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    • 针刺调节BDNF/TrkB信号通路改善中枢神经系统疾病的研究进展

    • Research Progress of Acupuncture in Improving Central Nervous System Diseases by Regulating BDNF/TrkB Signaling Pathway

    • 栗文静

      1 ,  

      白艳杰

      2 ,  
    • 中山大学学报(医学科学版)   2024年45卷第4期 页码:530-538
    • DOI:10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).20240617.002    

      中图分类号: R245
    • 纸质出版日期:2024-07-20

      收稿日期:2024-04-22

      录用日期:2024-06-13

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  • 栗文静,白艳杰.针刺调节BDNF/TrkB信号通路改善中枢神经系统疾病的研究进展[J].中山大学学报(医学科学版),2024,45(04):530-538. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).20240617.002.

    LI Wenjing,BAI Yanjie.Research Progress of Acupuncture in Improving Central Nervous System Diseases by Regulating BDNF/TrkB Signaling Pathway[J].Journal of Sun Yat-sen University(Medical Sciences),2024,45(04):530-538. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).20240617.002.

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    摘要

    BDNF/TrkB信号通路作为神经元生长、发育和突触可塑性的关键调节器,广泛参与中枢神经系统疾病的发生发展,如缺血性脑卒中、阿尔茨海默病、帕金森病和脊髓损伤等。研究表明针刺能调节BDNF/TrkB信号通路的活性,对以上疾病具有显著的治疗潜力,其作用机制与参与突触结构重塑,抑制神经细胞凋亡,促进神经发生和突触再生等有关。本文综述了BDNF/TrkB相关信号通路在中枢神经系统疾病中的作用以及针刺对该通路的调控机制,以期为临床治疗提供新思路。未来研究应深入探究针刺对BDNF/TrkB信号通路的精准调控,以开发更高效安全的治疗策略。

    Abstract

    As a key regulator of neuronal growth, development and synaptic plasticity, BDNF/ TrkB signaling pathway is widely involved in the occurrence and development of central nervous system diseases, such as ischemic stroke, Alzheimer's disease, Parkinson's disease and spinal cord injury. Studies have shown that acupuncture can regulate the activity of BDNF/TrkB signaling pathway, and has significant therapeutic potential for these diseases. Its mechanism of action is related to participating in synaptic remodeling, inhibiting neuronal apoptosis, and promoting neurogenesis or synaptic regeneration. This article reviews the role of BDNF/TrkB signaling pathway in central nervous system diseases and the regulation mechanism of acupuncture on this pathway, in order to provide new ideas for clinical treatment. Future studies should further explore the precise regulatory mechanism of acupuncture on BDNF/TrkB signaling pathway in order to develop more efficient and safe treatment strategies.

    关键词

    针刺; BDNF/TrkB信号通路; 中枢神经系统疾病; 缺血性脑卒中; 阿尔茨海默病; 帕金森病; 脊髓损伤; 作用机制

    Keywords

    acupuncture; BDNF/TrkB signaling pathway; central nervous system diseases; ischemic stroke; Alzheimer's disease; Parkinson's disease; spinal cord injury; mechanism of action

    中枢神经系统疾病是严重威胁人类健康的重大疾病之一,包括缺血性脑卒中(ischemic stroke, IS)、阿尔茨海默病(Alzheimer’s disease, AD)、帕金森(Parkinson’s disease, PD)和脊髓损伤(spinal cord injury, SCI)等。这些疾病常常伴随着神经元损伤、神经炎症、突触功能失调等复杂的病理生理变化,给患者的生活质量和健康带来了严重的影响

    1。越来越多的研究2强调,脑源性生长因子(brain-derived neurotrophic factor, BDNF)和/或其特异性受体酪氨酸激酶受体B(tyrosine kinase receptor B, TrkB)信号传导在中枢神经系统疾病发病机制和治疗中发挥着关键作用。BDNF是一种神经营养因子,其关键功能包括提高神经元可塑性,促进神经突生长以及调节多种下游信号通路2。此外,大量研究发现,脑组织和脊髓中BDNF和TrKB的水平变化与多种疾病的发病机制有关3。目前,一些研究4-5提出了靶向BDNF/TrKB信号通路治疗中枢神经系统疾病的新策略,如BDNF合成促进剂、TrKB激动剂、基因工程技术以及BDNF纳米载体递送等。然而这些治疗方法大多属于临床前研究或处于临床应用的早期阶段,其安全性和有效性有待验证。针刺作为中医的一种治疗手段,因具有安全有效、多途径和多靶点等特点在临床上被广泛接受。传统针刺是指通过手部施加力量,直接刺激穴位,以调节人体气血、阴阳平衡,达到治疗疾病的目的。而电针则是在传统针刺的基础上加入了电流刺激,可以更精确地调控治疗过程中的刺激强度和频率,提高治疗效果。二者都遵循着中医的经络学说和穴位理论,是针灸疗法中重要的治疗手段。近年来,针刺通过调控多种信号通路在治疗中枢神经系统疾病方面展现出显著的疗效,如针刺可以调控Janus激酶(JAK)/细胞信号转导转录因子(STAT)信号通路和核转录因子κB(NF-κB)信号通路抑制炎症因子的生成,从而减轻中枢神经系统的炎症损伤6。此外,针刺还可调节Notch信号通路促进神经元的分化和再生、激活激活核转录因子红系2相关因子2(Nrf2)/血红素加氧酶1(HO-1)信号通路提高抗氧化酶的表达,抑制氧化应激反应以及激活Wnt/β-连环蛋白(β-catenin)信号通路促进血管生成7-9。除此之外,已有研究10证实,针刺可以诱导BDNF、TrKB的蛋白表达以及调控BDNF/TrKB信号通路的传导,从而通过介导神经元存活、再生,提高突触可塑性等参与中枢神经系统疾病的病理生理过程。本文以BDNF/TrkB信号通路为切入点,对该通路在中枢神经系统中的功能以及针刺调控BDNF/TrkB信号通路治疗中枢神经系统相关疾病的作用机制进行综述,以期为临床治疗提供新的生物学依据。

