電針對脊髓損傷后軸突再生影響的研究進展①

鄭利強，江瓊，胡春蓉，伍亞民

電針對脊髓損傷后軸突再生影響的研究進展①

鄭利強1,2，江瓊3，胡春蓉2，伍亞民1

脊髓損傷后運動功能恢復一直是醫(yī)學界面臨的重大難題，而軸突再生是脊髓損傷后運動和神經(jīng)功能恢復的基礎(chǔ)和目標。目前研究認為，電針對脊髓損傷后軸突再生的作用明確。本文主要從膠質(zhì)瘢痕的形成、軸突生長抑制因子的作用、神經(jīng)營養(yǎng)因子的分泌以及神經(jīng)元內(nèi)在生長狀態(tài)等方面總結(jié)電針對脊髓損傷后軸突再生的作用。

脊髓損傷；軸突再生；電針；膠質(zhì)瘢痕；綜述

脊髓損傷(spinal cord injury)是一種嚴重致殘性疾病，給患者心理和身體帶來嚴重傷害。雖然目前臨床上不能通過有效治療使脊髓損傷后功能完全恢復，但是許多動物實驗研究表明，脊髓損傷后功能有不同程度的恢復。軸突通過再生的方法，與靶細胞可以形成功能性的突觸，這是脊髓損傷后運動和神經(jīng)功能恢復的基礎(chǔ)和目標。特殊情況下，軸突可以發(fā)芽、生長和延伸，通過這些方法，與靶細胞重新建立聯(lián)系，實現(xiàn)神經(jīng)的再次支配，進而使運動及神經(jīng)功能恢復。

一般來說，脊髓損傷后，損傷軸突再生或/和芽生并不少見，但由于膠質(zhì)瘢痕的形成、軸突生長抑制因子的存在、神經(jīng)營養(yǎng)因子分泌的不足以及神經(jīng)元內(nèi)在生長狀態(tài)等因素的影響，神經(jīng)損傷后軸突再生比較困難。近年來人們在不斷加強脊髓損傷后軸突再生的機制及其修復的實驗性治療的同時，開始注意采用傳統(tǒng)中醫(yī)學的理論和技術(shù)方法，探討其對脊髓損傷后軸突再生可能作用及機制，而其中電針對脊髓損傷的研究備受關(guān)注。本文主要就電針對損傷后軸突再生的影響進行綜述。

1 電針對膠質(zhì)瘢痕形成的影響

脊髓損傷后，星形膠質(zhì)細胞會增生性地生長，使脊髓在結(jié)構(gòu)形態(tài)上保持完整性，同時對神經(jīng)組織也會起到一定的營養(yǎng)和支持作用。后期，星形膠質(zhì)細胞持續(xù)被激活，分泌或合成抑制性的因子；同時膠質(zhì)細胞過度增生，會在損傷區(qū)形成致密的膠質(zhì)瘢痕。通過干細胞移植等方法，能使軸突有效再生，但是再生的軸突接觸到致密的膠質(zhì)瘢痕時，其軸突的再生就會受到抑制，停止生長[1]。膠質(zhì)瘢痕通過機械性屏障作用抑制軸突的再生及延長[2]，阻止脊髓損傷后的功能恢復。同時膠質(zhì)瘢痕也可以通過壓迫局部微血管，阻礙損傷部位血液的供應(yīng)[3]，影響功能恢復。

膠質(zhì)纖維酸性蛋白(glial fibrillary acidic protein,GFAP)與星形膠質(zhì)細胞的活化程度密切相關(guān)，是膠質(zhì)瘢痕形成的主要標志[4]。當GFAP表達下降，膠質(zhì)瘢痕的形成會受到明顯抑制，軸突的芽生會明顯增強[5]，這不僅說明GFAP對膠質(zhì)瘢痕的重要性，同時也證實通過抑制GFAP的表達能有效緩解膠質(zhì)瘢痕的形成，對軸突的再生有很好的促進作用。

