xì)胞產(chǎn)生的血管再生（從已有血管生長(zhǎng)出毛細(xì)血管）和由內(nèi)皮祖細(xì)胞（endothelial progenitor cells，EPCs）生成血管的血管新生。血管再生主要通過(guò)以下途徑發(fā)揮作用：首先，生長(zhǎng)因子的表達(dá)可提高半暗帶區(qū)內(nèi)皮細(xì)胞、膠質(zhì)細(xì)胞和神經(jīng)元的存活[9-10]；其次，新血管形成有助于清除壞死組織[11]；另外，這種促血管生成狀態(tài)創(chuàng)建了“血管龕”結(jié)構(gòu)，血管龕有助于神經(jīng)干細(xì)胞產(chǎn)生和遷移[12]。

近年來(lái)對(duì)神經(jīng)元、膠質(zhì)細(xì)胞和血管內(nèi)皮細(xì)胞、周細(xì)胞等組成的復(fù)合體——NVU[13]成為卒中后病理生理、藥物治療等方面的研究熱點(diǎn)。NVU中神經(jīng)元、膠質(zhì)細(xì)胞和血管內(nèi)皮細(xì)胞之間通過(guò)細(xì)胞-細(xì)胞間信號(hào)、神經(jīng)血管偶聯(lián)等機(jī)制，共同調(diào)節(jié)神經(jīng)遞質(zhì)的動(dòng)態(tài)平衡，維護(hù)血-腦屏障的穩(wěn)定。腦缺血損傷修復(fù)階段，NVU中多種細(xì)胞之間又通過(guò)偶聯(lián)、串話（crosstalk）等方式共同參與神經(jīng)血管的重塑[14]。在NVU中，新生的不成熟的神經(jīng)干/祖細(xì)胞與重構(gòu)的血管密切關(guān)聯(lián)，新生血管促進(jìn)神經(jīng)修復(fù)過(guò)程（神經(jīng)再生和突觸發(fā)生），進(jìn)而促進(jìn)神經(jīng)功能的恢復(fù)[15-16]。而神經(jīng)再生也可能促進(jìn)血管再生[17]。

2 運(yùn)動(dòng)療法的作用機(jī)制

運(yùn)動(dòng)療法是以中樞神經(jīng)系統(tǒng)可塑性為基礎(chǔ)發(fā)展起來(lái)的一種康復(fù)治療技術(shù)，是指利用器械、徒手或患者自身力量，通過(guò)某些運(yùn)動(dòng)方式（主動(dòng)或被動(dòng)運(yùn)動(dòng)等），使患者獲得全身或局部運(yùn)動(dòng)功能、感覺(jué)功能恢復(fù)的訓(xùn)練方法[18]。血管再生在運(yùn)動(dòng)療法中的作用越來(lái)越重要。2.1 運(yùn)動(dòng)療法與腦的可塑性和功能重組 Nudo等[19]使用皮質(zhì)內(nèi)微電極刺激的方法在成年松鼠猴體內(nèi)研究了腦損傷后皮質(zhì)重組的情況，結(jié)果顯示，松鼠猴患側(cè)前肢訓(xùn)練后可促進(jìn)明顯的皮質(zhì)功能重組，特別是缺血區(qū)周?chē)钠べ|(zhì)功能重組。Traversa等[20]應(yīng)用局部經(jīng)顱磁刺激圖探討了慢性卒中患者在強(qiáng)制性運(yùn)動(dòng)治療后腦的可塑性改變，發(fā)現(xiàn)治療后運(yùn)動(dòng)閾值無(wú)變化，但運(yùn)動(dòng)誘發(fā)電位（motor evoked potential，MEP）波幅明顯增高，皮質(zhì)運(yùn)動(dòng)輸出區(qū)擴(kuò)大，興奮區(qū)重心轉(zhuǎn)移，提示手皮質(zhì)運(yùn)動(dòng)區(qū)的興奮性升高和鄰近中樞的再募集，這和癱瘓肢體運(yùn)動(dòng)功能的提高一致。Kim等[21]采用功能磁共振成像（functional magenetic resonance imaging，fMRI）研究5例慢性卒中患者接受強(qiáng)制性運(yùn)動(dòng)療法（constraint induced movement therapy，CIMT）治療前后運(yùn)動(dòng)網(wǎng)絡(luò)的激活情況，所有患者治療后上肢功能都得到了顯著改善，3例患者治療后在損傷對(duì)側(cè)大腦半球主要運(yùn)動(dòng)區(qū)有激活現(xiàn)象，另外2例患者損傷同側(cè)的皮層運(yùn)動(dòng)區(qū)和輔助運(yùn)動(dòng)區(qū)激活增加。Levy等[22]利用fMRI觀察到，2例患者治療前僅在病變側(cè)半球出現(xiàn)散在的激活點(diǎn)；CIMT治療后，病變邊緣可見(jiàn)大量激活區(qū)，而且在病變同側(cè)感覺(jué)運(yùn)動(dòng)區(qū)、補(bǔ)充運(yùn)動(dòng)區(qū)、運(yùn)動(dòng)前區(qū)，甚至病變對(duì)側(cè)半球都可見(jiàn)到廣泛的激活。這些研究提示CIMT能明顯促進(jìn)腦損傷后的功能重組和神經(jīng)再生。運(yùn)動(dòng)無(wú)論對(duì)于功能性的可塑性還是結(jié)構(gòu)上的可塑性都是非常重要的。