    1 BDNF/TrkB信号通路分子生物学概括

    BDNF是一种多肽神经营养因子,其结构包括一个亲水性氨基端(N端)和一个疏水性羧基端(C端),C端的成熟活性结构域可与TrkB受体结合,从而介导了BDNF的生物学效应

    11。BDNF广泛分布在大脑中的各个区域,尤其在皮质和海马中高度活跃,因其在大脑中高表达且在轴突生长和新突触形成方面具有强大的调控能力,从而为中枢神经系统疾病的治疗提供了一个有希望的靶点2。最初,BDNF以脑源性神经生长因子前体(precursor for brain-derived neurotrophic factor, pro-BDNF)的形式从内质网分泌,然后在蛋白水解酶的作用下裂解为成熟脑源性神经生长因子(mature brain-derived neurotrophic factor, m-BDNF)。BDNF有两种不同的膜蛋白受体,分别为p75神经营养因子受体(p75 neurotrophin receptor, P75NTR)和TrkB。而研究发现BDNF促进神经元分化、再生以及提高突触可塑性来介导神经恢复的生物学效应主要是通过激活TrkB受体及其不同信号级联反应产生的12-13

    TrkB位于神经细胞膜上,是由胞浆区域、跨膜区域和胞外区域组成的一种跨膜蛋白。作为BDNF的特异性受体,TrkB参与调节神经元的存活、发育、突触可塑性和学习记忆等过程

    14。BDNF与TrKB受体结合后导致TrKB的磷酸化,进而激活多条下游信号通路,包括磷脂酶Cγ(phosphoinositide specific phospholipase Cγ, PLC-γ)/三磷酸肌醇(inositol-1,4,5-trisphosphate, IP3)/钙调素依赖蛋白(calmodulin-dependent protein kinase Ⅱ, CaMKⅡ)信号通路、磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase, PI3K)/蛋白激酶B(protein kinase B, PKB, 也称AKt)信号通路和丝裂原蛋白活化激酶(mitogen-activated protein kinase, MAPK)信号通路15

    2 BDNF/TrkB相关信号通路在中枢神经系统中的作用

    2.1 PLC-γ/IP3/CaMKⅡ信号通路

    PLC-γ是细胞信号传导的重要介质,能够催化磷脂酰肌醇二磷酸水解,产生IP3和二酰甘油。IP3可与其细胞内受体结合,诱导内质网配体门控的Ca2+通道开放,使细胞外的Ca2+进入细胞

    16。CaMKⅡ是细胞内Ca2+变化的重要感受器,主要在海马和突触后致密区中密集分布。研究发现,当细胞内Ca2+浓度升高时,Ca2+和钙调蛋白结合诱导CaMKⅡ的表达翻译,从而调控细胞周期、细胞骨架重组以及长时程增强(long-term potentiation, LTP)或长时程抑制(longterm depression, LTD),进而在卒中后认知障碍、阿尔兹海默症等疾病的恢复中发挥关键作用17-18。其中,海马中的LTP和LTD与突触可塑性密切相关,是影响学习记忆的生物学基础。研究19发现,PLC-γ/IP3/CaMKⅡ信号通路的激活可以进一步磷酸化CaMKⅡ的下游靶点(如AMPA受体的GluA1亚基),进而催化LTP的表达。相反,用肽抑制剂来阻断CaMKⅡ的催化活性或CaMKⅡ基因的缺失都会破坏LTP的形成20

    2.2 PI3K/Akt信号通路

    PI3K在BDNF与其特异性受体TrKB结合后被激活,然后催化细胞膜上的磷脂酰肌醇二磷酸转化为磷脂酰肌醇三磷酸,使Akt磷酸化并被激活

    21。据报道,PI3K/Akt信号通路通过参与细胞生存、增殖、代谢和凋亡等生理过程以及调控突触可塑性在中枢神经系统疾病中发挥着关键作用22。哺乳动物雷帕霉素靶蛋白(mammalian target of Rapamycin, mTOR)是促进神经元成熟和突触形成的主要调节因子23。研究24发现,PI3K/Akt信号通路可以上调其下游底物mTOR的磷酸化水平,提高突触递质传递效率,促进突触相关蛋白海马组织突触素(synaptophysin, SYN)和突触后致密蛋白95(postsynaptic density protein 95, PSD95)的表达,进而提高学习和记忆能力。此外,该信号通路还可以调控其他下游靶蛋白的活性,如B细胞淋巴瘤-2(B-cell lymphoma-2, Bcl-2)、糖原合成酶激酶3β(glycogen synthase kinase 3β, GSK3β)、半胱氨酸的天冬氨酸蛋白水解酶-3(cysteinyl aspartate-specific proteinase-3, caspase-3)以及转录因子FOXO家族等进而在中枢神经系统中发挥抑制细胞凋亡、促进细胞生长发育、调节炎症反应等生物学效应25-27

    2.3 MAPK信号通路

    BDNF与TrKB结合后还可激活MAPK级联反应。MAPK家族包括多个亚型,其中最常见的有细胞外调节蛋白激酶(extracellular signal-regulated kinase, ERK)、c-Jun N-末端激酶(c-Jun N-terminal Kinase, JNK)和p38丝裂原激活蛋白激酶(p38 mitogen activated protein kinases, p38MAPK),它们分别参与调节不同的细胞信号传导途径

