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氧化应激在脊髓损伤中的作用及机制研究进展

发表时间:2024年03月29日阅读量:292次下载量:859次下载手机版

作者: 马春伟 1, 2 张海鸿 1, 2

作者单位: 1. 兰州大学第二医院骨科(兰州 730030) 2. 兰州大学第二临床医学院(兰州 730030)

关键词: 脊髓损伤 氧化应激 信号通路 活性氧

DOI: 10.12173/j.issn.1004-5511.202312102

基金项目: 基金项目: 国家自然科学基金地区科学基金项目(31960175)

引用格式:马春伟, 张海鸿. 氧化应激在脊髓损伤中的作用及机制研究进展[J]. 医学新知, 2024, 34(3): 339-346. DOI:10.12173/j.issn.1004-5511.202312102.

Ma CW, Zhang HH. Research progress on the role and mechanism of oxidative stress in spinal cord injury[J]. Yixue Xinzhi Zazhi, 2024, 34(3): 339-346. DOI:10.12173/j.issn.1004-5511.202312102.[Article in Chinese]

摘要|Abstract

脊髓损伤(spinal cord injury,SCI)是严重影响中枢神经系统的疾病,其中氧化应激在SCI的继发性损伤中扮演关键角色。本文阐述了氧化应激在SCI中的作用、主要信号通路及现有治疗方法。重点关注Nrf-2、PI3K/AKT、TLR4/MyD88等通路在氧化应激调控中的作用,并探讨抗氧化疗法在减轻SCI症状中的潜力,旨在对深入理解SCI和优化治疗策略提供参考。

全文|Full-text

脊髓损伤(spinal cord injury, SCI)是中枢神经系统(central nervous system, CNS)的一种严重创伤性疾病,可导致受伤平面以下感觉、运动和括约肌功能障碍,进而引发截瘫、排尿和排便功能障碍等临床表现[1]。全球每年约25~50万人受SCI的影响,导致200~300万人致残 [2],给社会和患者带来巨大负担。SCI是一种具有破坏性的神经病理状态,其病理生理学包括急性和慢性阶段,并涉及缺血、氧化应激、炎症、细胞凋亡和运动功能障碍等一系列破坏性事件[3]。氧化应激是指活性氧(reactive oxygen, ROS)产生与机体抗氧化防御之间平衡失调的状态[4]。作为SCI重要的损伤标志和病理过程,减轻氧化应激有助于改善SCI后的症状和功能恢复。本文综述了SCI后氧化应激的作用及其相关机制,旨在为SCI的治疗提供新的思路。

1 脊髓损伤后氧化应激的发生机制

SCI的病理过程分为原发性和继发性损伤。原发性损伤是由外力直接造成的脊髓组织和细胞破坏[3]。继发性损伤是原发性损伤引发的级联反应,进一步导致脊髓组织损害和大量ROS的产生[5]。ROS既包括自由基,如超氧化物和羟基,也包括非自由基,如过氧化氢(H2O2)和单线态氧[4]。正常情况下,细胞会产生适量ROS,以维持平衡并修复损伤[6]。但在SCI中,ROS的过量生成打破了这一平衡,引发氧化应激[7]。SCI后谷氨酸水平上升,导致钙离子流入细胞并引发钙超载,激活线粒体内的NADPH氧化酶(reduced nicotinamide adenine dinucleotide phosphate oxidase, Nox),产生更多ROS和活性氮(reactive nitrogen species, RNS)[8],加剧线粒体功能障碍和氧化应激。ROS的其他来源包括细胞内的过氧化物体、溶酶体、内质网和氧化酶[9-10]。SCI引起的过量ROS和RNS对细胞DNA、脂质、蛋白质造成损害,引发细胞损伤和死亡,加剧了SCI的严重性[2]。

