5-羟色胺再摄取抑制剂在缺血性脑卒中中的应用及机制研究进展

doi:10.3969/j.issn.1006-9771.2019.07.007

摘要/Abstract

摘要： 以往5-羟色胺再摄取抑制剂(SSRIs)被广泛应用于改善脑卒中后抑郁，近年来SSRIs被认为是改善缺血性脑卒中后运动功能障碍的有效药物。目前关于SSRIs改善脑缺血后运动功能的机制研究内容较广泛，尚无统一结论；SSRIs能否确切改善脑缺血后运动功能存在矛盾的观点，且SSRIs应用于脑卒中治疗存在潜在风险。应有效评估SSRIs应用的收益与风险。

关键词: 缺血性脑卒中, 5-羟色胺再摄取抑制剂, 运动功能, 综述

Abstract: Serotonin selective reuptake inhibitors (SSRIs) have been widely used for post-stroke depression. Recently, SSRIs are considered as an effective drug to improve motor function after stroke. Mechanism of SSRIs improving motor function after ischemic stroke involves extensive factors, and there is no definitive conclusion yet. While, the effects of SSRIs on motor function after stroke remains debatable. Besides, there are potential risks of SSRIs in the treatment of stroke. It is necessary to evaluate the benefits and risks of SSRIs for patients with ischemic stroke.

Key words: ischemic stroke, serotonin selective reuptake inhibitors, motor function, review

中图分类号:

R743.3

李策, 张备, 白玉龙. 5-羟色胺再摄取抑制剂在缺血性脑卒中中的应用及机制研究进展[J]. 《中国康复理论与实践》, 2019, 25(7): 778-782.

LI Ce, ZHANG Bei, BAI Yu-long. Advance in Clinial and Mechanism Reseaches about Serotonin Selective Reuptake Inhibitors for Ischemic Stroke (review)[J]. 《Chinese Journal of Rehabilitation Theory and Practice》, 2019, 25(7): 778-782.

