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同濟(jì)大學(xué)附屬同濟(jì)醫(yī)院消化內(nèi)科,上海 200065

腦源性神經(jīng)營(yíng)養(yǎng)因子介導(dǎo)精神應(yīng)激誘發(fā)內(nèi)臟高敏感的研究進(jìn)展

董智瑀(綜述),許樹長(zhǎng)(審校)

同濟(jì)大學(xué)附屬同濟(jì)醫(yī)院消化內(nèi)科,上海200065

內(nèi)臟高敏感是腸易激綜合征慢性疼痛的重要發(fā)病機(jī)制。精神應(yīng)激既是腸易激綜合征發(fā)病的誘因,同時(shí)也調(diào)控大腦各腦區(qū)腦源性神經(jīng)營(yíng)養(yǎng)因子的表達(dá)水平。在精神應(yīng)激動(dòng)物模型中,腦源性神經(jīng)營(yíng)養(yǎng)因子(BDNF)可通過(guò)與高親和力受體TrkB結(jié)合,改變MAPK/ERK,CaMK、PI3K/Akt等信號(hào)通路關(guān)鍵分子表達(dá),同時(shí)伴多個(gè)腦區(qū)突觸可塑性改變,而內(nèi)臟痛覺傳導(dǎo)通路相關(guān)腦區(qū)突觸可塑性改變與內(nèi)臟高敏感形成相關(guān)。文章就BDNF與精神應(yīng)激誘發(fā)內(nèi)臟高敏感相關(guān)性作一綜述。

腦源性神經(jīng)營(yíng)養(yǎng)因子; 精神應(yīng)激; 內(nèi)臟高敏感; 腸易激綜合征

腦源性神經(jīng)營(yíng)養(yǎng)因子(brain-derived neurotrophic factor,BDNF) 是神經(jīng)營(yíng)養(yǎng)因子之一。內(nèi)臟高敏感(visceral hypersensitivity,HV)是腸易激綜合征(irritable bowel syndrome,IBS)慢性疼痛的重要發(fā)病機(jī)制。有研究表明,BDNF與內(nèi)臟高敏感的發(fā)生密切相關(guān)[1]。精神應(yīng)激既是IBS的重要誘發(fā)因素,也是各腦區(qū)BDNF表達(dá)水平的重要調(diào)節(jié)因素。因此,三者間有緊密的關(guān)聯(lián)。

1 BDNF的生物學(xué)特征

BDNF由4對(duì)反向平行β鏈構(gòu)成,含6個(gè)半胱氨酸殘基,形成3個(gè)二硫鍵。BDNF前原蛋白通過(guò)對(duì)信號(hào)肽疏水區(qū)的裂解,形成前體蛋白。一部分前體蛋白在內(nèi)質(zhì)網(wǎng)中將剩余的信號(hào)肽裂解,轉(zhuǎn)化為成熟的BDNF蛋白;另一部分轉(zhuǎn)運(yùn)至漿膜并以BDNF前體蛋白形式釋放。成熟的BDNF蛋白以同型二聚體蛋白形式被分泌至細(xì)胞外間質(zhì),通過(guò)與受體TrKB結(jié)合,激活細(xì)胞內(nèi)CaMK、MAPK、PI3K等信號(hào)通路,產(chǎn)生自分泌或旁分泌的作用[2]。BDNF在胎兒、新生兒和成人中樞神經(jīng)系統(tǒng)中廣泛分布,在中樞神經(jīng)系統(tǒng)發(fā)育、記憶和學(xué)習(xí)中起到重要作用。研究表明,BDNF在海馬中高表達(dá),并在神經(jīng)突觸信號(hào)傳遞和神經(jīng)可塑性中起主要作用;BDNF不僅影響神經(jīng)可塑性,還與NGF協(xié)同作用,共同增加中樞神經(jīng)系統(tǒng)谷氨酸能神經(jīng)遞質(zhì)的釋放,而該機(jī)制與中樞神經(jīng)系統(tǒng)持續(xù)致敏相關(guān);而中樞神經(jīng)系統(tǒng)神經(jīng)可塑性改變可引起慢性疼痛[3]。因此認(rèn)為,BDNF表達(dá)水平與慢性疼痛產(chǎn)生有重要關(guān)聯(lián)。

