運動預處理誘導腦缺血耐受機制的研究進展①

吳孝軍，朱路文，李宏玉，唐強

運動預處理誘導腦缺血耐受機制的研究進展①

吳孝軍1，朱路文2，李宏玉1，唐強2

運動預處理可誘導腦缺血性損傷耐受，具有顯著的腦神經(jīng)系統(tǒng)保護作用。運動預處理改善腦缺血性損傷的具體作用機制較為復雜，涉及多靶點、多途徑的調(diào)控，其中抑制細胞凋亡、促進腦神經(jīng)血管生成、抑制谷氨酸的過度激活以及調(diào)控炎癥反應是運動預處理誘導腦缺血耐受的關(guān)鍵機制。然而運動預處理誘導腦缺血耐受的機制遠不止于此，有待進一步研究和發(fā)現(xiàn)。

腦缺血；耐受；運動預處理；綜述

[本文著錄格式]吳孝軍，朱路文，李宏玉，等.運動預處理誘導腦缺血耐受機制的研究進展[J].中國康復理論與實踐,2015, 21(6):657-661.

CITED AS:Wu XJ,Zhu LW,Li HY,et al.Advance in mechanism of cerebral ischemia tolerance induced by exercise preconditioning (review)[J].Zhongguo Kangfu Lilun Yu Shijian,2015,21(6):657-661.

腦血管病(cerebrovascular disease,CVD)占我國最常見致殘和致死原因的第二位[1]，其中以腦血管阻塞性缺血所致的缺血性腦卒中最為常見，發(fā)病率約占腦卒中的70%[2]。尋找有效的防治手段，以減小腦缺血損傷后腦組織梗死的面積，成為預防醫(yī)學和臨床醫(yī)學的研究熱點。

運動預處理(exercise preconditioning,EP)，即在腦缺血前給予多次相同的運動訓練，可有效誘導腦缺血耐受，產(chǎn)生明顯腦神經(jīng)系統(tǒng)保護作用，并減緩因腦缺血引發(fā)的一系列腦組織損傷[3]。相比于其他預處理方式，其優(yōu)勢在于便于掌握，易被患者接受，臨床上便于操作。目前研究普遍認為運動預處理是與多個通道、多個水平、多個靶點密切相關(guān)的綜合性系統(tǒng)。

1 神經(jīng)元凋亡

缺血損傷后腦神經(jīng)細胞的損傷表現(xiàn)為兩種方式，一種是由于嚴重的腦組織損傷而導致的直接性病理死亡，而另一種則是細胞程序性凋亡(programmed cell death,PCD)，也就是所謂的細胞生理性死亡，是由于細胞內(nèi)部自殺程序在內(nèi)外界因素的刺激下被激活而導致的。細胞凋亡在腦組織缺血性損傷中，尤其是腦缺血再灌注性損傷中發(fā)揮著關(guān)鍵性作用[4-6]。腦缺血損傷發(fā)生后的遲發(fā)性神經(jīng)元死亡以凋亡為主[7]。如果能及時有效地阻止神經(jīng)元凋亡的發(fā)生發(fā)展，可以有效減輕由于腦缺血造成的腦組織損傷。

Tahamtan等發(fā)現(xiàn)運動預處理使缺血性損傷的腦組織海馬區(qū)保留更多存活的神經(jīng)元，有效減少神經(jīng)元凋亡[8]。Zhang等研究指出運動訓練有效緩解腦卒中后自噬現(xiàn)象，并降低神經(jīng)細胞凋亡[9]。Chaudhry等研究表明運動訓練誘發(fā)的神經(jīng)保護可能是通過調(diào)節(jié)基質(zhì)金屬蛋白酶-9(matrix metalloprotein-9,MMP-9)和細胞外調(diào)節(jié)蛋白激酶(extracellular regulated protein kinases 1/2, ERK1/2)的表達，以減少神經(jīng)細胞凋亡而實現(xiàn)的[10]。Liebelt等