    28-29。其中,ERK途径被认为是MAPK信号传导的经典途径,激活后的ERK可以进入细胞核并磷酸化多种转录因子,包括c-Fos、转录激活因子ETS样蛋白1、c-Myc和激活转录因子2等,进而调控基因的转录和表达,参与中枢神经系统再生过程30。而JNK和p38MAPK通路主要与细胞的炎症反应与凋亡有关31。值得注意的是,新的研究32发现,ERK的激活表现出对中枢神经系统有害的一面,在脱髓鞘小鼠模型中,MAPK/ERK通路抑制剂给药可促进小鼠脊髓和胼胝体中少突胶质前体细胞分化和髓鞘形成。另一项研究33也发现,阻断表皮生长因子/ERK信号传导可上调神经元分化因子TRIM32的水平,促进神经干细胞分化为成熟神经元,改善脊髓损伤。事实上,MAPK/ERK信号通路所表现出来的双重作用与其激活时间以及所涉及的复杂信号传导网络有关。因此在通过该信号途径治疗相关疾病时,要精确控制ERK的时空激活以及与神经元和胶质细胞其他通路的紧密合作30

    3 针刺调节BDNF/TrkB信号通路对中枢神经系统相关疾病的影响

    3.1 针刺调节BDNF/TrkB信号通路对缺血性脑卒中的影响

    IS仍然是导致全球死亡和残疾的主要原因之一。IS发生后,BDNF/TrkB信号通路通过调控神经细胞凋亡、提高突触可塑性等机制发挥重要的神经保护作用

    34。研究35发现,BDNF和TrkB在体外细胞模型和经历大脑中动脉闭塞(middle cerebral artery occlusion, MCAO)手术的小鼠海马体中的表达均降低,舒血宁注射逆转了这一现象,并通过激活BDNF/TrKB信号传导促进卒中后认知和运动缺陷的恢复。Li等36通过建立氧-葡萄糖剥夺和复氧(oxygenglucose deprivation/reperfusion, OGD/R)神经元细胞模型发现,胆酸通过激活BDNF/TrkB信号通路下调了促凋亡蛋白Bax以及炎症因子半胱天冬酶(caspase)-3和caspase-9的表达水平,并上调抗凋亡蛋白Bcl-2的表达,进而抑制了OGD/R诱导的神经细胞凋亡。相反,有研究37显示阻断BDNF/TrkB信号通路的传导可加剧缺血性脑卒中后的神经功能损伤。此外,Zhu等38发现,在大鼠MCAO模型中,增强海马区BDNF/TrkB信号通路的传导逆转了缺血大鼠海马区炎性因子肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α),白细胞介素(interleukin, IL)-1β和IL-6的上调,抑制了氧化应激,同时上调了突触可塑性相关蛋白的翻译,减轻了MCAO大鼠的空间学习和记忆障碍。

    针刺作为中医疗法的重要组成部分,在治疗IS方面展现出多途径多靶点的特点。研究

    39发现,电针治疗可显著提高脑梗死患者血清中的血管内皮生长因子(vascular endothelialgrowth factor, VEGF)、BDNF的水平,从而改善患者的脑血液动力学和神经功能。王琮民等40利用电针刺激MCAO大鼠的百会、风府、心俞、内关4个穴位,结果表明电针治疗能激活BDNF/TrkB/PI3K信号通路,抑制MCAO大鼠TNF-ɑ、IL-8、IL-2等炎性细胞因子的分泌,减少脑梗死体积,从而保护大鼠的神经功能。此外,针刺还可以通过增加纤溶酶原激活物蛋白的表达,促进pro-BDNF向m-BDNF转变,进而增强海马区m-BDNF的含量,这可能是针刺改善MCAO大鼠学习记忆障碍的机制之一41。随后,苏凯奇等42研究表明,电针刺激神庭、百会能上调BDNF/TrkB/PI3K/Akt通路相关蛋白的表达,增强海马LTP,提高脑缺血缺氧大鼠的认知能力。另一项研究43也发现,电针干预神庭、百会可促进SYN、PSD95的表达,进而改善卒中后认知障碍,其机制与激活BDNF/TrKB信号通路有关。此外,Sun等44发现通督调神针刺能增强BDNF/TrkB信号通路的活性,进而减轻卒中后的抑郁症状。

    3.2 针刺调节BDNF/TrkB信号通路对阿尔茨海默病的影响

    AD占全部痴呆类型的60%~80%,其特征性标志为β-淀粉样蛋白(amyloid β-protein, Aβ)沉积形成的老年斑和神经细胞内高度磷酸化的微管相关蛋白(tubulin-associated unit, tau)错误折叠引起的神经纤维缠结

    45。据报道,BDNF的生物合成及相关信号传导的破坏与AD的发病机制密切相关。Bharani等46对不同严重程度的AD患者和对照组患者死后脑组织中的BDNF水平进行测定,结果发现AD患者脑内BDNF的水平以及海马中TrKB的表达均远低于健康对照组,此外,研究进一步发现,脑内BDNF的表达水平与海马区Tau蛋白的积累负相关。一项新的研究47发现,AD患者除了脑部BDNF水平降低以外,其血清BDNF水平也会下降,且血清中BNDF的水平与AD患者出现认知障碍的严重程度一致。此外,BDNF/TrkB神经营养信号传导的缺陷还可以上调CCAAT增强子结合蛋白β的转录翻译,然后促进天冬酰胺内肽酶的表达,导致淀粉样前体蛋白和Tau片段化,最终导致AD48