2 BDNF與突觸可塑性

突觸傳遞效能增強(qiáng)或減弱伴突觸組織結(jié)構(gòu)改變稱為突觸可塑性,而長(zhǎng)時(shí)程增強(qiáng)(long-term potentiation,LTP)是研究突觸可塑性的最常見形式。當(dāng)強(qiáng)度低而高頻率刺激作用于神經(jīng)突觸時(shí),可引起短時(shí)間內(nèi)突觸傳遞效能增強(qiáng),該效應(yīng)被稱為早期LTP(early-LTP,E-LTP);當(dāng)強(qiáng)度高且高頻率的刺激作用于神經(jīng)突觸時(shí),可誘發(fā)長(zhǎng)時(shí)程的突觸效能增強(qiáng),且伴隨突觸結(jié)構(gòu)改變,該效應(yīng)被稱為晚期LTP(late-LTP,L-LTP)。在誘發(fā)LTP的過(guò)程中,PKA和MAPK/ERK信號(hào)通路被激活,引起相關(guān)轉(zhuǎn)錄因子CREB和Elk-1磷酸化以及下游基因如BDNF轉(zhuǎn)錄增強(qiáng)[4]。

E-LTP、BDNF通過(guò)磷酸化突觸蛋白增強(qiáng)突觸小泡的釋放,以增強(qiáng)突觸對(duì)刺激的應(yīng)答,并協(xié)助E-LTP誘發(fā);同時(shí),BDNF可通過(guò)活化靜息突觸來(lái)維持E-LTP[5]。在L-LTP,BDNF起關(guān)鍵作用。研究顯示,在實(shí)驗(yàn)動(dòng)物接受誘導(dǎo)L-LTP生成的刺激后,海馬內(nèi)BDNF轉(zhuǎn)錄在2～4 h明顯升高,伴L(zhǎng)-LTP產(chǎn)生;對(duì)TrkB-/-敲除小鼠進(jìn)行相應(yīng)刺激,無(wú)法產(chǎn)生L-LTP[6];而對(duì)BDNF+/-小鼠注射外源性BDNF能使其接受刺激,重新誘導(dǎo)出L-LTP;當(dāng)使用蛋白質(zhì)合成抑制劑抑制蛋白合成后,外源性BDNF仍能有效維持電刺激誘導(dǎo)的L-LTP生成[7]。表明,大腦內(nèi)BDNF是在L-LTP的刺激、誘導(dǎo)、維持中起最為關(guān)鍵作用的蛋白,但是否是唯一作用蛋白尚有待驗(yàn)證。

3 突觸可塑性與內(nèi)臟高敏感

LTP是突觸可塑性的一種變化形態(tài),而突觸可塑性可通過(guò)LTP進(jìn)行觀察和研究。研究表明,電刺激內(nèi)側(cè)丘腦-前扣帶回(medial thalamus-anterior cingulate cortex,MT-ACC)痛覺環(huán)路時(shí),VH大鼠會(huì)產(chǎn)生ACC局部的LTP,并易化MT與ACC間的突觸傳導(dǎo)[8];VH能易化海馬CA1區(qū)LTP,且該效應(yīng)受NR2B拮抗劑Ro 256981和酪氨酸激酶抑制劑的抑制[9]。但也有研究表明,海馬區(qū)突觸可塑性降低誘導(dǎo)了焦慮、抑郁等精神癥狀,并參與自主神經(jīng)系統(tǒng)的調(diào)控,影響IBS胃腸道動(dòng)力改變;而焦慮、抑郁等精神癥狀以及胃腸道動(dòng)力改變是IBS重要的特征性臨床表現(xiàn)之一[10]。可見,突觸可塑性改變?cè)贗BS內(nèi)臟高敏感的發(fā)生中發(fā)揮重要的作用。但其中LTP與內(nèi)臟高敏感間的因果聯(lián)系以及相互影響時(shí)的病理生理機(jī)制還需進(jìn)一步證明。