2 脊髓损伤后氧化应激对神经元及胶质细胞的影响

2.1 活性氧促进细胞凋亡

细胞凋亡,作为一种常见的程序性细胞死亡方式,是SCI后继发性损伤的主要病理特征,并对SCI的进展和恢复具有关键影响[11]。在SCI中,过量的ROS导致神经元凋亡,因此控制ROS水平对神经元保护极为重要[12]。Liu等[13]研究发现,在SCI模型大鼠中,伊马替尼激活Nrf2/HO-1通路,有效减轻了氧化应激、细胞凋亡和炎症。同样,Rao等[14]研究显示,通过减少ROS生成,可以减轻PC12细胞的凋亡和细胞周期停滞,增强存活率。因此,控制ROS产生以减少神经元和胶质细胞的凋亡成为SCI治疗的重要研究方向。

2.2 抑制活性氧可减轻炎症

炎症是身体对SCI的自然响应,目的是清除坏死的组织和细胞。然而,炎症标志物的增加会形成有毒的微环境,导致脊髓组织的细胞凋亡、空腔形成和神经胶质疤痕,加剧SCI并妨碍神经功能的恢复。氧化应激在促进炎症中扮演重要角色[15]。Liu等[16]发现,晚期氧化蛋白产物(advanced oxidation protein products,AOPP)通过激活Nox,使BV2细胞产生过量的ROS,并通过Nox4-ROS-MAPK-NF-κB信号通路诱导炎症。降低ROS水平能有效抑制SCI炎症[17]。Li等[18]研究表明,锌可减轻小鼠SCI后的ROS生成和氧化应激,抑制NLRP3炎症小体的活化。因此,有效控制ROS的产生和清除对于减轻SCI后的炎症和促进功能恢复具有重要意义。

2.3 活性氧与铁死亡

铁死亡作为一种新近发现的细胞死亡方式,与细胞凋亡、自噬、坏死等有所不同。铁死亡是由铁依赖的脂质过氧化引起,其特征包括线粒体体积缩小、膜密度增加、嵴减少或消失,以及膜外壁破裂等[19-20]。Ge等[21]研究表明,在小鼠SCI模型中,NRF2 / HO-1和GPX4通路能降低丙二醛(MDA)、ROS和脂质过氧化物水平,减轻神经元铁死亡和脊髓损伤。另一项研究发现,血红素处理可诱导神经元铁死亡,而生长分化因子15(growth differentiation factor15, GDF15)减少氧化应激后可降低此类死亡[22]。因此,在SCI治疗中,控制ROS的过量产生和脂质过氧化是关键,这有可能成为未来促进神经功能恢复的新靶点。

2.4 活性氧参与轴突变性

SCI发生后,原发性机械损伤及继发性病理反应会导致神经轴突损坏和神经功能受损。氧化应激作为神经退行性途径的一个诱导因素,会引起神经元死亡和神经轴突变性[23]。小胶质细胞和巨噬细胞等反应性细胞上调Nox等,产生ROS和RNS,进而损伤轴突,加剧神经变性[15]。Wang等[24]研究发现,在SCI大鼠模型和H2O2诱导的氧化应激小胶质细胞中,抑制小胶质细胞活化可减轻氧化应激,进而促进轴突再生和功能恢复。Zheng等[25]利用H2O2处理神经元以模拟SCI后的氧化应激环境,通过光生物调节(photobiomodulation, PBM)降低ROS水平,促进神经元存活和轴突再生。然而,Hervera等[26]的研究表明,适度的ROS通过NOX2-PI3K-p-Akt信号通路促进背根神经节细胞(dorsal root ganglion, DRG)轴突再生,这与先前的研究结果相悖。表明适量的ROS可能促进轴突再生,而过量的ROS可能导致神经元凋亡和轴突变性。未来应进一步探索ROS在轴突再生中的作用机制,并验证调节ROS水平是否有助于预防轴突变性和促进轴突再生。

