IJPN International Journal of Psychiatry and Neurology 2166-5788 Scientific Research Publishing 10.12677/IJPN.2022.113006 IJPN-54507 IJPN20220300000_29413977.pdf 医药卫生 内源性硫化氢在帕金森病中的作用研究进展 Research Progress on the Role of Endogenous Hydrogen Sulfide in Parkinson’s Disease 叶 浩楠 2 1 陆 永利 2 3 1 杨 红卫 2 3 1 三峡大学国家中医药管理局中药药理科研三级实验室，湖北 宜昌;三峡大学医学院机能学系，湖北 宜昌 三峡大学国家中医药管理局中药药理科研三级实验室，湖北 宜昌;三峡大学医学院机能学系，湖北 宜昌;三峡大学脑重大疾病研究所，湖北 宜昌 null 15 07 2022 11 03 33 40 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

帕金森病(Parkinson’s disease, PD)是仅次于阿尔茨海默病的第二大神经退行性疾病，以中脑黑质致密部中的多巴胺能神经元变性丢失和残存神经元胞质中形成嗜酸性路易小体为主要病理特征，临床多表现为静止性震颤、运动迟缓和肌肉僵直。PD的发病机制十分复杂，至今尚未完全阐明。但现有证据表明炎症反应、氧化应激和细胞凋亡与PD密切相关。硫化氢(H2S)是继一氧化氮(NO)和一氧化碳(CO)之后的第三种内源性气体信号分子，具有抗神经系统炎症、氧化应激和细胞凋亡的作用。近年来研究发现，内源性H2S可通过p38-丝裂原活化蛋白激酶/核转录因子Kappa B、Kelch样环氧氯丙烷相关蛋白1-核因子E2相关因子2/抗氧化反应元件、蛋白激酶C/磷脂酰肌醇3-激酶/蛋白激酶B/糖原合成激酶-3β等相关信号通路，分别发挥抗炎、抗氧化应激和抗凋亡的作用。本文阐述了内源性H2S相关信号通路在PD中的研究进展，旨在为临床治疗PD提供理论依据。 Parkinson’s disease (PD) is the second largest neurodegenerative disease after Alzheimer’s disease. Its main pathological features are the degeneration and loss of dopaminergic neurons in the dense part of substantia nigra and the formation of eosinophilic lewy bodies in the cytoplasm of residual neurons. Its clinical manifestations are static tremor, bradykinesia and muscle stiffness. The path-ogenesis of PD is extremely complex and has not been absolutely clarified so far, but the existing evidence shows that inflammatory response, oxidative stress and apoptosis are closely related to PD. H2S is the third endogenous gas signal molecule after NO and CO, which has the effects of anti-oxidant stress, nervous system inflammation and apoptosis. In recent years, it has been found that endogenous H2S can pass p38-mitogen-activated protein kinase/nuclear factor kappa-B, Kelch-like ECH-associated protein-1-NF-E2-related factor 2/Anti-oxidant reaction element, protein kinase C/phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase-3β and other related signal pathways, which play the roles of anti-inflammatory, anti-oxidative stress and anti-apoptosis respectively. This review describes the research progress of endogenous H2S-related signaling pathways in PD, aims at providing a theoretical basis for the clinical treatment of PD.

 帕金森病，内源性硫化氢，信号通路，神经炎症，氧化应激，Parkinson’s Disease Endogenous Hydrogen Sulfide Signal Pathway Neuroinflammation Oxidative Stress 摘要