發(fā)現(xiàn)運動預處理可以通過調(diào)控熱休克蛋白70(heat shock protein-70,HSP-70)和磷酸化ERK1/2的表達，減輕腦缺血/再灌注損傷[11]，ERK和HSP-70的抑制劑可同時使運動預處理產(chǎn)生的腦保護作用消失。磷酸化ERK1/2抑制劑可以有效減少腦組織受損，但不能導致HSP-70蛋白表達降低。這個現(xiàn)象表明，在運動預處理后的缺血性腦損傷中，HSP-70并非ERK1/2的下游調(diào)節(jié)蛋白。之前已有研究表明，HSP-70可通過抑制細胞凋亡誘導因子(apoptosis-inducing factor,AIF)并促進抗凋亡蛋白B淋巴細胞瘤-2基因(B-cell lymphoma-2,Bcl-2)家族，產(chǎn)生抗細胞凋亡作用[12]。ERK介導的信號通路在缺血誘導的細胞凋亡過程中發(fā)揮重要作用，可能與調(diào)節(jié)Bcl-2相關(guān)X蛋白(Bcl-2 associated x protein,Bax)蛋白/Bcl-2蛋白的表達有關(guān)[13-14]。運動預處理影響B(tài)cl-2和Bax蛋白表達產(chǎn)生腦保護作用的機制與低氧預處理的機制相類似，Bcl-2和Bax分別是調(diào)控神經(jīng)元凋亡分子家族中的核心成員[15]。王璐等也認為運動預處理能減少力竭運動誘導的大鼠大腦皮質(zhì)細胞凋亡，產(chǎn)生腦細胞保護作用，其對細胞凋亡的調(diào)控作用可能是通過影響B(tài)cl-2和Bax蛋白表達而實現(xiàn)的[16]。Cho和Ji等認為，原位末端轉(zhuǎn)移酶標記技術(shù)(TdT-mediated dUTP Nick-End Labeling,TUNEL)中顯示的陽性細胞代表凋亡細胞，其中半胱胺酸蛋白酶蛋白-3(caspase-3)是細胞凋亡的主要執(zhí)行者之一[17-18]。Choi等研究發(fā)現(xiàn)短期跑步鍛煉抑制缺氧缺血性損傷所誘導的DNA分裂，有效降低caspase-3的表達，從而對腦組織細胞凋亡產(chǎn)生抑制作用[19]。Zhang等也發(fā)現(xiàn)運動預處理可減小缺血性腦損傷腦梗死體積，減少神經(jīng)元凋亡，產(chǎn)生神經(jīng)保護作用，其機制可能與抑制caspase-3和上調(diào)Bcl-2的表達有關(guān)[20]。Zhao等還發(fā)現(xiàn)運動訓練降低細胞色素C和AIF的釋放，減少AIF遷移至細胞核并抑制caspases激活，從而阻斷關(guān)鍵的細胞凋亡途徑[21]。我們可以認為，運動預處理可以通過增加ERK 1/2和HSP-70的表達誘發(fā)腦缺血耐受，其中細胞凋亡誘導因子和抗凋亡蛋白發(fā)揮著重要作用。

2 腦血管生成及神經(jīng)再生

運動預處理通過多種機制誘導腦缺血耐受，包括促進神經(jīng)血管生成和血管內(nèi)皮生長因子(vascular endothelial growth factor,VEGF)的表達[3]。Thomas等在動物實驗中發(fā)現(xiàn)跑步訓練可刺激血管生成和神經(jīng)再生[22]。磁共振腦血管成像(magnetic resonance angiography,MRA)可以有效檢測腦血管發(fā)生的細微變化。Bullitt研究發(fā)現(xiàn)健康受試者在運動訓練以后，使用MRA檢測腦血管的情況時發(fā)現(xiàn)微血管數(shù)量發(fā)生變化[23]。Isaacs等認為較大強度的運動預處理導致中年雌性大鼠小腦中毛細血管的密度明顯增加[24]；同時運動訓練也能提高大鼠腦皮質(zhì)運動區(qū)的血管新生并增強中年大鼠紋狀體腦血管的完整性[25-27]。此外，Hu等發(fā)現(xiàn)7～14 d的運動活動可以提高微血管生成重要標志物CD31的表達[28]。Rhyu等在動物實驗中發(fā)現(xiàn)適當?shù)倪\動訓練導致猴腦皮質(zhì)血管密度增加，但在運動結(jié)束后3個月時血管密度又回到訓練前水平，說明持續(xù)的運動訓練才能發(fā)揮腦保護作用[29]。Zwagerman等認為運動預處理明顯增加大鼠短暫性腦缺血發(fā)作再灌注過程中腦血流量[30]。Zhang等研究表明運動訓練增加腦缺血損傷后腦皮質(zhì)微血管密度，改善血液流動能力，同時減少腦梗死體積，從而促進神經(jīng)功能恢復[31]。這其中所涉及的血管生成過程可能與Tie-2、p-Akt蛋白的表達增加有關(guān)。Zhang等發(fā)現(xiàn)缺血前跑步機訓練可以通過調(diào)節(jié)腦血流量(cerebral blood flow,CBF)和內(nèi)皮素-1(endothelin-1,ET-1)而防止缺血性腦組織損傷[32]。

