林敬銓，　童　亮，　高夢丹，　張金一，　劉學(xué)紅

(紹興文理學(xué)院醫(yī)學(xué)院，浙江 紹興 312000)

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PPARs介導(dǎo)脊髓損傷修復(fù)的研究進(jìn)展*

林敬銓，童亮，高夢丹，張金一，劉學(xué)紅△

(紹興文理學(xué)院醫(yī)學(xué)院，浙江 紹興 312000)

脊髓損傷(spinal cord injury，SCI)是一種嚴(yán)重的神經(jīng)系統(tǒng)功能障礙性疾病，能導(dǎo)致不同程度的感覺和運(yùn)動(dòng)功能障礙，主要包括原發(fā)性損傷和繼發(fā)性損傷。原發(fā)性損傷是指在外力的直接作用下導(dǎo)致脊髓組織機(jī)械性的破壞，其傷害通常是不可逆的；繼發(fā)性損傷是指在原發(fā)性損傷的基礎(chǔ)上出現(xiàn)病理生理方面的改變從而造成損傷區(qū)域漸進(jìn)性破壞，臨床上主要針對繼發(fā)性損傷采取相關(guān)治療措施。目前導(dǎo)致繼發(fā)性損傷機(jī)制主要包括炎癥反應(yīng)、自由基形成和脂質(zhì)過氧化、局部血管功能紊亂、離子失衡、興奮性谷氨酸中毒、細(xì)胞凋亡、軸突脫髓鞘、膠質(zhì)瘢痕形成等[1]。過氧化物酶體增殖物激活受體(peroxisome proliferator-activated receptors，PPARs)是一類配體激活的轉(zhuǎn)錄因子，其活化后產(chǎn)生的抗炎、抗氧化、抑制線粒體功能紊亂等生物學(xué)效應(yīng)在中樞神經(jīng)系統(tǒng)退行性病變和急性損傷中起到關(guān)鍵作用[2]，其表達(dá)程度的高低與SCI的預(yù)后關(guān)系密切，成為SCI治療中的一個(gè)有效靶點(diǎn)。

1PPARs的分子結(jié)構(gòu)與分布

PPARs于1990年首次被Issemann 等[3]報(bào)道，屬于核激素受體超家族成員之一，位于細(xì)胞核內(nèi)，目前研究發(fā)現(xiàn)PPARs亞型有PPARα、PPARδ/β和PPARγ，其基因分別定位于人類的22、6和3號染色體上。 PPARs各亞型與其它核受體相似，由A～F六個(gè)主要的功能區(qū)組成。N端的A區(qū)和B區(qū)通常稱為A/B區(qū)，是配體非依賴性的活性功能區(qū)(AF-1)，不同亞型該區(qū)活性差異較大，其活性受磷酸化調(diào)節(jié)；C區(qū)是由2個(gè)鋅指結(jié)構(gòu)模序組成的DNA結(jié)合區(qū)(DNA-binding domain，DBD)，由70個(gè)左右的氨基酸序列構(gòu)成，具有高度保守性，能夠和目標(biāo)基因上的PPAR反應(yīng)元件(peroxisome proliferator response element，PPRE)結(jié)合；D區(qū)為鉸鏈區(qū)(hinge region，HG)，連接C區(qū)和E區(qū)；E區(qū)屬于配體結(jié)合區(qū)(ligand-binding domain， LBD)，是配體依賴的活性功能區(qū)(AF-2)，該區(qū)氨基酸序列的不同決定了各PPARs亞型對不同配體的親和力；C端的F區(qū)功能目前并不是很明確[4]，見圖1。

PPARs在生物體內(nèi)廣泛分布，在肝臟、心臟、脾臟、腎臟、肌肉、脂肪組織等均有不同程度的分布[5]。在中樞神經(jīng)系統(tǒng)，PPARα、δ/β和γ在腦和脊髓的不同區(qū)域表達(dá)程度各不相同，神經(jīng)元和膠質(zhì)細(xì)胞均能檢測到PPARs的表達(dá)，PPARδ/β呈廣泛性分布，而PPARα和PPARγ則表現(xiàn)為區(qū)域性分布[6]。

Figure 1.The structure of PPARs. A/B: ligand-independent activation function 1 (AF-1) domain; C: DNA-binding domain (DBD); D: hinge region (HG); E: ligand-binding domain (LBD) and ligand-dependent activation function 2 (AF-2) domain; F: function is not well understood.