帕金森病(Parkinson’s disease, PD)是仅次于阿尔茨海默病的第二大神经退行性疾病，以中脑黑质致密部中的多巴胺能神经元变性丢失和残存神经元胞质中形成嗜酸性路易小体为主要病理特征，临床多表现为静止性震颤、运动迟缓和肌肉僵直。PD的发病机制十分复杂，至今尚未完全阐明。但现有证据表明炎症反应、氧化应激和细胞凋亡与PD密切相关。硫化氢(H2S)是继一氧化氮(NO)和一氧化碳(CO)之后的第三种内源性气体信号分子，具有抗神经系统炎症、氧化应激和细胞凋亡的作用。近年来研究发现，内源性H2S可通过p38-丝裂原活化蛋白激酶/核转录因子Kappa B、Kelch样环氧氯丙烷相关蛋白1-核因子E2相关因子2/抗氧化反应元件、蛋白激酶C/磷脂酰肌醇3-激酶/蛋白激酶B/糖原合成激酶-3β等相关信号通路，分别发挥抗炎、抗氧化应激和抗凋亡的作用。本文阐述了内源性H2S相关信号通路在PD中的研究进展，旨在为临床治疗PD提供理论依据。

 关键词

帕金森病，内源性硫化氢，信号通路，神经炎症，氧化应激

 Research Progress on the Role of Endogenous Hydrogen Sulfide in Parkinson’s Disease<sup> </sup>

Haonan Ye1,2, Yongli Lu1,2,3, Hongwei Yang1,2,3*

1Third-Grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional

Chinese Medicine, China Three Gorges University, Yichang Hubei

2Department of Functional Sciences, College of Medical Science, China Three Gorges University, Yichang Hubei

3Institute of Brain Grand Diseases, China Three Gorges University, Yichang Hubei

Received: Jun. 29th, 2022; accepted: Jul. 29th, 2022; published: Aug. 9th, 2022

 ABSTRACT

Parkinson’s disease (PD) is the second largest neurodegenerative disease after Alzheimer’s disease. Its main pathological features are the degeneration and loss of dopaminergic neurons in the dense part of substantia nigra and the formation of eosinophilic lewy bodies in the cytoplasm of residual neurons. Its clinical manifestations are static tremor, bradykinesia and muscle stiffness. The pathogenesis of PD is extremely complex and has not been absolutely clarified so far, but the existing evidence shows that inflammatory response, oxidative stress and apoptosis are closely related to PD. H2S is the third endogenous gas signal molecule after NO and CO, which has the effects of antioxidant stress, nervous system inflammation and apoptosis. In recent years, it has been found that endogenous H2S can pass p38-mitogen-activated protein kinase/nuclear factor kappa-B, Kelch-like ECH-associated protein-1-NF-E2-related factor 2/Anti-oxidant reaction element, protein kinase C/phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase-3β and other related signal pathways, which play the roles of anti-inflammatory, anti-oxidative stress and anti-apoptosis respectively. This review describes the research progress of endogenous H2S-related signaling pathways in PD, aims at providing a theoretical basis for the clinical treatment of PD.

Keywords:Parkinson’s Disease, Endogenous Hydrogen Sulfide, Signal Pathway, Neuroinflammation, Oxidative Stress

Copyright © 2022 by author(s) and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

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 1. 引言

帕金森病(Parkinson’s disease, PD)，又名震颤麻痹，是一种病因未明、进展缓慢，仅次于阿尔茨海默病的第二大神经退行性疾病 [ 1 ] 。在中国，65岁及以上居民中超过1.7%患有PD，PD给患者及其家庭造成了严重的经济和心理影响 [ 2 ] 。PD的主要病理特征是中脑黑质致密部中多巴胺能神经元变性丢失和残存神经元胞质中形成嗜酸性路易小体，并累及周围组织和其他中枢神经系统结构，引起肌肉僵直、静止性震颤、运动迟缓和姿势失衡等为主要特征的临床表现 [ 1 ] [ 3 ] 。迄今为止，左旋多巴(L-DOPA)是治疗PD最有效的药物，可以缓解PD患者的部分临床症状，但L-DOPA不能阻止病情进展，长期服用抗PD药物还会引起运动障碍等不良反应，并加速氧化应激引起的神经元变性 [ 1 ] [ 4 ] 。尽管PD的具体发病机制尚未完全阐明，但研究表明炎症反应、氧化应激和细胞凋亡在PD的病因中发挥关键作用 [ 5 ] 。因此，研究PD中炎症反应、氧化应激和细胞凋亡的分子机制，可能为预防和治疗PD提供新的理论依据。