    针刺作为非药物治疗的中医传统疗法,根据其病因病机辨证论治,可明显改善AD认知功能,减少并发症发生,且具有安全性高,不良反应少等优势。近年来,针刺治疗AD的作用机制成为了研究热点,针刺可通过调控脑内蛋白表达、改善突触可塑性、调控线粒体自噬、调控小胶质细胞的生理病理状态、抑制神经细胞凋亡、调节脑区能量代谢等途径改善AD

    49。早期研究50发现,电针刺激可上调AD小鼠海马中BDNF的表达,减少Aβ在大脑中的沉积,显著改善AD小鼠的学习和记忆障碍。同样,Wang等51也表明,电针干预可上调海马BDNF的表达,并在一定程度上维持海马LTP,减轻AD大鼠的认知缺陷。Lin等52研究了针刺防治AD的可能作用机制,结果发现针刺百会穴能够抑制Aβ异常过表达,抑制神经元凋亡,其机制与促进m-BDNF/pro-BDNF以及TrKB的表达增加,进而激活BDNF/TrKB信号通路密切相关。随后,研究53进一步证实,针刺百会能激活BDNF/TrKB信号通路,促进AD大鼠海马N-乙酰天冬氨酸以及谷氨酸的释放。其中N-乙酰天冬氨酸被认为是神经系统健康状况的敏感指标,其含量减少往往意味着神经元的损失、损坏或功能出现障碍。谷氨酸作为大脑和脊髓中关键的兴奋性神经递质,可以调节突触传递、神经元生长和分化以及能量代谢,其水平变化与神经元之间的信息传递密切相关,对于维持正常的神经系统功能至关重要。新的研究54在针刺百会和神庭穴的基础上采用腹针,取“引气归元”(中脘、下脘、关元和气海)、“腹四关”(双侧滑肉门和外陵)以及双侧的天枢和大横,结果发现基于“脑肠相通”的腹针联合常规针刺可进一步改善AD患者的认知功能障碍,其机制可能与上调BDNF的表达水平,激活BDNF/TrKB信号通路有关。

    3.3 针刺调节BDNF/TrkB信号通路对帕金森的影响

    PD在人群中的发病率逐年上升,是仅次于AD之后的第二大神经退行性疾病。PD主要侵犯人的大脑黑质区域,导致多巴胺能神经元(dopamine, DA)变性丢失和路易小体的形成,其中α-突触核蛋白(α-Synuclein, α-Syn)是路易小体的主要构成部分

    55。临床实验56表明,PD患者黑质中BDNF和TrKB的蛋白表达和mRNA水平显著降低,而二者的表达减少会导致α-syn的过表达和多巴胺能神经元的合成受到抑制。值得注意的是,α-syn被发现能直接与TrkB受体上的激酶结构域结合并抑制BDNF/TrKB信号传导,导致多巴胺能神经元死亡,然而BDNF反过来又可以抑制α-Syn-TrkB复合物的形成来减少TrkB的降解,揭示了α-syn与BDNF/TrKB信号通路之间的串扰57-58。Ding等59研究发现,阿魏酰低聚糖能够降低多巴胺能神经毒性,提高多巴胺能神经元的存活率,其神经保护作用是通过激活BDNF/TrKB信号通路抑制PD神经炎症介导的。此外,BDNF/TrKB信号通路的激活在各种运动方式预防或减缓PD导致的运动和非运动症状中发挥关键作用56

    中医学认为PD归属于“颤证”范畴,针刺可以通过激活BDNF/TrKB信号通路,有助于抑制黑质多巴胺能神经元的凋亡过程,并减轻神经炎症,从而改善PD运动及非运动症状,包括减少肌肉僵硬、增强运动协调能力以及缓解焦虑和抑郁等心理症状。Lin等

    60研究选取电针干预阳陵穴和太冲穴,结果发现电针可以增强1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP)诱导PD大鼠的BDNF水平及其下游信号分子Akt的磷酸化,抑制多巴胺神经元变形和细胞凋亡,改善MPTP诱导的异常行为,提示针刺具有调控BDNF/TrKB信号通路治疗PD的潜力。随后,Zhao等61研究了针刺治疗PD的作用机制,结果显示针刺PD小鼠的百会、印堂能够激活BDNK/TrKB信号通路对抗MPTP诱导的神经毒性,减少黑质多巴胺神经元的丢失。另有研究62表明,针刺还可以激活BDNF下游PI3K/AKt和MAPK/ERK信号通路,从而抑制神经元细胞凋亡和炎症反应,促进多巴胺能神经元的存活,改善大脑整体健康状况。Lee等63选择阳陵为主穴,昆仑为辅穴对MPTP诱导的小鼠进行电针干预3周,结果发现针刺可促进PD小鼠黑质区BDNK/TrKB通路相关蛋白活性的表达,阻止PD多巴胺能神经元变性及死亡,促进侧脑室下区的神经发生。

    3.4 针刺调节BDNF/TrkB信号通路对脊髓损伤的影响

    SCI是临床常见较严重的中枢神经系统损伤,由于脊髓神经元再生困难,因此促进神经元生长存活、减少继发性损伤和促进脊髓轴突的修复等是治疗SCI的关键,而BDNF/TrKB信号通路在该过程中起到不可或缺的作用。研究

    64发现,BDNF的激活可以通过与TrKB结合减轻SCI的炎症反应,而阻断BDNF/TrKB信号通路的传导逆转了其促进SCI神经功能恢复的生物学效应。Chen等65发现骨髓间充质干细胞携带的miR-26a-5p可负调控组蛋白甲基化转移酶2,进而激活BDNF/TrKB信号通路,增强K+-Cl-协同转运蛋白2的转录表达,抑制神经细胞凋亡,维持脊髓完整性。此外,研究66-67发现,跑步等体育锻炼可以改善神经肌肉接头处的BDNF/TrkB神经营养信号传导,并触发其下游自噬相关通路,从而介导神经元自噬和存活过程,对损伤局部起到保护作用。