從細(xì)胞分子水平探討運(yùn)動(dòng)療法對(duì)腦缺血后神經(jīng)再生相關(guān)機(jī)制的研究較少。有研究發(fā)現(xiàn)，腦缺血后的為期3周的CIMT可使大鼠腦內(nèi)基質(zhì)細(xì)胞衍生因子-1（stromal cell derived factor 1，SDF-1）蛋白的表達(dá)明顯上調(diào)[23]。離體實(shí)驗(yàn)證實(shí)SDF-1能夠通過(guò)抑制Rho激酶活性來(lái)促進(jìn)神經(jīng)元軸突延伸[24]。膠質(zhì)細(xì)胞生成的神經(jīng)軸突生長(zhǎng)抑制劑A（neurite outgrowth inhibitor-A, Nogo-A）、髓鞘相關(guān)蛋白、少突膠質(zhì)細(xì)胞髓鞘糖蛋白等均能抑制受損神經(jīng)元軸突的再生。上述各種物質(zhì)在與Nogo受體結(jié)合后激活Rho激酶而發(fā)揮其抑制作用[25-26]。注射N(xiāo)ogo信號(hào)下游分子Rho激酶的小分子抑制因子Y27632于脊髓損傷部位可導(dǎo)致類(lèi)似于Nogo或其受體失活時(shí)觀察到的促再生效應(yīng)[27]。Zhao等[28-29]發(fā)現(xiàn)CIMT顯著降低梗死周?chē)べ|(zhì)Nogo-A及RhoA的表達(dá)。

2.2 運(yùn)動(dòng)療法與血管再生 運(yùn)動(dòng)維持和改善腦血流灌注的方式包括側(cè)支循環(huán)的建立和微血管再生。越來(lái)越多的證據(jù)表明，運(yùn)動(dòng)鍛煉可能對(duì)腦血管病、血管性癡呆起到預(yù)防作用[30-31]。腦缺血前運(yùn)動(dòng)可通過(guò)很多機(jī)制誘導(dǎo)腦對(duì)缺血的耐受，包括上調(diào)血管內(nèi)皮生長(zhǎng)因子（vascular endothelial growth factor，VEGF）、刺激血管和神經(jīng)再生等機(jī)制[32]。側(cè)支動(dòng)脈向外生長(zhǎng)所致的“動(dòng)脈生成”也參與到運(yùn)動(dòng)所致的血管生成過(guò)程。