VEGF在血管生成的過程中發(fā)揮著關(guān)鍵作用，運動預處理通過上調(diào)VEGF和腦源性神經(jīng)營養(yǎng)因子(brain derived neurotrophic factor,BDNF)增加大鼠腦皮質(zhì)和紋狀體的血管密度[26]。Kang等研究指出運動預處理通過增加VEGF在運動皮層的表達來促進微血管的完整性[33]。Matsuda等認為局部缺血后運動預處理可上調(diào)中期因子(midkine,MK)、血小板內(nèi)皮細胞黏附分子1(platelet endothelial cell adhesion molecule-1,PECAM-1)和神經(jīng)生長因子，以改善梗死區(qū)周圍的血管生成[34]。Ma等研究指出運動預處理有效增加VEGF和基質(zhì)后金屬基質(zhì)蛋白酶-2(matrix metalloprotein-2,MMP-2)的基因和蛋白表達[35]。此外，運動預處理提高了胰島素樣生長因子(insulin-like growth factors,IGF)的表達，其與神經(jīng)、血管生成密切相關(guān)[36-37]。Lee等發(fā)現(xiàn)腦缺血后促血管生成素(angiopoietins,Ang)及其受體Tie-2構(gòu)成的Ang/ Tie-2系統(tǒng)在血管新生中發(fā)揮了關(guān)鍵性作用[38]。研究還發(fā)現(xiàn)適當強度的運動訓練在急性腦缺血病發(fā)生后導致腦梗死體積減小，同時增加腦缺血區(qū)周圍的血管密度。這一機制可能與促進Ang-1、Tie-2以及其下游磷脂酰肌醇3激酶(Phosphatidylinositol 3-kinase,PI3K)/蛋白激酶B(protein kinase B,PKB，也稱為Serine/threonine Kinase,Akt)的表達有關(guān)。

BDNF在增加突觸可塑性和促進神經(jīng)再生方面發(fā)揮著重要作用。Thomas等研究指出運動訓練提高包括BDNF在內(nèi)的多種生長因子表達水平，對于細胞存活、神經(jīng)突生長，以及其他形式的神經(jīng)再生具有重要意義[22]。Padilla等發(fā)現(xiàn)跑步訓練調(diào)節(jié)BDNF和突觸蛋白I的mRNA表達，促進腦卒中患者更好地恢復[39]。Liu等研究表明運動訓練促進線粒體功能，增加BDNF和腦抗氧化酶的表達，從而保持腦能量代謝穩(wěn)定[40]。Yang等研究發(fā)現(xiàn)主動運動訓練顯著增加BDNF的表達，后者通過上調(diào)小鼠大腦皮層和海馬區(qū)DNA修復的酶脫嘌呤/脫嘧啶核酸內(nèi)切酶-1(Apurinic/apyrimidinic endonuclease-1,APE1)的表達，以增強DNA的修復，減輕神經(jīng)元損傷[41]。神經(jīng)營養(yǎng)蛋白4(Neurotrophin-4,NT-4)屬于神經(jīng)營養(yǎng)因子家族，與BDNF相類似，都具有腦保護作用。Chung等發(fā)現(xiàn)跑步機訓練改變了NT-4及其受體trkB的表達，減輕大鼠缺血性腦損壞程度[42]。Zheng等研究表明運動訓練直接影響神經(jīng)功能恢復，這一過程與激活IGF-1/ Akt信號通路導致神經(jīng)祖細胞數(shù)量增加有關(guān)[43]。Zhang等研究表明運動預處理增加梗死區(qū)周圍IGF-1的表達及細胞增殖，促進腦缺血后神經(jīng)再生[31]。我們歸納認為，運動預處理通過調(diào)整一系列相關(guān)蛋白的表達，促進腦神經(jīng)血管再生，同時增加腦血流量，從而發(fā)揮腦神經(jīng)保護作用，保持神經(jīng)血管單元的完整性。