脊髓損傷后，電針刺激能有效降低損傷部位GFAP含量，阻止軸突變性，改善軸突再生[6]，可能與阻止膠質(zhì)瘢痕的形成有關(guān)。電針刺激足三里和內(nèi)庭，可使白質(zhì)中的空洞減少，抑制膠質(zhì)細胞增生，促進肢體功能的恢復[7]。這些研究提示，電針刺激可以通過有效降低GFAP含量，抑制星形膠質(zhì)細胞過度增生，從而減少膠質(zhì)瘢痕對軸突再生的阻礙作用，同時也創(chuàng)造出對軸突再生有利的微環(huán)境，促進軸突再生。

2 電針對軸突生長抑制因子的作用

脊髓損傷后會分泌大量抑制因子：GFAP、硫酸軟骨素蛋白聚糖(chondroitin sulfate proteoglycans,CSPGs)、硫酸角質(zhì)素蛋白多糖(keratin sulfate proteoglycan,KSPGs)、腱糖蛋白及斥性軸突導向分子(repulsive axon guidance molecules,RGM)等，阻礙軸突的有效再生。目前研究比較多的是CSPGs。

在中樞神經(jīng)系統(tǒng)(central nervous system,CNS)中，CSPGs主要參與構(gòu)成細胞外基質(zhì)，對軸突的生長和延伸有明顯的抑制作用。在CSPGs大量聚集的部位，會形成對軸突的生長有阻礙作用的屏障結(jié)構(gòu)，當使用硫酸軟骨素酶消除高表達的CSPGs時，神經(jīng)軸突會明顯生長[8]，同時伴隨運動及感覺功能的恢復[9]。

脊髓損傷后，星形膠質(zhì)細胞分泌的CSPGs大量聚集在損傷部位，參與膠質(zhì)瘢痕的形成，促使軸突末端生長錐塌陷[10-11]，嚴重影響軸突的再生及髓鞘化，使軸突和神經(jīng)功能的再生受到明顯抑制[12-13]。Davies等[14]將生長的神經(jīng)元軸突移植到大鼠脊髓損傷部位，當生長的軸突未與CSPGs接觸時，軸突生長未見停止；若軸突與之接觸則軸突就會停止生長，這充分表明軸突再生受到CSPGs抑制，同時其神經(jīng)功能的恢復也受到抑制。而在脊髓損傷后給予電針刺激，會明顯降低CSPGs的表達[6]，減弱CSPGs對軸突再生的抑制作用，明顯改善軸突再生，促進功能恢復。

3 電針增強神經(jīng)營養(yǎng)因子的表達

神經(jīng)營養(yǎng)因子是一種對神經(jīng)元的存活和生長至關(guān)重要的蛋白質(zhì)分子，通過其受體進入軸突，導致不同的信號通路激活或抑制細胞，調(diào)節(jié)蛋白表達，發(fā)揮其對神經(jīng)元的保護作用[15]。神經(jīng)營養(yǎng)因子也可以通過調(diào)節(jié)突觸可塑性[16-17]，促進損傷軸突的有效再生[18]，完成對脊髓損傷后功能恢復的作用。神經(jīng)營養(yǎng)因子在中樞神經(jīng)損傷后會反應(yīng)性增多，能有效改善局部微環(huán)境，積極預(yù)防繼發(fā)性損傷。雖然損傷后神經(jīng)營養(yǎng)因子會明顯增高，但仍然不能滿足損傷后功能恢復的需要。目前研究較多的有神經(jīng)生長因子(nerve growth factor,NGF)、腦源性神經(jīng)營養(yǎng)因子(brain-derived neurotrophic factor,BDNF)和神經(jīng)營養(yǎng)素-3(neurotrophin-3,NT-3)。

NGF是一個典型的神經(jīng)營養(yǎng)因子，在維持神經(jīng)元的存活及促進軸突延伸方面有顯著的效果[19-20]。電針能促使NGF及NGF高親和力受體TrkA表達增高[21]，通過上調(diào)神經(jīng)營養(yǎng)因子的表達，促進神經(jīng)元功能的恢復[22]。貓背根神經(jīng)節(jié)受損后，電針刺激可以使受損神經(jīng)元中NGF含量明顯增加，有助于損傷后的功能恢復[23]。電針刺激環(huán)跳穴，可以增加NGF的含量，調(diào)節(jié)Fos的表達，促進神經(jīng)損傷的修復[24]。