2.5 其他方面

神经病理性疼痛(neuropathic pain, NP)作为SCI的一种常见并发症,影响着多达60%的SCI患者[27]。ROS在NP的发生中发挥关键作用,SCI导致的过量ROS会激活细胞内磷酸化钙调蛋白依赖性蛋白激酶II(P-CamKII),导致神经元过度兴奋和疼痛[28-29]。降低氧化应激有助于减轻SCI后的超敏反应和痛觉异常[30]。因此,控制ROS和脂质过氧化在SCI治疗中对缓解NP至关重要。

3 调控脊髓损伤氧化应激的相关通路

脊髓损伤后的氧化应激不仅加剧了神经组织的损害,而且影响了损伤后的恢复过程。大量研究证明,可以通过调控Nrf-2等相关信号通路来有效缓解脊髓损伤后的氧化应激(图1)。

  • 图1 相关信号通路在脊髓损伤后发挥抗氧化应激作用
    Figure1.Related signaling pathways play an anti-oxidative stress role after spinal cord injury
    注:通过抗氧化疗法调控相关信号通路(Nrf-2、PI3K/AKT、TLR4/MyD88、Notch、JNK/p66),可有效减少来自线粒体、过氧化物酶体、溶酶体、内质网和氧化酶产生的ROS,从而减轻细胞凋亡、铁死亡和炎症,促进轴突再生,减轻神经病理性疼痛;Endoplasmic reticulum:内质网;Lysosome:溶酶体;Mitochondria:线粒体;Oxidase:氧化酶;Peroxisome:过氧化物酶体;ROS:活性氧;Protein:蛋白质;Lipids:脂质。

3.1 Nrf-2信号通路

核因子红细胞系2相关因子2(Nrf-2)是一种关键转录因子,参与调控多种ROS解毒酶。在氧化应激下,Nrf-2从KEAP-1中解离并迁移到细胞核,与抗氧化反应元件(ARE)结合,调控包括血红素加氧酶-1(HO-1)和醌氧化还原酶-1(NQO-1)在内的抗氧化基因和酶的表达,以消除ROS并减轻氧化应激[31]。Nrf-2途径在抗氧化应激中扮演着重要角色。Li等[32]的研究发现,在用H2O2处理的骨髓间充质干细胞(bone marrow stem cell, BMSC)模拟SCI氧化应激模型和SCI大鼠中,辅酶Q10能通过上调Nrf-2/ NQO-1的表达来抑制氧化应激和减少细胞凋亡。Xia等[33]的研究也表明,靶向上调Nrf-2的表达可以减少脂多糖(lipopolysaccharide, LPS)诱导的星形胶质细胞的氧化应激、炎症和凋亡。因此,Nrf-2作为一条经典的抗氧化应激通路,其靶向干预能有效调控SCI后的氧化应激水平,减少细胞损伤,并促进SCI的恢复。

3.2 PI3K/AKT信号通路

PI3K/AKT信号通路由磷脂酰肌醇3激酶(PI3K)和下游的蛋白激酶B(AKT)构成,是细胞生理和病理过程中的一条关键途径。PI3K分为I类、II类和III类三种亚型,其中I类研究最为广泛。在此通路中,PI3K将磷脂酰肌醇(3,4)-二磷酸二钠(PIP2)转化为磷脂酰肌醇(3,4,5)-三磷酸(PIP3),从而激活AKT。激活的AKT通过磷酸化级联反应调控下游效应分子,此过程受脂质和蛋白质磷酸酶的调节[34]。PI3K/AKT通路在SCI后的炎症、细胞死亡和胶质瘢痕形成中发挥着重要作用[35]。例如,He等[36]发现,在乙醇诱导的氧化应激模型中,激活PI3K/AKT通路可以减少ROS的生成,从而缓解氧化应激,减轻神经元的氧化损伤。Li等[37]发现,上调AKT的磷酸化能够减少ROS生成,而用抑制剂阻断PI3K/AKT通路会逆转这种保护效果。这些发现表明,PI3K/AKT通路在调节SCI的细胞炎症和凋亡以及氧化应激中发挥重要作用,为SCI氧化应激的治疗提供新的靶点。