    中医学中SCI属于“体惰”“痿证”之症,而督脉瘀阻,气血运化失司是SCI的中医病理病机。针刺可以通过激活BDNF/TrkB信号通路促进受损神经元再生,提高突触可塑性,治疗SCI。早期研究

    68发现,针刺大椎穴和命门穴,可以显著上调SCI大鼠脊髓组织中BDNFmRNA及其蛋白表达水平,促进脊髓受损部位的轴突再生,诱导功能性运动恢复。另外,叶青等69人选择电针联合经颅磁刺激干预SCI大鼠,结果发现,与单纯的经颅磁刺激或电针相比,联合治疗更加有效地改善了SCI大鼠神经功能损伤症状,减少受损脊髓出血、促进神经元再生,而其作用机制与上调激素中BDNF及TrkB以及下调p75NTR的表达有关。随后,研究70进一步发现,电针可以使BDNF与TrkB高亲和力结合,激活BDNF/TrkB信号通路,同时抑制proBDNF/p75NTR信号传导,进而实现脊髓受损部位的神经再生和修复。除此之外,神经元自噬与SCI继发性损伤程度密切相关,研究71发现,夹脊穴埋线能激活BDNF/TrkB信号通路,进而促进细胞自噬活动、减轻炎症反应以改善脊髓损伤后运动和神经功能损伤。

    4 小 结

    综上所述,BDNF/TrkB信号通路在中枢神经系统疾病中的作用已经得到了广泛的关注,该信号通路的激活对多种中枢神经系统疾病的发生和发展具有重要的影响。针刺作为一种传统的治疗方法,通过调节BDNF/TrkB信号通路,参与突触结构重塑,促进神经发生和突触再生,抑制炎症反应等在中枢神经系统疾病的临床症状和预后方面显示出一定的潜力和疗效。然而,当前仍存在一些挑战需要面对和解决。首先,尽管我们已经初步了解了针刺对BDNF/TrkB信号通路的调控作用,但其具体的作用机制非常复杂。BDNF/TrkB信号通路参与了多种细胞信号转导途径,而针刺可能通过多种途径影响该信号通路的活性,因此需要深入研究其具体的作用机制。其次,针刺对BDNF/TrkB信号通路的调控并不局限于本文所回顾的这几种神经系统疾病,未来学者们可以继续探究针刺通过该信号通路对更多神经系统疾病的影响。最后,当前有关针刺调控BDNF/TrKB信号传导的研究大多数仍为动物实验研究,因此今后应积极开展相关临床研究,为中枢神经系统疾病的治疗提供新靶点。在未来的研究中,我们还应该关注如何结合传统医学和现代医学的优势,进一步探索针刺对BDNF/TrkB信号通路的精准调控机制,从而为中枢神经系统疾病的治疗开发出更加有效的新型治疗策略。

    参考文献

    1

    Rothwell JAntal ABurke Det al. Central nervous system physiology [J]. Clin Neurophysiol202113212): 3043-3083. [百度学术] 

    2

    Wang CSKavalali ETMonteggia LM. BDNF signaling in context: from synaptic regulation to psychiatric disorders [J]. Cell20221851): 62-76. [百度学术] 

    3

    Eyileten CSharif LWicik Zet al. The Relation of the brain-derived neurotrophic factor with microRNAs in neurodegenerative diseases and ischemic stroke [J]. Mol Neurobiol2021581): 329-347. [百度学术] 

    4

    Zagrebelsky MKorte M. Are TrkB receptor agonists the right tool to fulfill the promises for a therapeutic value of the brain-derived neurotrophic factor? [J]. Neural Regen Res2024191): 29-34. [百度学术] 

    5

    Zhu Z HJia FAhmed Wet al. Neural stem cell-derived exosome as a nano-sized carrier for BDNF delivery to a rat model of ischemic stroke [J]. Neural Regen Res2023182): 404-409. [百度学术] 

    6

    Lai HCChang QYHsieh CL. Signal transduction pathways of acupuncture for treating some nervous system diseases [J]. Evid Based Complement Alternat Med201920192909632. [百度学术] 

    7

    Jianyi XJinyan XUMao Het al. Scalp acupuncture Yikang therapy on Baihui (GV20), Sishencong (EX-HN1), Zhisanzhen, Niesanzhen improves neurobehavior in young rats with cerebral palsy through notch signaling pathway [J]. J Tradit Chin Med2023432): 337-342. [百度学术] 

    8

    Shen JHao CYuan Set al. Acupuncture alleviates CUMS-induced depression-like behaviors of rats by regulating oxidative stress, neuroinflammation and ferroptosis [J]. Brain Res20241826148715. [百度学术] 

    9

    Jin GYJin LLJin BXet al. Neural control of cerebral blood flow: scientific basis of scalp acupuncture in treating brain diseases [J]. Front Neurosci2023171210537. [百度学术] 

    10

    Miao CLi XZhang Y. Effect of acupuncture on BDNF signaling pathways in several nervous system diseases [J]. Front Neurol2023141248348. [百度学术] 

    11

    Arévalo JCDeogracias R. Mechanisms controlling the expression and secretion of BDNF [J]. Biomolecules2023135): 789. [百度学术] 