3 谷氨酸興奮性毒性

缺血性腦卒中后谷氨酸的過量釋放加重腦組織損傷程

度[44]。Danbolt等認為谷氨酸轉(zhuǎn)運體1(Glutamate transporter-1, GLT-1)在去除腦組織谷氨酸時發(fā)揮最重要的作用[45]。Yang等發(fā)現(xiàn)運動預處理上調(diào)腦缺血后GLT-1的表達，減少細胞外谷氨酸濃度，降低腦梗死體積和改善神經(jīng)功能[46]。Kalandadze等發(fā)現(xiàn)蛋白激酶C(protein kinase C,PKC)的激活可降低細胞表面GLT-1的表達，這可能會抑制細胞外谷氨酸的消除[47]。此外，P13K/ Akt通路也參與這一保護機制[48]。

Zhang等認為缺血前運動預處理可以抑制谷氨酸過度釋放，這可能會涉及事件相關(guān)激酶ERK1/2的變化[49]。Wang等研究表明運動預處理通過調(diào)節(jié)興奮性氨基酸轉(zhuǎn)運蛋白2(excitatory amino acid transporters 2,EAAT-2)和ERK1/2的表達，誘導腦缺血耐受[50]。Zhang等的研究還發(fā)現(xiàn)運動預處理能抑制谷氨酸受體的表達，如代謝型谷氨酸受體5(metabotropic glutamate receptors 5,mGluR5)和N-甲基-D-天冬氨酸受體亞基2B型(N-methyl-D-aspartate receptor 2B subunit,NR2B)，減輕谷氨酸過度釋放的神經(jīng)毒性[51]。Wang等認為運動預處理可以通過上調(diào)GLT-1表達促進缺血性損傷后谷氨酸的攝取，抑制NR2B和mGluR5的表達水平，以減少谷氨酸興奮性毒性，這可能涉及兩條信號通路：PKC-A-GLT-1-谷氨酸和PI3K/Akt信號-GLT-1-谷氨酸[52]。因此，運動預處理可以通過調(diào)節(jié)谷氨酸系統(tǒng)的興奮性毒性誘導腦缺血耐受。

4 炎癥反應

腦缺血性損傷可迅速引發(fā)缺血后的炎癥反應。正常的炎癥反應可以有效地減少進入機體的病原微生物，以此來保持我們的機體健康；但是炎癥反應的過度活化進一步加重腦組織的損傷。Jander等發(fā)現(xiàn)炎癥介質(zhì)在保護性預處理過程中發(fā)揮著明顯作用，成為缺血性腦卒中后防治的重要靶點[53]。