動(dòng)物實(shí)驗(yàn)表明運(yùn)動(dòng)能促進(jìn)大鼠齒狀回的神經(jīng)和血管再生[33]。Pereira等[34]應(yīng)用MRI顯示運(yùn)動(dòng)也能增加成人齒狀回的腦血容量，而皮質(zhì)腦血容量的增加與缺血后血管再生有相關(guān)性[35]。規(guī)范的運(yùn)動(dòng)鍛煉可影響NVU中神經(jīng)和血管再生間的復(fù)雜作用，能增強(qiáng)腦神經(jīng)血管網(wǎng)絡(luò)的功能。有研究發(fā)現(xiàn)[36]，運(yùn)動(dòng)療法能減小大腦中動(dòng)脈閉塞大鼠腦缺血后的梗死體積，降低其神經(jīng)功能缺損程度，減輕腦損傷。并且，這與內(nèi)皮型一氧化氮合酶（endothelial nitric oxide

synthase，eNOS）表達(dá)增加、一氧化氮依賴的血管舒張及局部腦血流量增加有關(guān)。大鼠卒中后運(yùn)動(dòng)能促進(jìn)血管再生和改善長(zhǎng)期的神經(jīng)功能預(yù)后，而且抑制內(nèi)皮的NOS或血管生成效應(yīng)會(huì)消除運(yùn)動(dòng)鍛煉對(duì)神經(jīng)修復(fù)的有益作用[37]。運(yùn)動(dòng)療法還能通過(guò)降低大鼠細(xì)胞間黏附分子1（intercellular adhesion molecule 1，ICAM-1）的表達(dá)導(dǎo)致腦源性神經(jīng)營(yíng)養(yǎng)因子（brainderived neurotrophic factor，BDNF）過(guò)表達(dá)來(lái)抑制炎癥損傷[38]。還有研究表明，大鼠在急性腦缺血之前的自發(fā)運(yùn)動(dòng)鍛煉可增加VEGF水平，后者可激活eNOS。短期的運(yùn)動(dòng)鍛煉即能增加人血液循環(huán)中EPCs的數(shù)量[39]，大鼠4周的鍛煉就可導(dǎo)致持久的循環(huán)EPCs增加[40]。Gertz等[37]通過(guò)大鼠大腦中動(dòng)脈缺血再灌注模型發(fā)現(xiàn)運(yùn)動(dòng)能促進(jìn)循環(huán)中的EPCs進(jìn)入缺血區(qū)，通過(guò)血管再生和血管舒張來(lái)增加微血管的密度和腦血流量，改善長(zhǎng)期的預(yù)后。運(yùn)動(dòng)訓(xùn)練還能促進(jìn)有缺血癥狀的患者循環(huán)中趨化性細(xì)胞因子受體4（chemotaxis cytokines receptors 4，CXCR4）的表達(dá)，后者可促進(jìn)和提高EPCs進(jìn)入內(nèi)皮網(wǎng)絡(luò)[41]。

目前大量研究表明，EPCs、VEGF、BDNF等的表達(dá)可能會(huì)從細(xì)胞分子水平闡明腦缺血后血管再生的相關(guān)機(jī)制。腦缺血損傷是解剖結(jié)構(gòu)上的，而其功能恢復(fù)卻可通過(guò)運(yùn)動(dòng)鍛煉重新獲得。因此，現(xiàn)代神經(jīng)發(fā)育理論已不再將注意力集中在損傷的部位和喪失的功能上，而是強(qiáng)調(diào)什么功能尚保留，什么功能可通過(guò)訓(xùn)練重新獲得。運(yùn)動(dòng)療法不受窄的時(shí)間窗的限制，能使更多患者獲益。運(yùn)動(dòng)療法通過(guò)刺激卒中后修復(fù)機(jī)制可以促進(jìn)內(nèi)源性神經(jīng)干細(xì)胞的激活、血管再生、神經(jīng)軸突的再生，有可能達(dá)到治療缺血性腦損傷的目的，但各種細(xì)胞因子之間具體的誘導(dǎo)過(guò)程，以及還有哪些神經(jīng)遞質(zhì)和神經(jīng)傳導(dǎo)途徑參與神經(jīng)功能恢復(fù)，還有待進(jìn)一步研究。

1 于頻. 系統(tǒng)解剖學(xué)[M]. 4版. 北京:人民衛(wèi)生出版社,1999:264.