参考文献

1 de KeyserJ, SulterG, LuitenP G. Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing? [J]. Trends Neurosci, 1999, 22(12): 535-540.
2 ChenH F, PanX L, WangJ W, et al. Protein-drug interactome analysis of SSRI-mediated neurorecovery following stroke [J]. Biosystems, 2014, 120: 1-9.
3 RueterL E, FornalC A, JacobsB L. A critical review of 5-HT brain microdialysis and behavior [J]. Rev Neurosci, 1997, 8(2): 117-137.
4 MostertJ P, KochM W, HeeringsM, et al. Therapeutic potential of fluoxetine in neurological disorders [J]. Cns Neurosci Ther, 2008, 14(2): 153-164.
5 HackettM L, PicklesK. Part I: frequency of depression after stroke: an updated systematic review and meta-analysis of observational studies [J]. Int J Stroke, 2014, 9(8): 1017-1025.
6 FlasterM, SharmaA, RaoM. Poststroke depression: a review emphasizing the role of prophylactic treatment and synergy with treatment for motor recovery [J]. Top Stroke Rehabil, 2013, 20(2): 139-150.
7 ParienteJ, LoubinouxI, CarelC, et al. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke [J]. Ann Neurol, 2001, 50(6): 718-729.
8 PaolucciS, AntonucciG, GrassoM G, et al. Post-stroke depression, antidepressant treatment and rehabilitation results. A case-control study [J]. Cerebrovasc Dis, 2001, 12(3): 264-271.
9 CholletF, TardyJ, AlbucherJ F, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial [J]. Lancet Neurol, 2011, 10(2): 123-130.
10 MeadG E, HsiehC F, LeeR, et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery [J]. Cochrane Database Syst Rev, 2012, 11: CD009286.
11 RobinsonR G, SchultzS K, CastilloC, et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study [J]. Am J Psychiatry, 2000, 157(3): 351-359.
12 PlegerB, SchwenkreisP, GrunbergC, et al. Fluoxetine facilitates use-dependent excitability of human primary motor cortex [J]. Clin Neurophysiol, 2004, 115(9): 2157-2163.
13 NannettiL, PaciM, PasquiniJ, et al. Motor and functional recovery in patients with post-stroke depression [J]. Disabil Rehabil, 2005, 27(4): 170-175.
14 GonzenbachR R, TaegtmeyerA B, LuftA, et al. Fluoxetine and motor recovery after ischaemic stroke [J]. Lancet Neurol, 2011, 10(6): 499-500.
15 ShinT K, KangM S, LeeH Y, et al. Fluoxetine and sertraline attenuate postischemic brain injury in mice [J]. Korean J Physiol Pharmacol, 2009, 13(3): 257-263.
16 LimC M, KimS W, ParkJ Y, et al. Fluoxetine affords robust neuroprotection in the postischemic brain via its anti-inflammatory effect [J]. J Neurosci Res, 2009, 87(4): 1037-1045.
17 NgK L, GibsonE M, HubbardR, et al. Fluoxetine maintains a state of heightened responsiveness to motor training early after stroke in a mouse model [J]. Stroke, 2015, 46(10): 2951-2960.
18 ZhuB G, SunY, SunZ Q, et al. Optimal dosages of fluoxetine in the treatment of hypoxic brain injury induced by 3-nitropropionic acid: implications for the adjunctive treatment of patients after acute ischemic stroke [J]. CNS Neurosci Ther, 2012, 18(7): 530-535.
19 LoubinouxI, TombariD, ParienteJ, et al. Modulation of behavior and cortical motor activity in healthy subjects by a chronic administration of a serotonin enhancer [J]. Neuroimage, 2005, 27(2): 299-313.
20 Gerdelat-MasA, LoubinouxI, TombariD, et al. Chronic administration of selective serotonin reuptake inhibitor (SSRI) paroxetine modulates human motor cortex excitability in healthy subjects [J]. Neuroimage, 2005, 27(2): 314-322.
21 BerendsH I, NijlantJ, van PuttenM, et al. Single dose of fluoxetine increases muscle activation in chronic stroke patients [J]. Clin Neuropharmacol, 2009, 32(1): 1-5.
22 QiaoJ, WangJ, WangH, et al. Regulation of astrocyte pathology by fluoxetine prevents the deterioration of Alzheimer phenotypes in an APP/PS1 mouse model [J]. Glia, 2016, 64(2): 240-254.
23 ShanH, BianY, ShuZ, et al. Fluoxetine protects against IL-1beta-induced neuronal apoptosis via downregulation of p53 [J]. Neuropharmacology, 2016, 107: 68-78.
24 SiepmannT, PenzlinA I, KepplingerJ, et al. Selective serotonin reuptake inhibitors to improve outcome in acute ischemic stroke: possible mechanisms and clinical evidence [J]. Brain Behav, 2015, 5(10): e00373.
25 TiradentesR V, PiresJ G, SilvaN F, et al. Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity [J]. Braz J Med Biol Res, 2014, 47(7): 554-559.
26 GreeneJ, BanasrM, LeeB, et al. Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment: pharmacological and cellular characterization [J]. Neuropsychopharmacology, 2009, 34(11): 2459-2468.
27 TakebayashiM, HashimotoR, HisaokaK, et al. Plasma levels of vascular endothelial growth factor and fibroblast growth factor 2 in patients with major depressive disorders [J]. J Neural Transm (Vienna), 2010, 117(9): 1119-1122.
28 SchmidtH D, DumanR S. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior [J]. Behav Pharmacol, 2007, 18(5-6): 391-418.
29 DempseyR J, SailorK A, BowenK K, et al. Stroke-induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: effect of exogenous IGF-1 and GDNF [J]. J Neurochem, 2003, 87(3): 586-597.
30 WiltroutC, LangB, YanY, et al. Repairing brain after stroke: a review on post-ischemic neurogenesis [J]. Neurochem Int, 2007, 50(7-8): 1028-1041.