4 BDNF在精神應(yīng)激誘發(fā)內(nèi)臟高敏感發(fā)生中的作用機(jī)制

研究表明,精神應(yīng)激狀態(tài)下杏仁核BDNF表達(dá)升高伴隨杏仁核體積增大以及精神癥狀易感性提高[11];母嬰分離模型大鼠杏仁核和延髓腹內(nèi)側(cè)區(qū)域BDNF及其受體TrkB表達(dá)伴L(zhǎng)TP重要生物標(biāo)記pERK顯著升高,可能與LTP介導(dǎo)的精神應(yīng)激下內(nèi)臟高敏感有關(guān)[12]。精神應(yīng)激狀態(tài)下,海馬[13]、結(jié)腸黏膜[14]BDNF表達(dá)均顯著升高;通過(guò)TrkB拮抗劑使用也證實(shí)BDNF與精神應(yīng)激下內(nèi)臟高敏感以及結(jié)腸動(dòng)力異常的相關(guān)性。關(guān)于其機(jī)制,有研究顯示,海馬組織在BDNF培養(yǎng)下,能通過(guò)MAPK/ERK途徑增加神經(jīng)元胞膜NR2B受體表達(dá)[15],而海馬CA1區(qū)域LTP形成與NR2B密切相關(guān)[9]。故推測(cè),精神應(yīng)激狀態(tài)下各腦區(qū)高表達(dá)的BDNF通過(guò)MAPK/ERK途徑及其下游NR2B-LTP,介導(dǎo)精神應(yīng)激下的內(nèi)臟高敏感狀態(tài);并通過(guò)CaMK、PI3K等信號(hào)通路發(fā)揮生物學(xué)效應(yīng)。但這些信號(hào)通路是否也作用于BDNF介導(dǎo)的精神應(yīng)激下內(nèi)臟高敏感尚有待進(jìn)一步的實(shí)驗(yàn)證明。

但也有研究報(bào)道,精神應(yīng)激能通過(guò)激活HPA軸,使血清內(nèi)糖皮質(zhì)激素水平上升,并改變神經(jīng)元細(xì)胞BDNF表達(dá),引起精神應(yīng)激狀態(tài)下血清和海馬BDNF表達(dá)下降[16];和精神應(yīng)激狀態(tài)下海馬[17]、脊髓[18]BDNF表達(dá)顯著下降。這些精神應(yīng)激下BDNF表達(dá)下降的相反結(jié)論,需更詳盡的實(shí)驗(yàn)、臨床研究驗(yàn)證。

5 結(jié)語(yǔ)

各腦區(qū)BDNF表達(dá)上升與精神應(yīng)激誘導(dǎo)內(nèi)臟高敏感效應(yīng)相關(guān),LTP在其中發(fā)揮重要的作用,但如何通過(guò)LTP介導(dǎo)并發(fā)揮作用還需進(jìn)一步證實(shí)。同時(shí),精神應(yīng)激可引起各腦區(qū)BDNF表達(dá)降低,并通過(guò)降低突觸可塑性介導(dǎo)IBS相關(guān)的焦慮、抑郁等精神癥狀及胃腸道動(dòng)力改變。因此,BDNF與精神應(yīng)激誘發(fā)內(nèi)臟高敏感的相關(guān)性,仍需進(jìn)一步研究證明。

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Researchprogressonbrain-derivedneurotrophicfactormediatingvisceralhypersensitivityinducedbypsychogenicstress

DONGZhiyu,XUShuchang

DepartmentofGastroenterology,TongjiHospitalAffiliatedtoTongjiUniversity,Shanghai200065,China

Visceral hypersensitivity is the important pathogenic mechanism of irritable bowel syndrome.Psychogenic stress is not only the cause of irritable bowel syndrome,but also a regulator of the expression of brain-derived neurotrophic factor (BDNF) in brain regions.In animal models of psychogenic stress,BDNF regulates MAPK/ERK,CaMK,and PI3K/Akt signal pathways through combining with high affinity nerve growth factor receptor TrkB and is accompanied with the change of synaptic plasticity in many brain regions associated with the formation of visceral hypersensitivity.Here,we reviewed the relationship between BDNF and visceral hypersensitivity induced by psychogenic stress.

Brain-derived neurotrophic factor; Psychogenic stress; Visceral hypersensitivity; Irritable bowel syndrome

R574.4

A

2095-378X(2017)03-0209-03

2017-04-28)

董智瑀(1994—),男,同濟(jì)大學(xué)醫(yī)學(xué)院在讀本科生

許樹長(zhǎng),電子信箱:xschang@163.com

10.3969/j.issn.2095-378X.2017.03.017