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丙戊酸治疗急性脑血管病的作用机制和研究进展论文

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摘要:近年来我国脑血管病的发生率逐渐增加。脑血管病的发病率、死亡率和致残率十分高。脑血管病主要分为:①缺血性,又称脑梗死。②出血性,分为脑出血和蛛网膜下腔出血。急性脑血管病发生后,继发性脑损伤的不良反应发生率相对较高,因此迫切需要有效的治疗方法。如何有效减少急性脑血管事件后神经损伤,提高患者的生活质量是临床研究的重点。丙戊酸(VPA)是一种广谱的抗癫痫药物,VPA的分子结构十分简单,是两个丙基附着在乙酸部分上,是一种组蛋白脱乙酰基酶(HDAC)抑制剂,常用于治疗癫痫和双相情感障碍。在神经退行性疾病的细胞和动物模型中,VPA具有神经保护作用[1]。VPA对缺氧缺血性脑损伤和脑出血也有治疗和保护作用[2]。在短暂缺血的大鼠模型中,用VPA进行缺血后治疗可降低脑梗塞体积和神经系统损伤[3],并显示出抗炎特性。本文就近年来对丙戊酸在脑血管疾病中的研究进展作一综述。

关键词:丙戊酸;急性脑卒中;神经保护

本文引用格式:王子棠,汤小玲,陈梅玲.丙戊酸治疗急性脑血管病的作用机制和研究进展[J].世界最新医学信息文摘,2019,19(80):110-111,113.

The Mechanism and Research Progress of Valproic Acid in the Treatment of Acute Cerebrovascular Disease

WANG Zi-tang,TANG Xiao-ling,CHEN Mei-ling*

(Guilin Medical University,Guilin Guangxi)

ABSTRACT:In recent years,the incidence of cerebrovascular disease in China has gradually increased.The incidence,mortality and disability rate of cerebrovascular diseases are very high.Cerebrovascular diseases are mainly divided into:(1)ischemia,also known as cerebral infarction.(2)Hemorrhagic,divided into cerebral hemorrhage and subarachnoid hemorrhage.After the occurrence of acute cerebrovascular disease,the incidence of adverse reactions of secondary brain injury is relatively high,so effective treatment is urgently needed.How to effectively reduce nerve injury after acute cerebrovascular events and improve the quality of life of patients is the focus of clinical research.Valproic acid(VPA)is a broad-spectrum antiepileptic drug.Its molecular structure is very simple.VPA is a histone deacetylase(HDAC)inhibitor with two propyl groups attached to acetic acid.It is often used to treat epilepsy and bipolar affective disorder.VPA has neuroprotective effects in cell and animal models of neurodegenerative diseases[1].VPA also has therapeutic and protective effects on hypoxic-ischemic brain injury and cerebral hemorrhage[2].In the rat model of transient ischemia,post-ischemic treatment with VPA can reduce the volume of cerebral infarction and neurological damage[3],and show anti-inflammatory properties.This article reviews the research progress of valproic acid in cerebrovascular diseases in recent years.

KEY WORDS:VPA;Cerebrovascular diseases;Neuroprotection

0引言

近年来我国脑血管病的发生率逐渐增加。脑血管病的发病率、死亡率和致残率十分高。脑血管病主要分为:①缺血性,又称脑梗死。②出血性,分为脑出血和蛛网膜下腔出血。急性脑血管病发生后,继发性脑损伤的不良反应发生率相对较高,因此迫切需要有效的治疗方法。如何有效减少急性脑血管事件后神经损伤,提高患者的生活质量是临床研究的重点。

丙戊酸(VPA)是一种广谱的抗癫痫药物,VPA的分子结构十分简单,是两个丙基附着在乙酸部分上,是一种组蛋白脱乙酰基酶(HDAC)抑制剂,常用于治疗癫痫和双相情感障碍。在神经退行性疾病的细胞和动物模型中,VPA具有神经保护作用[1]。VPA对缺氧缺血性脑损伤和脑出血也有治疗和保护作用[2]。在短暂缺血的大鼠模型中,用VPA进行缺血后治疗可降低脑梗塞体积和神经系统损伤[3],并显示出抗炎特性。本文就近年来对丙戊酸在脑血管疾病中的研究进展作一综述。