硫化氢(H2S)被认为是继一氧化氮(NO)和一氧化碳(CO)之后的第三种内源性气体信号分子，参与调节多种生理和病理的过程 [ 6 ] 。内源性H2S主要是以L-半胱氨酸和L-同型半胱氨酸为基质，在胱硫醚-β-合酶(Cystathionine-β-synthase, CBS)、胱硫醚-γ-裂解酶 (Cystathionine-γ-lyase, CSE)和3-巯基丙酮酸转硫酶(3-mercaptopyruvate sulfurtransferase, MPST)的催化下生成 [ 7 ] 。其中，CBS是神经系统中合成H2S的主要酶，已在海马、脑干、小脑和大脑中发现CBS的表达 [ 8 ] [ 9 ] ，因此，脑中内源性H2S的水平主要取决于CBS的变化。研究表明，内源性H2S不仅具有促进海马长时程、调节钙稳态、维持细胞内PH值等重要生理功能，也在神经退行性疾病的病理过程中起着重要作用 [ 4 ] [ 5 ] 。例如，CBS过表达或使用H2S供体可为PD大鼠提供神经保护，说明脑内H2S含量可影响PD的致病过程 [ 10 ] [ 11 ] 。在PD动物模型中，发现H2S可通过多种信号传导途径抑制PD中的炎症反应、氧化应激和细胞凋亡 [ 5 ] [ 12 ] [ 13 ] 。这些结果提示研究H2S及其相关信号通路可能为PD的治疗提供新思路。因此，我们着重就内源性H2S及其介导的相关信号通路在炎症反应、氧化应激和细胞凋亡中的保护作用进行综述，旨在为预防和治疗PD提供理论依据。

 2. 内源性H<sub>2</sub>S抑制p38-丝裂原活化蛋白激酶/核转录因子Kappa B信号通路 发挥抗炎作用 2.1. 内源性H<sub>2</sub>S与p38-丝裂原活化蛋白激酶信号通路

1988年，McGeer等 [ 14 ] 发现人类尸检脑组织中的黑质致密部存在反应性胶质细胞，首次揭示了神经炎症参与PD的发病机制。PD脑内的小胶质细胞激活涉及一系列小胶质细胞衍生的神经毒性因子，如活性氧、诱导型一氧化氮合酶(Inducible nitric oxide synthase, iNOS)、环氧合酶-2 (Cyclooxygenase-2, COX-2)、促炎细胞因子等 [ 15 ] 。PD患者的脑细胞中，白介素-1β (Interleukin-1β, IL-1β)、白介素-6 (Interleukin-6, IL-6)、肿瘤坏死因子-α (Tumor necrosis factor-α, TNF-α)和脂多糖(Lipopolysaccharide, LPS)等促炎细胞因子激活受体和受体相关蛋白，磷酸化激活的丝裂原活化蛋白激酶的激酶(Mitogen-activated protein kinase kinase of kinases, MAPKKK)随后激活丝裂原活化蛋白激酶(Mitogen-activated protein kinase of kinases, MAPKK)中的MKK3和MKK6，最终特异性激活p38 [ 15 ] 。p38的激活是通过高度保守的三级酶促级连反应实现的，即MAPKKK、MAPKK和丝裂原活化蛋白激酶(Mitogen-activated protein kinase, MAPK) [ 16 ] 。p38-MAPK是炎症基因表达的关键调节因子，参与调控小胶质细胞和星形胶质细胞介导的神经炎症 [ 17 ] [ 18 ] 。激活的p38-MAPK可直接激活转录因子或磷酸化下游MAPK活化蛋白激酶2 (MAPK-activated protein kinase 2, MK2)间接促进炎性介质的表达 [ 19 ] [ 20 ] 。磷酸化激活的MK2会促使小胶质细胞和星形胶质细胞释放促炎细胞因子诱导慢性炎症反应，进而引起黑质纹状体中多巴胺能神经元变性坏死 [ 19 ] 。研究发现，H2S通过抑制激活的p38和核转录因子Kappa B (Nuclear factor kappa-B, NF-κB)磷酸化异二聚体(p50-p65)核易位发挥抗炎作用 [ 5 ] 。