BDNF是一種具有促進神經(jīng)元存活及分化、誘導軸突再生的神經(jīng)營養(yǎng)因子[25-26]。Jin等[27]將能表達BDNF的細胞移植到脊髓損傷部位4～5周后發(fā)現(xiàn)軸突生長距離較對照組明顯增長；通過皮質(zhì)脊髓束的順行示蹤發(fā)現(xiàn)，外源性BDNF可以促進損傷部位軸突的明顯再生[28]；BDNF也可以通過介導脊髓的再髓鞘化，對損傷部位軸突有一定的促進作用[29]。督脈電針能誘導BDNF蛋白表達增加，對神經(jīng)元的存活及皮質(zhì)脊髓束的修復有積極的治療作用，促進脊髓損傷后的功能恢復[30]。與非電針組相比，電針組能增加BDNF在小、中神經(jīng)元中的表達[23]，促進其神經(jīng)再生。

NT-3對于脊髓灰質(zhì)神經(jīng)元，特別是腹側(cè)角運動神經(jīng)元的存活和正常功能，發(fā)揮重要作用[31]，對損傷后的神經(jīng)元也有積極的治療作用，促進軸突的有效再生[32-33]。Huang等[34]研究表明，電針通過上調(diào)NT-3的表達，促進內(nèi)源性少突膠質(zhì)前體細胞(oligodendrocyte precursor cells,OPCs)增殖和分化，抑制損傷脊髓脫髓鞘，促進髓鞘的有效再生。Mo等[35]認為，電針刺激大椎和命門穴能上調(diào)NT-3的表達，對神經(jīng)元的存活及軸突再生有明顯的促進作用[15]，可能是通過防止能合成和分泌NT-3的某些細胞的凋亡完成的[35]。電針治療能增加NT-3的表達，促進NT-3受體基因修飾的間充質(zhì)干細胞向少突膠質(zhì)細胞樣細胞分化，改善脊髓脫髓鞘病變[36]，對脊髓損傷有神經(jīng)保護作用[37]。

4 電針改善神經(jīng)元內(nèi)在生長狀態(tài)

CNS損傷后軸突再生和修復困難的主要原因是神經(jīng)元生長狀態(tài)不同。與周圍神經(jīng)神經(jīng)元相比，即使將中樞神經(jīng)神經(jīng)元種植在良好的生長底物上，CNS神經(jīng)元軸突再生能力也相對較弱。在神經(jīng)元內(nèi)在生長狀態(tài)不變的情況下，僅僅通過阻斷膠質(zhì)瘢痕及其他微環(huán)境的抑制信號，無法使神經(jīng)元髓鞘有效再生[38]。提高神經(jīng)元內(nèi)在生長狀態(tài)已成為脊髓損傷后軸突再生的熱點，近幾年研究比較多的是如何通過提高環(huán)磷酸腺苷(cyclic adenosine monophosphate,cAMP)/蛋白激酶A(protein kinase A,PKA)水平、抑制Rho/Rho相關(guān)卷曲螺旋形成蛋白激酶(Rho associated coiled-coil forming protein kinase,ROCK)信號傳導促進損傷后軸突的再生。

cAMP是對哺乳動物神經(jīng)元存活和分化、神經(jīng)突長度及神經(jīng)導向有調(diào)節(jié)作用的細胞內(nèi)信號[39]。cAMP通過激活PKA完成對神經(jīng)突起和生長錐的調(diào)節(jié)作用[40-41]。采用cAMP類似物培養(yǎng)神經(jīng)細胞，能促進神經(jīng)元存活及神經(jīng)突起生長[42]。適宜濃度的cAMP可以使生長錐保持運動，并防止崩解[43]，進而對神經(jīng)突生長有明顯的促進作用[44]。神經(jīng)損害后，當細胞內(nèi)cAMP水平高表達時，PKA能夠被激活，從而抑制各種信號傳遞，抑制軸突再生[45-46]。有研究表明，電針能通過降低cAMP和PKA活化[47]，調(diào)節(jié)cAMP/PKA表達水平[48]，促進損傷后軸突的再生[45]。