Wang等研究表明炎癥反應在急性缺血性腦卒中中發(fā)揮重要作用，神經(jīng)元損傷加重白細胞浸潤、微血管損傷和自由基的產(chǎn)生[54]。Berti等認為許多炎性細胞因子如腫瘤壞死因子α(tumor necrosis factor-α,TNF-α)、白細胞介素1β(interleukin-1β, IL-1β)和白細胞介素6(interleukin-6,IL-6)，都參與缺血性腦卒中后的炎癥反應[55]。Park等發(fā)現(xiàn)運動預處理通過調(diào)節(jié)TNF-α和IL-1β可部分阻止沙鼠腦缺血后海馬神經(jīng)元凋亡[56]。Ding等認為運動預處理可以通過降低炎癥介質(zhì)的表達和引起白細胞的積聚，降低腦缺血/再灌注損傷[57]。運動預處理可以有效降低腦缺血區(qū)皮層上TNF-α受體表達，這一結(jié)論表明TNF-α參與多次重復運動預處理誘導的腦缺血耐受[58]。Laflamme等研究表明，Toll樣受體4(toll like receptor 4,TLR4)在中樞神經(jīng)系統(tǒng)內(nèi)的表達是其介導腦缺血后炎癥反應的基礎[59]。腦缺血前的運動預處理可以有效下調(diào)TLR4的表達，降低腦組織損傷[60]，降低其引發(fā)的炎性細胞因子級聯(lián)反應[61]，通過下調(diào)TLR2和TLR4抑制核因子-kB(nuclear factor-kB,NF-kB)和髓樣分化因子(myeloiddifferentiationfactor88,MyD88)的過度表達[62]，從而減輕腦缺血損傷中白細胞遷移、滲透和積累。

最新相關(guān)研究表明，腦缺血再灌注后24 h，在運動預處理組血清中TNF-α、IL-1β及IL-6的含量均顯著降低，腦缺血區(qū)域皮質(zhì)的病理性損傷明顯減輕，神經(jīng)功能得到明顯改善。這表明運動預處理可降低腦缺血再灌注損傷過程中與炎癥反應相關(guān)因子的濃度，有效抑制由于炎癥所引起的級聯(lián)反應，因而減輕腦缺血再灌注后腦組織的損傷，發(fā)揮腦神經(jīng)系統(tǒng)保護作用[63]。

5小結(jié)

綜上所述，運動預處理通過抑制神經(jīng)細胞凋亡，促進神經(jīng)血管再生，抑制谷氨酸過度釋放，減輕炎癥反應，以誘導腦缺血耐受。未來很可能會更多通過分子機制層面來探討這一耐受機制。無論以什么樣的方法和形式來闡明運動預處理誘導腦缺血耐受的機制都將有利于提高人們對缺血性腦損傷的認識，為運動訓練作為缺血性腦卒中的有效防治措施提供堅實的理論基礎，鼓勵具有腦卒中危險因素的患者積極參加各種運動項目。

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Advance in Mechanism of Cerebral Ischemia Tolerance Induced by Exercise Preconditioning(review)

WU Xiao-jun1,ZHU Lu-wen2,LI Hong-yu1,TANG Qiang2
1.Heilongjiang University of Chinese Medicine,Harbin,Heilongjiang 150040,China;2.The Second Hospital Affiliated to Heilongjiang University of Chinese Medicine,Harbin,Heilongjiang 150001,China

Cerebral ischemia tolerance was induced by exercise preconditioning,which protected the brain from injury.The detailed mechanism of exercise preconditioning protecting cerebral ischemia injury was complicated,which involving the regulation of multiple target point and multi-path,such as inhibiting cell apoptosis,promoting angiogenesis in the brain,inhibiting the excessive activation of glutamic acid as well as the regulation of inflammation.More mechanisms were still unknown.

cerebral ischemia;tolerance;exercise preconditioning;review

10.3969/j.issn.1006-9771.2015.06.006

R743.3

A

1006-9771(2015)06-0657-05

2015-03-17

2015-04-20)

1.哈爾濱市科技創(chuàng)新人才專項基金(青年后備人)(No.2014RFQGJ150)；2.黑龍江中醫(yī)藥大學領軍人才計劃項目(No.2012RCL02)；3.黑龍江省高?？萍紕?chuàng)新團隊計劃項目(No.2013TD007)。

1.黑龍江中醫(yī)藥大學，黑龍江哈爾濱市150040；2.黑龍江中醫(yī)藥大學附屬第二醫(yī)院，黑龍江哈爾濱市150001。作者簡介：吳孝軍(1990-)，男，遼寧遼陽市人，碩士研究生，主要研究方向：腦卒中中醫(yī)康復的基礎研究。通訊作者：唐強(1963-)，男，四川大竹縣人，博士，教授，主要研究方向：神經(jīng)系統(tǒng)疾病中醫(yī)康復基礎與臨床。E-mail:tangqiang1963@163.com。