圖1PPARs結(jié)構(gòu)示意圖

2PPARs的配體及其神經(jīng)保護(hù)作用

根據(jù)配體來源不同，PPARs的配體分為生理性(內(nèi)源性)配體和人工合成配體?；ㄉ南┧岬拇x衍生物8-羥基二十碳四烯酸(8S-HETE)和白三烯B4(LTB4)等是PPARα的生理性配體，PPARα的人工合成配體主要有貝特類藥物(如非諾貝特、苯扎貝特、環(huán)丙貝特和吉非貝齊等)、Wy-14643、GW2331、GW7647等；PPARδ/β的生理性配體多數(shù)為不飽和脂肪酸如花生四烯酸、亞油酸和環(huán)前列腺素等，其人工合成配體主要有GW0742、GW501516、L165041和L-783483等；PPARγ能被脂肪酸及其衍生物(如二十二碳六烯酸、花生四烯酸和亞油酸等)、前列腺素衍生物(15d-PGJ2、PGA2和PGD2等)等生理性配體激活，其人工合成配體最為廣泛應(yīng)用的是用于治療2型糖尿病的噻唑烷二酮類(thiazolidinediones，TZDs)藥物(如羅格列酮、匹格列酮、環(huán)格列酮和曲格列酮等)[7-8]。

PPARs活化后能改善許多中樞神經(jīng)退行性病變?nèi)绨柎暮Ｄ?Alzheimer disease，AD)、帕金森病(Parkinson disease, PD)、肌萎縮側(cè)索硬化(amyotrophic lateral sclerosis, ALS)和多發(fā)性硬化癥(multiple sclerosis, MS)等，和中樞神經(jīng)系統(tǒng)急性損傷如外傷性腦損傷(traumatic brain injury，TBI)和SCI等的病理過程，其機(jī)制主要涉以下幾個(gè)方面：促進(jìn)軸突再生；抑制線粒體功能紊亂；抑制Th1和Th17細(xì)胞的分化；促進(jìn)少突膠質(zhì)前體細(xì)胞(oligodendrocyte precursor cells，OPCs)的成熟分化；極化巨噬細(xì)胞，使之從炎性的M1細(xì)胞向抗炎的M2細(xì)胞轉(zhuǎn)化[9]。

3PPARs配體調(diào)控的信號傳導(dǎo)通路

3.1PPRE依賴性的轉(zhuǎn)錄激活/抑制這是最經(jīng)典的PPARs的調(diào)節(jié)機(jī)制，當(dāng)配體未與PPARs結(jié)合時(shí)，輔助抑制因子(corepressor，CoR)和組蛋白去乙?；?histone deacetylases，HDACs)通過與PPARs結(jié)合抑制靶基因的轉(zhuǎn)錄；當(dāng)配體進(jìn)入細(xì)胞核內(nèi)與PPARs分子上的E區(qū)結(jié)合后，使得PPARs的分子構(gòu)象發(fā)生變化，導(dǎo)致其與輔助因子的結(jié)合能力發(fā)生改變，活化的PPARs與CoR和HDACs的親和力下降，使之解離，同時(shí)激活的PPARs與類維生素X受體(retinoid X receptor，RXR)形成PPARs/RXR異源二聚體，該二聚體吸引輔助活化因子(coavtivator，CoA)與組蛋白乙酰轉(zhuǎn)移酶(histone acetyl transferases，HAT)，使得PPARs分子上的C區(qū)與目標(biāo)基因啟動(dòng)子上的PPRE結(jié)合，啟動(dòng)目標(biāo)基因的轉(zhuǎn)錄激活[10-11]，見圖2。