3.3 TLR4 / MyD88信号通路

Toll样受体(Toll-like receptor, TLR)是一组能够响应病原体、细胞因子和各类应激源刺激的模式识别受体,它们激活MyD88依赖性途径和MyD88非依赖性途径两个主要的下游途径[38]。SCI后,激活的TLR4 / MyD88信号通路会增加炎症相关基因的表达,从而引发炎症[39]。此外,TLR4 / MyD88途径不仅参与炎症反应,还与SCI中的氧化应激密切相关。Li等[40]的研究显示,H2O2可在体外诱导神经干/祖细胞(NSPC)的氧化应激和凋亡,而使用TLR4/MyD88抑制剂TAK-242可显著减少NSPC产生的ROS,并增加抗氧化酶表达和细胞存活率。Zhang等[41]也发现,TLR4抑制剂TLR4-IN-C34显著减少了LPS诱导的小胶质细胞中的ROS产生。这些研究表明,活化的TLR4 / MyD88通路促进ROS产生,因此,作为一个潜在的靶点,未来有必要更深入探究该通路在氧化应激中的作用机制。

3.4 Notch信号通路

Notch信号通路作为一种在进化上高度保守的机制,参与多种正常生理和病理过程。在Notch通路中,经过三次裂解的受体直接进入细胞核,调控靶基因的表达[42]。Notch在SCI继发性损伤中扮演着关键角色,影响神经元分化、神经炎症和轴突再生等过程[43]。Li等[44]的研究显示,H2O2处理的星形胶质细胞在经历氧化应激和细胞凋亡增加后,使用Notch抑制剂DAPT可以有效逆转这些现象。同样,Lv等[45]发现,激活的Notch通路会提高氧化应激水平。因此,Notch通路在SCI后的氧化应激响应中发挥显著作用,是一个重要的研究焦点和潜在的治疗靶标。

3.5 JNK/p66信号通路

C-Jun氨基末端蛋白激酶(JNK)是丝裂原活化蛋白激酶(MAPK)家族的一部分,分为三个主要亚型:JNK1和JNK2广泛分布于多种组织,而JNK3主要存在于大脑、心肌、平滑肌和睾丸[46]。特定刺激激活MAP3K,进而导致MAP2K和JNK的连续磷酸化,激活的JNK随后介导p66的磷酸化[46-47]。研究表明,激活的JNK/p66信号通路能诱导大量ROS的产生,加剧氧化应激下的细胞损伤[47]。Cheng等[48]的研究发现,在SCI大鼠模型中,激活JNK/p66通路导致了ROS的过量产生和氧化应激损伤。因此,将JNK/p66通路作为干预靶点,减少ROS的产生,可能有助于减轻SCI中由氧化应激引起的损害。

4 活性氧作为脊髓损伤后的治疗靶点

4.1 抗氧化剂

在SCI治疗中,众多天然化合物已显示出显著的抗氧化、抗炎和抗凋亡效果[49]。例如,研究表明迷迭香酸(RA),一种水溶性多酚类植物化学物质,在SCI大鼠模型中展现出这些特性,并促进了功能恢复,体外实验亦证实了其效果[50]。同样,青藤碱,从中草药提取的一种生物碱,在SCI治疗中同样能减轻氧化应激和炎症[51]。这些发现突显了天然化合物在SCI治疗中的潜力。

微小RNA(microRNA, miRNA)和长链非编码RNA(lncRNA)作为基因调控的非编码RNA,在SCI治疗中显示了较大潜力[52]。例如,miRNA可以调节SCI导致的氧化应激和炎症,如过表达microRNA-299a-5p减轻了小鼠SCI的症状[53]。同样,lncRNA如CASC9可减轻LPS诱导的氧化应激和细胞凋亡[54]。这些研究结果表明,非编码RNA是治疗SCI后氧化应激有希望的干预靶点。