Hu等 [ 21 ] 通过Western Blot分析发现，外源性和内源性H2S通过减弱LPS对iNOS表达的刺激作用来减少促炎因子NO的生成，而使用特异的p38-MAPK抑制剂SB203580也可模拟出该效应，提示上述过程可能涉及p38-MAPK信号通路。同时，外源性应用硫氢化钠(NaHS)和SB203580均可显著减少LPS诱导的BV-2小胶质细胞p38-MAPK磷酸化来减少促炎因子TNF-α的分泌 [ 21 ] 。这表明，H2S在BV-2小胶质细胞中的抗炎作用部分是通过抑制p38-MAPK活性实现的，证实H2S可通过抑制p38-MAPK信号通路发挥部分抗炎作用。鱼藤酮是一种常用于建立PD体内外模型的毒素。在鱼藤酮诱导的人神经母细胞瘤(SH-SY5Y)细胞模型中，使用NaHS可阻止鱼藤酮诱导的p38-MAPK磷酸化，减弱鱼藤酮诱导的神经炎症 [ 22 ] 。此外，释放H2S的非甾体抗炎药物不仅可以减少TNF-α和IL-6的释放，也可以抑制p38-MAPK和NF-κB的激活起到抗炎作用 [ 23 ] (见图1)。由此看来，研究内源性H2S如何抑制p38-MAPK信号通路来保护多巴胺能神经元对PD的治疗具有重大意义。

 2.2. 内源性H<sub>2</sub>S与核转录因子Kappa B信号通路

NF-κB是一种促炎反应的转录因子，介导的神经炎症在PD的发病机制中发挥关键作用 [ 24 ] [ 25 ] 。细胞外促炎细胞因子首先激活核转录因子B抑制蛋白激酶(Phospho-inhibitor of NF-κB kinase, IKK)，核转录因子B抑制蛋白激酶β (Inhibitor of NF-κB kinase β, IKKβ)是IKK复合物中的催化亚单位，是启动NF-κB信号通路的重要激酶，激活的IKKβ可磷酸化、泛素化核转录因子B抑制蛋白(Inhibitor of NF-κB, IκB)，IκB经蛋白酶降解后使NF-κB的磷酸化异二聚体(p50-p65)经核膜进入细胞核，与NF-κB反应元件结合并激活TNF-α、IL-β、IL-6、iNOS、COX-2等促炎症介质，最终导致PD中多巴胺能神经元进行性退化 [ 25 ] 。有文献表明，内源性H2S通过抑制NF-κB信号通路减轻PD动物模型中的炎症反应，起到保护多巴胺能神经元的作用 [ 5 ] 。Hu等 [ 26 ] 通过建立鱼藤酮诱导的PD模型，发现使用鱼藤酮处理后显著提高了细胞核中p50-p65蛋白水平，进而激活NF-κB，但使用NaHS后可消除p50-p65的核易位，减少了促炎细胞因子的释放，具有保护多巴胺能神经元的功能(见图1)。目前，内源性H2S如何抑制NF-κB发挥抗炎的具体机制尚未完全阐明，PD动物模型中常表现为p50-p65亚单位核易位 [ 5 ] 。但是，内源性H2S是否可以通过NF-κB信号通路中的其它结合亚单位或蛋白质发挥抗炎作用仍不清楚。因此，研究内源性H2S在NF-κB信号通路中的具体机制将有助于寻找治疗PD的新靶点。