3.2PPRE非依賴性的抑制PPARs也可不與PPRE結(jié)合，而直接與靶蛋白結(jié)合，抑制該蛋白與其DNA反應(yīng)元件的結(jié)合。PPARα能干擾平滑肌細(xì)胞中AP-1和NF-κB與其目標(biāo)基因的結(jié)合，通過與p65和c-Jun蛋白的直接結(jié)合抑制血管的炎癥反應(yīng)[12]。PPARγ與p65/p50蛋白的結(jié)合抑制巨噬細(xì)胞在LPS刺激下IL-12的分泌，與NFAT的結(jié)合抑制IL-2和IL-12在激活的T淋巴細(xì)胞中的分泌，通過干擾c-Jun在T細(xì)胞中的激活而作用于IFN-γ基因的啟動(dòng)子[13-15]。

4PPARs與SCI

PPARs由于其在中樞神經(jīng)系統(tǒng)的廣泛分布，其介導(dǎo)的生物學(xué)功能在中樞神經(jīng)系統(tǒng)疾病的病理過程中發(fā)揮著至關(guān)重要的作用[16-19]，脊髓作為中樞神經(jīng)系統(tǒng)的重要功能組成部分，PPARs在其損傷過程中的作用已成為目前神經(jīng)科學(xué)領(lǐng)域研究的熱點(diǎn)。研究表明，當(dāng)SCI發(fā)生時(shí)應(yīng)用PPARs各亞型相應(yīng)的配體，配體可通過與組織細(xì)胞內(nèi)PPARs的結(jié)合，激活其介導(dǎo)的信號傳導(dǎo)通路，從而產(chǎn)生相應(yīng)的生物學(xué)效應(yīng)，對于SCI的病理以及病理生理過程具有一定的拮抗作用。PPARs各亞型與SCI的關(guān)系分述如下。

4.1PPARγ與SCIPPARγ是目前在SCI方面研究最多的PPARs亞型，PPARγ合成激動(dòng)劑TZDs能防止SCI時(shí)的神經(jīng)元損傷、運(yùn)動(dòng)功能失常、髓鞘丟失、神經(jīng)病理性疼痛和炎癥反應(yīng)[20]，PPARγ的生理性配體15-脫氧前列腺素J2(15-deoxy-Δ12,14-prostaglandin J2，15d-PGJ2)和二十二碳六烯酸(docosahexaenoic acid，DHA)能減少SCI時(shí)脊髓炎癥(iNOS、TNF-α、IL-1β)和組織損傷、中性粒細(xì)胞的組織滲入、NF-κB的激活和硝基酪氨酸的表達(dá)、細(xì)胞凋亡等[21-22]，DHA還能改善體外培養(yǎng)的背根神經(jīng)節(jié)細(xì)胞在過氧化氫刺激下的氧化應(yīng)激反應(yīng)。據(jù)報(bào)道，羅格列酮治療的大鼠在SCI時(shí)能促進(jìn)內(nèi)源性神經(jīng)前體細(xì)胞(neural progenitor cells，NPCs)的增殖，減少NF-κB的表達(dá)，但卻未見明顯的內(nèi)源性NPCs分化為神經(jīng)元[23]。匹格列酮能減少脊髓組織星形膠質(zhì)細(xì)胞和NF-κB的激活，減少炎癥介質(zhì)TNF-α、IL-1β和IL-6的釋放，通過PPARγ依賴和非依賴的機(jī)制改善神經(jīng)病理性疼痛[24-25]。此外，雄激素睪酮單獨(dú)或聯(lián)合一種同化激素諾龍能抵抗SCI后引起的腓腸肌中PPARγ輔助活化因子PGC-1α表達(dá)水平的下降，并使得PGC-1α蛋白更易進(jìn)入細(xì)胞核，改善大鼠SCI后后肢癱瘓肌肉的萎縮和肌纖維的能量代謝[26]。然而Yan等[27]發(fā)現(xiàn)SCI后骨骼中高表達(dá)的PPARγ可能通過RANKL/OPG信號軸使得骨質(zhì)再吸收，同時(shí)還使得骨髓間充質(zhì)干細(xì)胞更多地分化為脂肪細(xì)胞而不是成骨細(xì)胞，導(dǎo)致骨質(zhì)的丟失，因此PPARγ激動(dòng)劑是否有利于SCI的預(yù)后尚存在爭議，見圖2。