Sirtuins,一组NAD依赖的蛋白脱乙酰酶(SIRT1-7),在调节SCI相关氧化还原通路中发挥关键作用[12]。Chen等[55]的研究发现,SCI大鼠中SIRT6表达降低,而上调SIRT6能明显减轻氧化应激、炎症和细胞凋亡。Li等[56]的研究则表明SIRT4通过改善线粒体功能,有助于改善MDA、乳酸脱氢酶(LDH)和ROS的代谢,促进SCI恢复。这些研究表明Sirtuins在改善SCI后的氧化应激和功能恢复方面具有潜力。

微量元素,如锌和硒,在人体中具有重要生物学功能。研究显示,它们能降低SCI后ROS的产生,从而减轻氧化应激损伤[18, 57]。在SCI治疗中,提升抗氧化剂的溶解度、生物利用度和生物相容性是较大挑战。近期,纳米颗粒和外泌体的应用被发现能有效提高抗氧化剂的治疗效果,代表了治疗SCI的新方向[58-59]。

4.2 线粒体移植

线粒体在细胞的病理生理活动中扮演着关键角色,特别是在维持三磷酸腺苷(ATP)生成和细胞稳态方面。SCI导致线粒体功能障碍,引发ROS过量产生、线粒体DNA损伤和ATP生成减少等问题。新型线粒体移植策略已被提出以改善这些问题[60]。Lin等[61]的研究通过向SCI大鼠受损部位移植同种异体线粒体,发现可以显著改善炎症和氧化应激,促进细胞存活和功能恢复。此外,线粒体移植在改善脊髓缺血再灌注损伤方面也显示出潜力[62],其可能成为治疗SCI的一个有希望的策略。

4.3 针灸治疗

针灸,作为中医的重要组成部分,拥有悠久的历史,并适用于治疗多种疾病。针灸通过在特定穴位插针,结合多种操作手段来进行治疗[63]。研究表明,针灸能促进SCI功能恢复。Cheng等[48]研究表明,电针能激活JNK/p66途径,抑制ROS生成,从而改善SCI后的功能恢复。同样,Dai等[64]研究指出,电针通过激活Nrf2 / HO-1途径,有助于SCI的恢复。作为一种非侵入性治疗,针灸副作用较少,因此在SCI治疗中具有潜在的价值。

5 结语

SCI会导致不可逆的损害,目前研究重点在于减少SCI后的继发性损伤,特别是氧化应激这一关键领域。众多研究显示,氧化应激对SCI的进展有重大影响,因此改善氧化应激是治疗SCI的关键方向。本文详细阐述了SCI后氧化应激的影响、相关信号通路的干预机制及治疗方法。Nrf-2、PI3K/AKT、TLR4 / MyD88、Notch、JNK/p66等信号通路在调控SCI的氧化应激中发挥着作用。研发针对这些通路的特异性激活剂或抑制剂,是未来治疗SCI的一个重要方向。天然化合物因其多样的药理作用、易获取性、低成本及显著疗效,在治疗SCI方面具有巨大潜力,并有望在临床应用中发挥作用。线粒体移植作为一种新兴治疗策略,通过替换受损细胞中的线粒体,减少ROS的产生,增加能量生成,从而挽救受损细胞。尽管如此,线粒体移植的来源和方法仍存在争议,需要更多的研究来解决。目前,SCI氧化应激的研究主要局限于实验室,还缺乏临床证据支持其有效性和可行性,因此未来需要开展更多临床试验来发展相关药物和治疗方法。

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《医学新知》由国家新闻出版总署批准,中国农工民主党湖北省委主管,武汉大学中南医院和中国农工民主党湖北省委医药卫生工作委员会主办的综合性医学学术期刊,国内外公开发行。

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