    12

    Tejeda GSDíaz-Guerra M. Integral characterization of defective BDNF/TrkB signalling in neurological and psychiatric disorders leads the way to new therapies [J]. Int J Mol Sci2017182): 268. [百度学术] 

    13

    Ferreira FFRibeiro FFRodrigues RSet al. Brain-derived neurotrophic factor (BDNF) role in cannabinoid-mediated neurogenesis [J]. Front Cell Neurosci201812441. [百度学术] 

    14

    Wang JYu HLi Xet al. A TrkB cleavage fragment in hippocampus promotes depressive-like behavior in mice [J]. Brain Behav Immun202411956-83. [百度学术] 

    15

    Niu CYue XAn JJet al. Genetic dissection of BDNF and TrkB expression in glial cells [J]. Biomolecules2024141): 91. [百度学术] 

    16

    Jang HJSuh PGLee YJet al. PLCγ1: Potential arbitrator of cancer progression [J]. Adv Biol Regul201867179-189. [百度学术] 

    17

    Lee JChen XNicoll RA. Synaptic memory survives molecular turnover [J]. Proc Natl Acad Sci U S A202211942): e2211572119. [百度学术] 

    18

    Xiao KLi YChitwood RAet al. A critical role for CaMKII in behavioral timescale synaptic plasticity in hippocampal CA1 pyramidal neurons [J]. Sci Adv2023936): eadi3088. [百度学术] 

    19

    Yasuda RHayashi YHell JW. CaMKII: a central molecular organizer of synaptic plasticity, learning and memory [J]. Nat Rev Neurosci20222311): 666-682. [百度学术] 

    20

    Incontro SDíaz-Alonso JIafrati Jet al. Author correction: The CaMKII/NMDA receptor complex controls hippocampal synaptic transmission by kinase-dependent and independent mechanisms [J]. Nat Commun201891): 5205. [百度学术] 

    21

    Li CSui CWang Wet al. Baicalin attenuates oxygen-glucose deprivation/reoxygenation-induced injury by modulating the BDNF-TrkB/PI3K/Akt and MAPK/Erk1/2 signaling axes in neuron-astrocyte cocultures [J]. Front Pharmacol202112599543. [百度学术] 

    22

    Long HZCheng YZhou ZWet al. PI3K/AKT signal pathway: a target of natural products in the prevention and treatment of Alzheimer's disease and Parkinson's disease [J]. Front Pharmacol202112648636. [百度学术] 

    23

    Xu TLiu JLi XRet al. The mTOR/NF-κB pathway mediates neuroinflammation and synaptic plasticity in diabetic encephalopathy [J]. Mol Neurobiol2021588): 3848-3862. [百度学术] 

    24

    Zhou SLiu JSun Yet al. Dietary choline metabolite TMAO impairs cognitive function and induces hippocampal synaptic plasticity declining through the mTOR/P70S6K/ 4EBP1 pathway [J]. Food Funct2023146): 2881-2895. [百度学术] 

    25

    Wolf PSchoeniger AEdlich F. Pro-apoptotic complexes of BAX and BAK on the outer mitochondrial membrane [J]. Biochim Biophys Acta Mol Cell Res2022186910): 119317. [百度学术] 

    26

    Asadi MTaghizadeh SKaviani Eet al. Caspase-3: Structure, function, and biotechnological aspects [J]. Biotechnol Appl Biochem2022694): 1633-1645. [百度学术] 

    27

    Lin JSong TLi Cet al. GSK-3β in DNA repair, apoptosis, and resistance of chemotherapy, radiotherapy of cancer [J]. Biochim Biophys Acta Mol Cell Res202018675): 118659. [百度学术] 

    28

    Martin-Vega ACobb MH. Navigating the ERK1/2 MAPK Cascade [J]. Biomolecules20231310): 1555. [百度学术] 

    29

    Gałgańska HJarmuszkiewicz WGałgański Ł. Carbon dioxide and MAPK signalling: towards therapy for inflammation [J]. Cell Commun Signal2023211): 280. [百度学术] 

    30

    Wen XJiao LTan H. MAPK/ERK pathway as a central regulator in vertebrate organ regeneration [J]. Int J Mol Sci2022233): 1464. [百度学术] 

    31

    Zhao TZhou YZhang Det al. Inhibition of TREM-1 alleviates neuroinflammation by modulating microglial polarization via SYK/p38MAPK signaling pathway after traumatic brain injury [J]. Brain Res20241834148907. [百度学术] 

    32

    Suo NGuo YEHe Bet al. Inhibition of MAPK/ERK pathway promotes oligodendrocytes generation and recovery of demyelinating diseases [J]. Glia2019677): 1320-1332. [百度学术] 

    33

    Xue WZhao YXiao Zet al. Epidermal growth factor receptor-extracellular-regulated kinase blockade upregulates TRIM32 signaling cascade and promotes neurogenesis after spinal cord injury [J]. Stem Cells2020381): 118-133. [百度学术] 

    34

    Liu WWang XO'Connor Met al. Brain-derived neurotrophic factor and its potential therapeutic role in stroke comorbidities [J]. Neural Plast202020201969482. [百度学术] 

    35

    Li ZWang HXiao Get al. Recovery of post-stroke cognitive and motor deficiencies by Shuxuening injection via regulating hippocampal BDNF-mediated neurotrophin/Trk signaling [J]. Biomed Pharmacother2021141111828. [百度学术] 

    36

    Li CWang XYan Jet al. Cholic acid protects in vitro neurovascular units against oxygen and glucose deprivation-induced injury through the BDNF-TrkB signaling pathway [J]. Oxid Med Cell Longev202020201201624. [百度学术] 