4.2PPARα與SCIPPARα在SCI后扮演了重要的角色，PPARα基因敲除小鼠相比正常小鼠SCI后，炎癥反應(yīng)和組織損傷更為嚴(yán)重[28]。小鼠SCI時(shí)，生理性PPARα配體十六酰胺乙醇(palmitoylethanolamide，PEA)激活PPARα產(chǎn)生的生物學(xué)效應(yīng)與SCI時(shí)PPARγ的激活相似，亦能減少脊髓炎癥和組織損傷、中性粒細(xì)胞滲入、硝基酪氨酸形成、iNOS和促炎因子的表達(dá)、NF-κB的激活、細(xì)胞凋亡等[29]，進(jìn)一步研究發(fā)現(xiàn)SCI后PEA的抗炎和神經(jīng)保護(hù)作用不僅僅涉及PPARα，也與PPARγ和PPARδ/β有關(guān)[30]。血腦屏障(blood-brain barrier，BBB)與血脊髓屏障(blood-spinal cord barrier，BSCB)有著相似的組織結(jié)構(gòu)，研究發(fā)現(xiàn)腦部的HIV感染將導(dǎo)致腦血管毒性、星形膠質(zhì)細(xì)胞增生和神經(jīng)元丟失，PPARα激動(dòng)劑非諾貝特通過抑制ERK1/2和Akt信號通路，增加緊密連接蛋白claudin-5和ZO-1的表達(dá)水平，保護(hù)HIV-1特異的Tat蛋白誘導(dǎo)的BBB通透性改變，同時(shí)減少星形膠質(zhì)細(xì)胞增生和神經(jīng)元丟失[31]。然而Almad等[32]報(bào)道，PPARα合成激動(dòng)劑吉非貝齊對小鼠SCI后的運(yùn)動(dòng)功能和組織病理沒有改善作用。此外研究發(fā)現(xiàn)降血脂藥物辛伐他汀在SCI中的抗炎作用也是由PPARα介導(dǎo)的[33],見圖2。

Figure 2.Molecular mechanisms and biological effects of PPARs signaling pathway after SCI. (1): upon binding of a ligand to the PPARs, the receptors make a conformational change, CoR dissociation coincides with heterodimerization of the PPAR with the RXR, and transcriptional CoA is recruited along with HAT, which fires the transcription of target genes; (2): the biological effects of PPARγ activation; (3): the biological effects of PPARα activation; (4): the biological effects of PPARδ/β activation.

圖2脊髓損傷后PPARs介導(dǎo)的生物學(xué)作用及其分子機(jī)制示意圖

4.3PPARδ/β與SCIPPARδ/β廣泛分布于腦和脊髓，能促進(jìn)離體少突膠質(zhì)細(xì)胞的分化和髓鞘的形成， PPARδ/β的mRNA和蛋白質(zhì)水平在SCI后明顯增加，在損傷區(qū)邊緣出現(xiàn)大量的PPARδ/β+的新生少突膠質(zhì)細(xì)胞[34]。PPARδ/β人工合成配體GWO742預(yù)處理能顯著減少SCI體外模型時(shí)下游細(xì)胞和分子p38 MAPK、JNK/SAP激酶、NF-κB的激活、神經(jīng)營養(yǎng)因子BDNF和DDNF的丟失、COX2的表達(dá)、細(xì)胞死亡等[35]，此外GWO742還能增加糖尿病大鼠脊髓組織PPARδ/β的表達(dá)，延長糖尿病大鼠SCI后的生存時(shí)間[36]。替米沙坦能夠減少脊髓組織炎癥指標(biāo)HMGB1和RAGE的表達(dá)，促進(jìn)SCI后PPARδ/β和p-AMPK的表達(dá)，改善大鼠SCI后的運(yùn)動(dòng)功能和疼痛反應(yīng)[37],見圖2。