1丙戊酸在急性脑血管病的抗炎作用

1.1急性脑血管疾病后的炎性改变


小胶质细胞介导的神经炎症在无论是在脑缺血损伤或是脑出血损伤中都具有重要作用。同样炎症细胞因子(IL-1β和TNF-α)、iNOS和COX-2过表达可诱导炎症反应[4]。急性脑血管疾病(如脑梗死、脑出血等)发生时,脑组织出现一系列由激活的小胶质细胞和渗入的白细胞介导的复杂的炎症改变。释放大量炎性介质,造成全身性的炎性反应,如:Iκ-Bα激酶激活,降解Iκ-Bα,激活NF-κB,其介导肿瘤坏死因子a、b发生炎性反应[5];激活的小胶质细胞和渗入的白细胞介导IL-1、IL-2、TNF-α[6];一氧化氮、过度的氧自由基和白激素1、6、8的表达,对大脑神经元细胞造成的炎症损伤。

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1.2丙戊酸的抗炎作用

VPA的抗炎作用可能涉及多种机制。已发现VPA可激活热休克因子(hsp70的转录因子)并增强sp1(一种介导hsp70表达的细胞保护转录因子)的乙酰化[7-12]。hsp70能抑制小胶质细胞活化、核因子-kappa B(NF-κB)、IL-6、Fas配体、髓过氧化物酶和iNOS,VPA增加了hsp70的表达,因此具有抗炎作用[13]。有研究表明[14]VPA不引起人小胶质细胞凋亡,但它能改变其表型,对这些细胞的生理和病理行为有重要影响,即VPA可引起小胶质细胞活化降低,起减轻神经炎症的作用;有研究表明[6],在EAE大鼠的淋巴结中,VPA处理抑制了某些Th1-和Th17相关分子(如IL-12p35、IFN-C、IL-6和IL-17)的mRNA水平及其特异性转录因子T-bet和RORCT,提示VPA可以减弱Th1和Th17的反应。而其最主要是通过抑制NF-κB,在神经元、胶质细胞、脑血管细胞中都含有NF-κB位点[15-17],NF-κB通路激活可启动NLRP3的转录,NLRP3是一种胞质蛋白,主要参与免疫炎性应答反应,在细胞低钾,急性神经细胞损伤时都会激活NLRP3炎性小体,从而产生炎症反应。而VPA则可通过抑制NF-κB来抑制NLRP3介导的炎性小体聚集和激活[18]。

2丙戊酸在急性脑卒中的抗凋亡作用

2.1急性脑血管病发生后的神经细胞凋亡现象


细胞凋亡是细胞正常死亡的一种形式,是一种程序性死亡,但当发生急性脑血管病时,产生大量氧自由基,引起离子自稳机制,引起相关原癌基因表达,会造成神经元细胞的凋亡机制不适当地激活[19]。CYt-C,Bcl-2,BAX基因是神经细胞中最主要调控凋亡的调控基因[20]。ICH时,在血肿周围区能检测出Bax蛋白、Bcl-x蛋白表达水平明显高于正常脑组织,这些蛋白诱导促进细胞凋亡的发生[21]。SAH时,伴随着线粒体外膜通透性的增加,使胞浆移位,导致细胞色素的释放。细胞色素C在激活、诱导细胞调亡方面具有重要意义。细胞色素C释放入细胞浆后,激活caspase级联反应,Caspase-3以无活性的caspase-3前体存在,当有效刺激产生,caspase-3则被激活,使核酸内切酶释放并激活,诱导细胞凋亡[22]。hdacs是一个酶家族[23],在慢性神经退行性疾病和急性中枢神经系统损伤中都观察到HDAC介导的组蛋白低乙酰化[24-28]。在MCAO诱导的小鼠缺血性卒中的早期阶段,HDAC3的表达水平也显著增加。