Rho/ROCK信號通路在介導神經(jīng)軸突再生方面有重要作用。由于Ras同源基因A(Ras homolog gene A,RhoA)有控制細胞骨架重組及動力學的能力，所以其在負調(diào)控軸突生長方面起關(guān)鍵性作用，被作為眾多軸突再生抑制劑的主要靶標[49]。在培養(yǎng)背根神經(jīng)元過程中，可以通過激活ROCK來抑制神經(jīng)突的生長[50]。ROCK在軸突生長和微管組裝中具有重要作用[51]。CNS損害后所有髓鞘相關(guān)抑制因子通過各自相關(guān)信號途徑，最終都作用于RhoA，激活ROCK，對軸突再生產(chǎn)生抑制性作用[52]。研究表明RhoA/ROCK信號通路既可以通過調(diào)節(jié)激動蛋白致使生長錐塌陷，也可以調(diào)節(jié)細胞骨架中的微管及中間絲[53]來發(fā)揮其抑制軸突的作用。

脊髓損傷后，電針大椎和命門穴治療7 d，大鼠運動功能改善，脊髓凋亡細胞量下降，同時伴有RhoA和Nogo-A蛋白及mRNA下降，說明電針通過下調(diào)RhoA和Nogo-A的表達促進脊髓損傷的恢復[54]。電針刺激可以增強軸突再生和皮質(zhì)脊髓束的投射，可能是通過調(diào)節(jié)RhoA和生長相關(guān)蛋白-43(growth-associated protein-43,GAP-43)的表達[55]，改善神經(jīng)功能的恢復。

綜上所述，電針從膠質(zhì)瘢痕形成、軸突生長抑制因子、神經(jīng)營養(yǎng)因子缺乏以及神經(jīng)元內(nèi)在生長狀態(tài)等分子機制方面促進脊髓損傷后軸突的再生，對改善脊髓損傷后功能恢復有一定療效，可作為脊髓損傷后治療的一個重要方向，但其臨床效果有待進一步研究。

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Research Progress of Electroacupuncture onAxonal Regeneration after Spinal Cord Injury(review)

ZHENG Li-qiang1,2,JIANG Qiong3,HU Chun-rong2,WU Ya-min1
1.Daping Hospital of the Third Military Medical University,Chongqing 400042,China;2.Chongqing Ninth People's Hospital,Chongqing 400700,China;3.Chongqing Medical University,Chongqing 400016,China

The restoration of motor function after spinal cord injury is a major problem in the medical field,in which axonal regeneration is the basis and goal of motor and neurological recovery.Researches showed that electroacupuncture was effective on axonal regeneration after spinal cord injury.In this paper,the mechanisms were summarized from the aspects of the formation of glial scar,the role of axon growth inhibitory factor,the secretion of neurotrophic factor and the growth status of neurons.

spinal cord injury;axon regeneration;electroacupuncture;glial scar;review

WU Ya-min.E-mail:yaminwu65@hotmail.com

R651.2

A

1006-9771(2017)12-1380-04

[本文著錄格式]鄭利強，江瓊，胡春蓉，等.電針對脊髓損傷后軸突再生影響的研究進展[J].中國康復理論與實踐,2017,23(12):1380-1383.

CITED AS:Zheng LQ,Jiang Q,Hu CR,et al.Research progress of electroacupuncture on axonal regeneration after spinal cord injury(review)[J].Zhongguo Kangfu Lilun Yu Shijian,2017,23(12):1380-1383.

國家自然科學基金項目(No.30772299)。

1.第三軍醫(yī)大學大坪醫(yī)院野戰(zhàn)外科研究所三室，創(chuàng)傷、燒傷與復合傷國家重點實驗室，重慶市400042；2.重慶市第九人民醫(yī)院，重慶市400700；3.重慶醫(yī)科大學，重慶市400016。作者簡介：鄭利強(1987-)，男，漢族，河南焦作市人，碩士，醫(yī)師，主要研究方向：神經(jīng)康復。通訊作者：伍亞民，男，博士，博士生導師，主要研究方向：脊柱、脊髓損傷。E-mail:yaminwu65@hotmail.com。

10.3969/j.issn.1006-9771.2017.12.003

2017-07-26

2017-09-11)