綜上所述，在發(fā)生SCI時(shí)應(yīng)用PPARα、δ/β和γ相應(yīng)的配體，激活其介導(dǎo)的信號傳導(dǎo)通路后，均能起到抗炎(特別是對下游分子NF-κB的抑制)和減少神經(jīng)元的丟失作用。PPARγ的激活能促進(jìn)NPCs增值，但卻在一定程度上導(dǎo)致骨質(zhì)的丟失；PPARα的激活能維持病理狀態(tài)下BBB/BSCB的穩(wěn)定性，但并非所有的PPARα激動(dòng)劑均能改善SCI預(yù)后；PPARδ/β的激活對于糖尿病合并SCI的預(yù)后具有積極的意義。此外一些非PPARs配體藥物也表現(xiàn)出PPARs依賴的藥理作用，而其具體機(jī)制有待進(jìn)一步闡明。

5問題與展望

PPARs活化后產(chǎn)生的抗炎和神經(jīng)保護(hù)等多種生物學(xué)效應(yīng)恰能針對SCI后繼發(fā)性損傷中的多種病理生理改變起到一定的作用，然而由于PPARs在機(jī)體內(nèi)分布廣泛，導(dǎo)致其激動(dòng)后定會產(chǎn)生相應(yīng)的副作用。闡明SCI時(shí)PPARs基因的表達(dá)調(diào)控以及基因之間的相互作用關(guān)系，選擇開發(fā)具有組織特異性的PPARs激動(dòng)劑，減弱激動(dòng)后產(chǎn)生相應(yīng)的副作用，將是SCI后藥物治療的一個(gè)新途徑。

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(責(zé)任編輯: 林白霜， 羅森)

[ABSTRACT]Spinal cord injury (SCI) is a devastating disease of the central nervous system. It elicits permanent neurological dysfunction. The neuroinflammation is a key point within the secondary damage in the locoal area of SCI. Peroxisome proliferator-activated receptors (PPARs), a group of ligand-activated transcription factors, play a critical role in the degenerative diseases in the central nervous system and acute traumatic injury because of their biological effects of anti-inflammation and neuroprotection when they are activated. This article reviews the signal transduction pathway mediated by PPARs and the progress of PPARs in the repair of SCI.

Progress of PPARs in repair of spinal cord injury

LIN Jing-quan, TONG Liang, GAO Meng-dan, ZHANG Jin-yi, LIU Xue-hong

(MedicalCollegeofShaoxingUniversity,Shaoxing312000,China.E-mail:liuxueh6588@126.com)

[關(guān)鍵詞]過氧化物酶體增殖物激活受體； 脊髓損傷； 信號通路

[KEY WORDS]Peroxisome proliferator-activated receptors; Spinal cord injury; Signaling pathway

[文章編號]1000- 4718(2016)05- 0956- 05

[收稿日期]2015- 12- 24[修回日期] 2016- 01- 27

*[基金項(xiàng)目]浙江省自然科學(xué)基金資助項(xiàng)目(No.LY15H170001)

通訊作者△Tel： 0575-88345099； E-mail： liuxueh6588@126.com

[中圖分類號]R363

[文獻(xiàn)標(biāo)志碼]A

doi:10.3969/j.issn.1000- 4718.2016.05.033

雜志網(wǎng)址： http://www.cjpp.net