 3. 内源性H<sub>2</sub>S通过Kelch样环氧氯丙烷相关蛋白1-核因子E2相关因子2/抗氧化反应元件信号通路发挥抗氧化应激作用

PD的分子机制尚不清楚，但是氧化应激和线粒体功能障碍与多巴胺能神经元变性密切相关 [ 27 ] [ 28 ] 。尽管内源性H2S本身不是一种强还原剂，但内源性H2S可间接通过Kelch样环氧氯丙烷相关蛋白1 (Kelch-like ECH-associated protein-1, Keap1)-核因子E2相关因子2 (NF-E2-related factor 2, Nrf2)/抗氧化反应元件(anti-oxidant reaction element, ARE)信号通路发挥强大的抗氧化作用 [ 6 ] [ 8 ] 。Nrf2是一种调节多种基因的转录因子，参与调控抗氧化反应 [ 29 ] 。在正常生理情况下，Nrf2主要与其抑制剂Keap1结合存在于细胞质中 [ 30 ] 。氧化应激时，Keap1通过Clu3-E3途径促进Nrf2泛素化和降解，Nfr2经翻译修饰后调节Keap1蛋白中的半胱氨酸残基与Keap1分离，随后Nrf2易位到细胞核并与含有ARE序列的启动子结合并激活抗氧化基因和蛋白的转录 [ 29 ] [ 31 ] 。ARE是一种顺式作用调节元件，存在于某些基因的启动子序列，如谷胱甘肽还原酶(glutathione reductase, GR)、谷氨酸半胱氨酸连接酶催化亚基(glutamate-cysteine ligase catalytic subunit, GCLC)、谷氨酸半胱氨酸连接酶修饰亚基(glutamate-cysteine ligase modifier subunit, GCLM)等 [ 29 ] [ 30 ] 。

谷胱甘肽(glutathione, GSH)在抗氧化防御系统和神经氧化还原稳态的维持中起着重要作用，GSH的升高不仅可以延缓多巴胺能神经元的丢失，还有助于识别与PD进展相关的突变蛋白 [ 32 ] 。Jain等 [ 33 ] 首次报道了H2S通过上调GCLC和GCLM来增加细胞内GSH和降低IL-1β，提示硫化氢可能通过Keap1-Nrf2/ARE信号通路发挥作用抗氧化应激作用。此后的研究证实了H2S通过硫化Keap1使其与Nrf2分离，激活的Nrf2可增加GR的表达和活性，促进氧化型谷胱甘肽(oxidized glutathione, GSSG)转化为GSH，并增加GSH/GSSG比值来提高多巴胺能神经元的抗氧化应激能力 [ 6 ] [ 30 ] 。6-羟基多巴胺(6-hydrogen dopamine, 6-OHDA)诱导的PD大鼠模型显示，内源性H2S可激活Nfr2/ARE信号通路，上调抗氧化基因的表达发挥抗氧化应激作用 [ 4 ] (见图1)。上述研究表明，内源性H2S通过相关信号通路发挥抗氧化应激作用的潜力。因此，研究H2S在Keap1-Nfr2/ARE信号通路中的抗氧化应激作用可能为PD的药物开发提供新思路。

 4. 内源性H<sub>2</sub>S激活蛋白激酶C/磷脂酰肌醇3-激酶/蛋白激酶B/糖原合成激酶-3β信号通路发挥抗凋亡作用

越来越多研究发现，内源性H2S通过蛋白激酶C (Protein kinase C, PKC)/磷脂酰肌醇3-激酶(Phosphatidylinositol 3-kinase, PI3K)/蛋白激酶B (Protein kinase B, Akt)/糖原合成激酶-3β (Glycogen synthase kinase-3β, GSK-3β)信号通路介导β-连环蛋白(β-catenin)核易位、促凋亡蛋白失活和增加抗凋亡因子Bcl-2表达，以此来促进多巴胺能神经元存活发挥抗凋亡作用 [ 34 ] [ 35 ] 。内源性H2S通过PI3K/Akt信号通路使GSK-3β失活，而磷酸化的GSK-3β可稳定β-catenin，随后β-catenin转移到细胞核中，介导基因转录进而促进神经发生 [ 34 ] 。研究发现，激活的PI3K/Akt信号也可使BAD和Caspase-9在内的多种促凋亡蛋白失活，从而促进多巴胺能神经元存活。此外，内源性H2S还可以激活PKCα和PKCε亚型来促进Bcl-2的表达，发挥抗凋亡作用 [ 35 ] 。