    37

    Gong CHe XLi Get al. miR-497-5p promoted neuronal injury in ischemic stroke by inhibiting the BDNF/TrkB/PI3K/Akt pathway [J]. Gen Physiol Biophys2024432): 175-183. [百度学术] 

    38

    Zhu XQGao D. Naringenin alleviates cognitive dysfunction in rats with cerebral ischemia/reperfusion injury through up-regulating hippocampal BDNF-TrkB signaling: involving suppression in neuroinflammation and oxidative stress [J]. Neuroreport2024354): 216-224. [百度学术] 

    39

    刘洁张建刚马登飞. 电针对脑梗死患者血清VEGF/Flt-1、BDNF表达以及临床效果的影响 [J]. 中华中医药学刊2023423): 231-234. [百度学术] 

    Liu JZhang JGMa DF. Effect of electroacupuncture on expressions of serum VEGF/Flt-1 and BDNF in patients with cerebral infarction [J]. Chin Arch Tradit Chin Med2023423): 231-234. [百度学术] 

    40

    王琮民闫纪琳李海涛. 电针对脑梗死大鼠脑组织中BDNF/TrkB/PI3K信号通路的影响 [J]. 中医药导报2022285): 52-56. [百度学术] 

    Wang CMYan JLLi HTet al. Effect of electroacupuncture on BDNF/TrkB/Pl3K signal pathway in brain tissue of rats with cerebral infarction [J]. Hunan Guid J Tradit Chin Med Pharmacol2022285): 52-56. [百度学术] 

    41

    余明月苏凯奇申昕. 电针对脑缺血再灌注学习记忆障碍大鼠海马脑源性神经营养因子转化和突触可塑性的影响[J]. 针刺研究2024494): 391-397. [百度学术] 

    Yu MYSu KQShen Xet al. Effect of electroacupuncture on proBDNF/mBDNF and synaptic plasticity in rats with learning and memory impairment after cerebral ischemia-reperfusion[J]. Acupunct Res2024494): 391-397. [百度学术] 

    42

    苏凯奇吕转吴明莉. 电针对缺血再灌注后学习记忆障碍大鼠BDNF/TrkB/PI3K/Akt通路的影响及对海马神经元保护作用研究 [J]. 中国全科医学20232633): 4187-4193. [百度学术] 

    Su KQLu ZWu MLet al. Effect of electroacupuncture on BDNF/TrkB/Pl3K/Akt pathway and hippocampal neuronal protection in rats with learning and memory impairment after ischemia reperfusion [J]. Chin Gen Pract20232633): 4187-4193. [百度学术] 

    43

    袁洁高静苏凯奇. 电针对脑缺血再灌注损伤诱导的学习记忆障碍大鼠BDNF/TRKB/CREB信号通路和海马突触可塑性的影响 [J]. 针刺研究2023489): 843-851. [百度学术] 

    Yuan JGao JSu KQet al. Electroacupuncture improves learning and memory impairment and enhances hippocampal synaptic plasticity through BDNF/TRKB/CREB signaling pathway in cerebral ischemia-reperfusion injury rats [J]. Acupunct Res2023489): 843-851. [百度学术] 

    44

    孙培养储浩然李难. “通督调神”针刺对脑卒中后抑郁大鼠海马CREB/BDNF/TrkB信号通路的影响 [J]. 中国针灸2022428):907-913. [百度学术] 

    Sun PYChu HRLi Net al. Effect of Tongdu Tiaoshen acupuncture on CREB/BDNF/TrkB signaling pathway of hippocampus in rats with post-stroke depression [J]. Chin Acu-Mox2022428): 907-913. [百度学术] 

    45

    Xing YLi PJia Yet al. Association of inflammatory bowel disease and related medication exposure with risk of Alzheimer's disease: an updated meta-analysis [J]. Front Aging Neurosci2022141082575. [百度学术] 

    46

    Bharani KLLedreux AGilmore Aet al. Serum pro-BDNF levels correlate with phospho-tau staining in Alzheimer's disease [J]. Neurobiol Aging20208749-59. [百度学术] 

    47

    Angelucci FVeverova KKatonová Aet al. Serum PAI-1/BDNF ratio is increased in Alzheimer's disease and correlates with disease severity [J]. ACS Omega2023839): 36025-36031. [百度学术] 

    48

    Wang ZHXiang JLiu Xet al. Deficiency in BDNF/TrkB neurotrophic activity stimulates δ-Secretase by upregulating C/EBPβ in Alzheimer's disease [J]. Cell Rep2019283): 655-669.e5. [百度学术] 

    49

    Wu LDong YZhu Cet al. Effect and mechanism of acupuncture on Alzheimer's disease: a review [J]. Front Aging Neurosci2023151035376. [百度学术] 

    50

    Li XGuo FZhang Qet al. Electroacupuncture decreases cognitive impairment and promotes neurogenesis in the APP/PS1 transgenic mice [J]. BMC Complement Altern Med20141437. [百度学术] 

    51

    Wang XShen FKong Let al. Effects of low frequency electroacupuncture on expression of BDNF in hippocampus of Alzheimer’s disease model rats [J]. Journal of Hubei University of Chinese Medicine2015175): 7-9. [百度学术] 

    52

    Lin RChen JLi Xet al. Electroacupuncture at the Baihui acupoint alleviates cognitive impairment and exerts neuroprotective effects by modulating the expression and processing of brain-derived neurotrophic factor in APP/PS1 transgenic mice [J]. Mol Med Rep2016132): 1611-1617. [百度学术] 

    53

    Lin RLi LZhang Yet al. Electroacupuncture ameliorate learning and memory by improving N-acetylaspartate and glutamate metabolism in APP/PS1 mice [J]. Biol Res2018511): 21. [百度学术] 