2.2丙戊酸的抑制细胞凋亡作用

HDAC通过催化组蛋白赖氨酸残基的乙酰基水解来参与脱乙酰化过程[28,29]。作为泛HDAC抑制剂,VPA可以恢复正常的乙酰化状态[30-32]。VPA直接结合到I类(HDAC 1、2、3和8亚型)和IIA类(HDAC 4、5、7和9亚型)的活性位点,并抑制其催化活性,导致组蛋白超乙酰化[30-32]。丙戊酸可通过独立于组蛋白的超乙酰化选择性调节转录因子来直接抑制HDAC,激活ERK途径,并抑制促凋亡分子并提高抗氧化酶和hsp70水平[13,18,34]。HSP70有多种机制可抗细胞凋亡。Caspase-3激活后会直接诱导细胞凋亡,而HSP70可抑制Caspase-3的激活[35]。HSP70还可以抑制JNK的兴奋性细胞毒性作用,并且防止蛋白聚集,减少大脑损伤[22]。PI3K/Akt信号通路同时也会激活,Akt可磷酸化多种酶,如GSK-3β,导致其失去活性,而抑制神经细胞的凋亡[21,33,34]。GSK-3β是一种糖原合成激酶,可磷酸化BAX,使BAX进入胞内,直接诱导caspase级联反应[22]。而TRB3和PTEN会减少Akt的活化,VPA则抑制TRB3和PTEN,促进了PI3K/Akt信号通路,缓解了神经细胞的凋亡。

3丙戊酸对于血脑屏障的保护作用及机制

3.1急性脑卒中对血脑屏障的损害


基质金属蛋白酶9(MMP9)是MMP蛋白家族的成员,它是一组20多种锌依赖性蛋白酶,对包括胶原和弹性蛋白在内的细胞外基质成分具有蛋白水解酶活性,含有参与血管生成、细胞迁移、生长和凋亡的大量蛋白质[36]。MMP9被认为是通过降解脑血管周围基底膜的主要成分来破坏缺血后血脑屏障的发病机制的关键。因此,缺血诱导的MMP9上调可能与随后的脑损伤密切相关。MMP9可降解毛细血管周围基底膜的主要成分,导致血脑屏障(BBB)的破坏。

3.2丙戊酸对血脑屏障的保护及机制

MMP-9是一种干扰BBB完整性的关键蛋白酶,VPA阻断MMP-9升高的能力以及claudin-5 and ZO-1的下调参与了该药物对BBB的保护[12,37]。有实验表明[38],缺血缺氧的脑组织的MMP9蛋白水平的升高主要是由pERK1/2介导,而经过丙成酸治疗后,MMP9蛋白水平明显下降。丙戊酸通过抑制pERK1/2减少MMP9的表达,进而减轻血脑屏障的破坏[36,37]。也有报道称[39],其他BBB-稳定分子,如活化蛋白C,通过抑制NF-kB依赖性MMP-9途径来减少BBB破坏。因此,VPA诱导的NF-κB激活阻滞可抑制MMP-9转录。创伤后VPA治疗能显著降低MCAO诱导的BBB破坏。这种BBB保护可能包括NF-κB激活和mmp-9的表达。

4丙戊酸的神经保护作用

GLT-1是一种谷氨酸转运体,其作为是减少细胞外谷氨酸溢出。GLT-1的过度表达可减少缺血性灰质和白质损伤,HDAC抑制可在体外上调glt-1的表达[40]。VPA作为HDAC抑制剂,使用VPA治疗可增加脑梗死周围区域GLT-1的表达,这表明上调的GLT-1可通过清除卒中后细胞外谷氨酸的升高而减少少突胶质细胞的死亡。VPA治疗可提高神经母细胞中的乙酰化组蛋白H4,这表明在HDAC抑制剂诱导的神经发生中,调控神经母细胞中的组蛋白乙酰化可能参与[41]。除了HDAC抑制外,VPA还调节GABA基因表达、钠通道和NMDA信号,所有这些都可能影响白质修复和神经发生。VPA使GABA脑细胞内降解减少,合成增多,最后使GABA上升,降低兴奋性氨基酸的毒性,对神经细胞损伤有保护作用[42]。

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5小结

本文主要关注在当前对脑血管疾病损伤中VPA的神经保护特性和潜在机制的认识上。VPA通过多种途径减轻中枢神经系统损伤,改善急性中枢神经系统损伤后的功能结果,包括抗炎、抗凋亡和神经营养作用。但在急性中枢神经系统损伤的潜在新适应症,仍需进一步的临床研究和长期的大型随机临床试验。

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