研究发现脑室下区(Subventricular zone, SVZ)中由神经干细胞生成的多巴胺能神经元可显著提高PD患者的功能表现，例如缓解PD患者的运动功能障碍、改善认知和自主神经症状，这提示神经发生可能是治疗成人PD的可行措施 [ 36 ] [ 37 ] 。Wang等 [ 34 ] 建立1-甲基-4-苯基-1，2，3，6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP)诱导的小鼠模型，使用NaHS作为H2S的供体，发现H2S不仅可以延缓黑质纹状体中多巴胺能神经元的丢失，还可以通过调节Akt/GSK-3β/β-catenin信号通路促进小鼠成体神经干细胞的生长，证明了H2S可促进成年PD小鼠的神经生发进而发挥神经保护功能。在6-OHDA诱导的SH-SY5Y细胞损伤模型中发现，NaHS逆转了PKCα、PKCε和Akt的下调，使抗凋亡基因Bcl-2表达增加和促凋亡蛋白(BAD、Caspase-9等)失活，证实内源性H2S在PD中的神经保护作用涉及PKC依赖的PI3K/Akt信号通路 [ 35 ] (见图1)。因此，上述研究明确了内源性H2S通过PKC/PI3K/Akt/GSK-3β信号通路保护多巴胺能神经元的观点。

图1. 内源性H2S在PD中所介导的主要信号转导途径

1) 抗炎作用：细胞外刺激激活受体及受体相关蛋白，首先通过MAPKKK和MKK3/6途径激活p38-MAPK，激活的p38-MAPK可直接激活转录因子或通过下游激酶MK2间接促进炎性介质的表达。其次通过IKKβ-NEMO磷酸化IκB，磷酸化的p50-p65在IκB降解后经核膜入核，激活相关炎症介质。内源性H2S通过抑制p38-MAPK和p50-p65核易位来发挥抗炎作用。2) 抗氧化应激：内源性H2S硫化Keep1激活Nrf2，激活的Nrf2易位到细胞核与ARE结合，启动抗氧化基因和蛋白的转录发挥抗氧化应激作用。3) 抗细胞凋亡：内源性H2S通过PI3K/Akt途径抑制GSK-3β，β-catenin转移到细胞核中介导基因转录从而促进神经发生，激活的Akt还可抑制促凋亡蛋白BAD和Caspase-9的表达。此外，内源性H2S也可激活PKC来促进Bcl-2的表达，与上述信号通路共同发挥抗凋亡作用。

 5. 结论与展望

内源性H2S是人类发现的第三种气体信号分子，在神经退行性疾病的神经保护中发挥关键性作用。大量研究表明，H2S介导的相关信号通路在PD中扮演重要角色。内源性H2S通过p38-MAPK/NF-κB、Keap1-Nrf2/ARE和PKC/PI3K/Akt/GSK-3β等相关信号通路来抑制PD中的炎症反应、氧化应激和细胞凋亡，进而保护黑质纹状体中的多巴胺能神经元。目前尚未发现通过内源性H2S治疗PD患者的临床案例，但近年来通过鱼藤酮、6-OHDA和MPTP诱导的PD细胞和动物模型发现，内源性H2S可通过上述三条信号通路发挥部分抗炎、抗氧化应激和抗细胞凋亡作用，对诱导的PD大鼠和小鼠模型有一定治疗作用。PD的发病机制十分复杂，至今尚未完全阐明。目前治疗PD主要通过多巴胺能替代疗法，只能减轻患者的临床症状，并不能阻止疾病的进展。因此，我们迫切需要寻找治疗PD的新方法来逆转PD的进行性发展。通过更深入的研究内源性H2S在PD中的信号通路和神经分子机制，将有助于我们更好的理解PD的发病机制，为进一步研发抗PD的靶向药物提供新的思路和策略。

 文章引用

叶浩楠,陆永利,杨红卫. 内源性硫化氢在帕金森病中的作用研究进展Research Progress on the Role of Endogenous Hydrogen Sulfide in Parkinson’s Disease[J]. 国际神经精神科学杂志, 2022, 11(03): 33-40. https://doi.org/10.12677/IJPN.2022.113006

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