    54

    杨淑荃范德辉罗孟西. 腹针对轻中度阿尔茨海默病患者认知功能及血清5-HT、BDNF、IGF-1的影响 [J]. 上海针灸杂志2023425): 485-490. [百度学术] 

    Yang SQFan DHLuo MXet al. Effects of abdominal acupuncture on cognitive function and serum 5-HT, BDNF and lGF-1 in patients with mild-to-moderate Alzheimer's disease. [J]. Shanghai J Acu-mox2023425): 485-490. [百度学术] 

    55

    Simon DKTanner CMBrundin P. Parkinson disease epidemiology, pathology, genetics, and pathophysiology [J]. Clin Geriatr Med2020361): 1-12. [百度学术] 

    56

    Paterno APolsinelli GFederico B. Changes of brain-derived neurotrophic factor (BDNF) levels after different exercise protocols: a systematic review of clinical studies in Parkinson's disease [J]. Front Physiol2024151352305. [百度学术] 

    57

    Kang SSZhang ZLiu Xet al. TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson's disease [J]. Proc Natl Acad Sci U S A201711440): 10773-10778. [百度学术] 

    58

    阎晨刘涛宣斐. 基于α-synuclein表达探讨七氟烷对小鼠树突棘状态与学习记忆功能的影响[J]. 遵义医科大学学报2022454):470-477. [百度学术] 

    Yan CLiu TXuan F.Effects of Sev of lurane on dendritic spines as well as learning and memory function in mice via α-synuclein[J]. J Zunyi Med Univ2022454):470-477. [百度学术] 

    59

    Ding YZhou MZheng Ret al. Feruloylated oligosaccharides ameliorate MPTP-induced neurotoxicity in mice by activating ERK/CREB/BDNF/TrkB signalling pathway [J]. Phytomedicine2023108154512. [百度学术] 

    60

    Lin JGChen CJYang HBet al. Electroacupuncture promotes recovery of motor function and reduces dopaminergic neuron degeneration in rodent models of Parkinson's disease [J]. Int J Mol Sci2017189): 1846. [百度学术] 

    61

    Zhao YLuo DNing Zet al. Electro-acupuncture ameliorated MPTP-induced Parkinsonism in mice via TrkB neurotrophic signaling [J]. Front Neurosci201913496. [百度学术] 

    62

    Zhao YZhang ZQin Set al. Acupuncture for Parkinson's disease: efficacy evaluation and mechanisms in the dopaminergic neural circuit [J]. Neural Plast202120219926445. [百度学术] 

    63

    Lee YLee HBae CHet al. Electroacupuncture at GB34 modulates neurogenesis and BDNF-ERK signaling in a mouse model of Parkinson's disease [J]. J Tradit Complement Med2023133): 263-269. [百度学术] 

    64

    Li XWu QXie Cet al. Blocking of BDNF-TrkB signaling inhibits the promotion effect of neurological function recovery after treadmill training in rats with spinal cord injury [J]. Spinal Cord2019571): 65-74. [百度学术] 

    65

    Chen MLin YGuo Wet al. BMSC-Derived Exosomes Carrying miR-26a-5p Ameliorate Spinal Cord Injury via Negatively Regulating EZH2 and Activating the BDNF-TrkB-CREB Signaling [J]. Mol Neurobiol20241-19. [百度学术] 

    66

    Li XSong XFang Let al. Body weight-supported treadmill training ameliorates motoneuronal hyperexcitability by increasing GAD-65/67 and KCC2 expression via TrkB signaling in rats with incomplete spinal cord injury [J]. Neurochem Res2022476): 1679-1691. [百度学术] 

    67

    Głowacka AJi BSzczepankiewicz AAet al. BDNF spinal overexpression after spinal cord injury partially protects soleus neuromuscular junction from disintegration, increasing VAChT and AChE transcripts in soleus but not tibialis anterior motoneurons [J]. Biomedicines20221011): 2851. [百度学术] 

    68

    Tu WZJiang HZhang Let al. Electro-acupuncture at governor vessel improves neurological function in rats with spinal cord injury [J]. Chin J Integr Med20171-7. [百度学术] 

    69

    叶青李志刚时素华. 督脉电针联合重复经颅磁刺激对脊髓损伤后大鼠脊髓BDNF及其受体TrkB和p75~(NTR)表达的影响 [J]. 针灸临床杂志2022388): 57-65. [百度学术] 

    Ye QLi ZGShi SHet al. Impacts of DU meridian EA combined with r TMS on expressions of BDNF and its receptors of TrkB and p75NTR in SCl rats [J]. Clin J Acu-mox2022388): 57-65. [百度学术] 

    70

    叶青时素华姚海江. 基于BDNF-TrkB/proBDNF-p75~(NTR)信号通路探讨电针治疗脊髓损伤的分子机制 [J]. 河南中医2023437): 1100-1106. [百度学术] 

    Ye QShi SHYao HJet al. Probe into the molecular mechanism of electroacupunture therapy for spinal cord injury based on the BDNF-TrkB/proBDNF-p75NTR signaling pathway [J]. Henan Tradit Chin Med2023437): 1100-1106. [百度学术] 

    71

    王镌李玥蒋伟. 夹脊穴埋线对大鼠脊髓损伤后自噬及BDNF/TrkB通路的调控作用 [J]. 现代中西医结合杂志20233221): 2947-2953. [百度学术] 

    Wang JLi YJiang W. Regulation of spinal cord embedding on autophagy and BDNF/TrkB pathway after spinal cord injury in rats [J]. Mod J Integr Tradit Chin West Med20233221): 2947-2953. [百度学术] 

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