2 Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future[J].Neuropharmacology, 2008, 55:363-389.

3 陳萍, 陳立云, 王擁軍. 缺血性卒中的神經(jīng)血管單元保護(hù)研究進(jìn)展[J]. 中國(guó)卒中雜志, 2007, 2:1003-1008.

4 Navarro-Sobrino M, Rosell A, Hernandez-Guillamon M, et al. A large screening of angiogenesis biomarkers and their association with neurological outcome after ischemic stroke[J]. Atherosclerosis, 2011, 216:205-211.

5 Hagg T. From neurotransmitters to neurotrophic factors to neurogenesis[J]. Neuroscientist,2009, 15:20-27.

6 Arvidsson A, Collin T, Kirik D, et al.Neuronal replacement from endogenous precursors in the adult brain after stroke[J].Nat Med, 2002, 8:963-970.

7 Thored P, Arvidsson A, Cacci E, et al.Persistent production of neurons from adult brain stem cells during recovery after stroke[J]. Stem Cells, 2006, 24:739-747.

8 Greenberg DA, Jin K. From angiogenesis to neuropathology[J]. Nature, 2005, 438:954-959.

9 Ding J, Cheng Y, Gao S, et al. Effects of nerve growth factor and noggin-modified bone marrow stromal cells on stroke in rats[J]. J Neurosci Res, 2011, 89:222-230.

10 Jiang WL, Zhang SP, Zhu HB, et al. Effect of 8-o-acetyl shanzhiside methylester increases angiogenesis and improves functional recovery after stroke[J]. Basic Clin Pharmacol Toxicol,2011, 108:21-27.

11 Manoonkitiwongsa PS, Jackson-Friedman C, McMillan PJ, et al. Angiogenesis after stroke is correlated with increased numbers of macrophages:The clean-up hypothesis[J]. J Cereb Blood Flow Metab, 2001, 21:1223-1231.

12 Petraglia AL, Marky AH, Walker C, et al.Activated protein C is neuroprotective and mediates new blood vessel formation and neurogenesis after controlled cortical impact[J]. Neurosurgery, 2010, 66:165-171.

13 Stroke Progress Review Group of National Institute of Neurological Disorders and Stroke.Report of the Stroke Progress Review Group of 2002[EB/OL]. http://www.ninds.nih.gov/about_ninds/groups.[2002-04-14](2014-03-20).

14 Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis[J]. J Comp Neurol, 2000, 425:479-494.

15 Beck H, Plate KH. Angiogenesis after cerebral ischemia[J]. Acta Neuropathol, 2009, 117:481-496.

16 Li Y, Chopp M. Marrow stromal cell transplantation in stroke and traumatic brain injury[J]. Neurosci Lett, 2009, 456:120-123.

17 Taguchi A, Soma T, Tanaka H, et al.Administration of CD34+cells after stroke enhances neurogenesis via angiogenesis in a mouse model[J]. J Clin Invest, 2004, 114:330-338.

18 中村隆一. 腦卒中康復(fù)[M]. 朱裕祥, 譯. 上海:華東師范大學(xué)出版社, 1994:89.

19 Nudo RJ, Wise BM, Sifuentes F, et al.Neursubsratees for the effects of rehabilitative training on motor recover following ischemic infarct[J]. Science, 1996, 272:1791-1794.

20 Traversa R, Cicinelli P, Bassi A, et al. Mapping of motor cortical reorganization after stroke:a brain stimulation study with focal magnetic pulses[J]. Stroke, 1997, 28:110-117.

21 Kim YH, Park JW, Ko MH, et al. Plastic changes of motor network after constraint-induced movement therapy[J]. Yonsei Med J, 2004, 45:241-246.

22 Levy CE, Nichols DS, Schmalbrok PM, et al. Functional MRI evidence of cortical reorganizition in upper-limb stroke hemiplegia treated with constraint-induced movement therapy[J]. Am J Phys Med Rehabit, 2001, 80:4-12.

23 趙傳勝, 戚其學(xué), 趙珊珊, 等. 腦缺血后強(qiáng)制性運(yùn)動(dòng)療法對(duì)內(nèi)源性神經(jīng)干細(xì)胞及基質(zhì)細(xì)胞衍生因子-1水平的影響[J]. 中國(guó)血液流變學(xué)雜志, 2007, 17:521-524.

24 Chalasani SH, Sabelko KA, Sunshine MJ, et al. A chemokine, SDF-1, reduces the effectiveness of multiple axonal repellents and is required for normal axon pathfinding[J]. J Neurosci, 2003,23:1360-1371.

25 Schwab ME. Nogo and axon regeneration[J]. Curr Opin Neurobiol, 2004, 14:118-124.

26 He Z, Koprivica V. The nogo signaling pathway for regeneration block[J]. Annu Rev Neurosci,2004, 27:341-368.

27 Fournier AE, Takizawa BT, Strittmatter SM. Rho kinase inhibition enhances axonal regeneration in the injured CNS[J]. J Neurosci, 2003, 23:1416-1423.

28 Zhao S, Zhao M, Xiao T, et al. Constraintinduced movement therapy overcomes the intrinsic axonal growth-inhibitory signals in stroke rats[J]. Stroke, 2013, 44:1698-1705.

29 翟志永, 聶瑩雪, 趙傳勝, 等. 強(qiáng)制性運(yùn)動(dòng)療法對(duì)大鼠腦缺血再灌注后神經(jīng)修復(fù)及Rho激酶表達(dá)的影響[J].中國(guó)醫(yī)科大學(xué)學(xué)報(bào), 2008, 37:295-298.

30 Rolland Y, van Kan GA, Vellas B. Healthy brain aging:role of exercise and physical activity[J].Clin Geriatr Med, 2010, 26:75-87.

31 Leung FP, Yung LM, Laher I, et al. Exercise,vascular wall and cardiovascular diseases:an update. Part 1[J]. Sports Med, 2008, 38:1009-1024.

32 Zhang F, Wu Y, Jia J. Exercise preconditioning and brain ischemic tolerance[J]. Neuroscience,2011, 177:170-176.

33 Vander Borght K, Kóbor-Nyakas DE, Klauke K, et al. Physical exercise leads to rapid adaptations in hippocampal vasculature:temporal dynamics and relationship to cell proliferation and neurogenesis[J]. Hippocampus, 2009, 19:928-936.

34 Pereira AC, Huddleston DE, Brickman AM, et al. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus[J].Proc Natl Acad Sci USA, 2007, 104:5638-5643.

35 Seevinck PR, Deddens LH, Dijkhuizen RM. Magnetic resonance imaging of brain angiogenesis after stroke[J]. Angiogenesis,2010, 13:101-111.

36 Endres M, Gertz K, Lindauer U, et al.Mechanisms of stroke protection by physical activity[J]. Ann Neurol, 2003, 54:582-590.

37 Gertz K, Priller J, Kronenberg G, et al.Physical activity improves long-term stroke outcome via endothelial nitric oxide synthasedependent augmentation of neovascularization and cerebral blood flow[J]. Circ Res, 2006,99:1132-1140.

38 Ding YH, Young CN, Luan X, et al. Exercise preconditioning ameliorates inflammatory injury in ischemic rats during reperfusion[J]. Acta Neuropathol, 2005, 109:237-246.

39 Rehman J, Li J, Parvathaneni L, et al. Exercise acutely increases circulating endothelial progenitor cells and monocyte/macrophagederived angiogenic cells[J]. J Am Coll Cardiol,2004, 43:2314-2318.

40 Laufs U, Werner N, Link A, et al. Physical training increases endothelial progenitor cells,inhibits neointima formation, and enhances angiogenesis[J]. Circulation, 2004, 109:220-226.

41 Sandri M, Adams V, Gielen S, et al. Effects of exercise and ischemia on mobilization and functional activation of blood-derived progenitor cells in patients with ischemic syndromes:results of 3 randomized studies[J].Circulation, 2005, 111:3391-3399.