31 TiraboschiE, TarditoD, KasaharaJ, et al. Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades [J]. Neuropsychopharmacology, 2004, 29(10): 1831-1840.
32 LonzeB E, GintyD D. Function and regulation of CREB family transcription factors in the nervous system [J]. Neuron, 2002, 35(4): 605-623.
33 MercierG, LennonA M, RenoufB, et al. MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes [J]. J Mol Neurosci, 2004, 24(2): 207-216.
34 RiefW, BarskyA J, BingelU, et al. Rethinking psychopharmacotherapy: the role of treatment context and brain plasticity in antidepressant and antipsychotic interventions [J]. Neurosci Biobehav Rev, 2016, 60: 51-64.
35 OfekK, SchoknechtK, Melamed-BookN, et al. Fluoxetine induces vasodilatation of cerebral arterioles by co-modulating NO/muscarinic signalling [J]. J Cell Mol Med, 2012, 16(11): 2736-2744.
36 KhodanovichM, KiselA, KudabaevaM, et al. Effects of fluoxetine on hippocampal neurogenesis and neuroprotection in the model of global cerebral ischemia in rats [J]. Int J Mol Sci, 2018. DOI： info:doi/10.3390/ijms19010162.
37 SinghD P, ChopraK. Flavocoxid, dual inhibitor of cyclooxygenase-2 and 5-lipoxygenase, exhibits neuroprotection in rat model of ischaemic stroke [J]. Pharmacol Biochem Behav, 2014, 120: 33-42.
38 DhamiK S, ChurchwardM A, BakerG B, et al. Fluoxetine and citalopram decrease microglial release of glutamate and D-serine to promote cortical neuronal viability following ischemic insult [J]. Mol Cell Neurosci, 2013, 56: 365-374.
39 LiW L, CaiH H, WangB, et al. Chronic fluoxetine treatment improves ischemia-induced spatial cognitive deficits through increasing hippocampal neurogenesis after stroke [J]. J Neurosci Res, 2009, 87(1): 112-122.
40 ArvidssonA, CollinT, KirikD, et al. Neuronal replacement from endogenous precursors in the adult brain after stroke [J]. Nat Med, 2002, 8(9): 963-970.
41 VaswaniM, LindaF K, RameshS. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review [J]. Prog Neuropsychopharmacol Biol Psychiatry, 2003, 27(1): 85-102.
42 SunX, SunX, LiuT, et al. Fluoxetine enhanced neurogenesis is not translated to functional outcome in stroke rats [J]. Neurosci Lett, 2015, 603: 31-36.
43 OhabJ J, FlemingS, BleschA, et al. A neurovascular niche for neurogenesis after stroke [J]. J Neurosci, 2006, 26(50): 13007-13016.
44 SunY, SunX, QuH, et al. Neuroplasticity and behavioral effects of fluoxetine after experimental stroke [J]. Restor Neurol Neurosci, 2017, 35(5): 457-468.
45 CorbettA M, SieberS, WyattN, et al. Increasing neurogenesis with fluoxetine, simvastatin and ascorbic acid leads to functional recovery in ischemic stroke [J]. Recent Pat Drug Deliv Formul, 2015, 9(2): 158-166.
46 PengL, GuL, LiB, et al. Fluoxetine and all other SSRIs are 5-HT2B agonists － Importance for their therapeutic effects　[J]. Curr Neuropharmacol, 2014, 12(4): 365-379.
47 HertzL, RothmanD L, LiB, et al. Chronic SSRI stimulation of astrocytic 5-HT2B receptors change multiple gene expressions/editings and metabolism of glutamate, glucose and glycogen: a potential paradigm shift [J]. Front Behav Neurosci, 2015, 9: 25.
48 DiazS L, Narboux-NemeN, BoutourlinskyK, et al. Mice lacking the serotonin 5-HT2B receptor as an animal model of resistance to selective serotonin reuptake inhibitors antidepressants [J]. Eur Neuropsychopharmacol, 2016, 26(2): 265-279.
49 WindleV, CorbettD. Fluoxetine and recovery of motor function after focal ischemia in rats [J]. Brain Res, 2005, 1044(1): 25-32.
50 ZhaoC S, PuurunenK, SchallertT, et al. Behavioral and histological effects of chronic antipsychotic and antidepressant drug treatment in aged rats with focal ischemic brain injury [J]. Behav Brain Res, 2005, 158(2): 211-220.
51 WangM T, ChuC L, YehC B, et al. Antidepressant use and risk of recurrent stroke: a population-based nested case-control study [J]. J Clin Psychiatry, 2015, 76(7): e877-e885.
52 HeY, CaiZ, ZengS, et al. Effect of fluoxetine on three-year recurrence in acute ischemic stroke: a randomized controlled clinical study [J]. Clin Neurol Neurosurg, 2018, 168: 1-6.
53 MortensenJ K, LarssonH, JohnsenS P, et al. Post stroke use of selective serotonin reuptake inhibitors and clinical outcome among patients with ischemic stroke: a nationwide propensity score-matched follow-up study [J]. Stroke, 2013, 44(2): 420-426.
54 PintoC B, Saleh VelezF G, LopesF, et al. SSRI and motor recovery in stroke: reestablishment of inhibitory neural network tonus [J]. Front Neurosci, 2017, 11: 637.
55 AlperK, SchwartzK A, KoltsR L, et al. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports [J]. Biol Psychiatry, 2007, 62(4): 345-354.
56 LiepertJ. Update on pharmacotherapy for stroke and traumatic brain injury recovery during rehabilitation [J]. Curr Opin Neurol, 2016, 29(6): 700-705.
57 FoltinR W, HaneyM, ComerS D, et al. Effect of fluoxetine on food intake of humans living in a residential laboratory [J]. Appetite, 1996, 27(2): 165-181.
58 RieckmannN, KronishI M, ShapiroP A, et al. Serotonin reuptake inhibitor use, depression, and long-term outcomes after an acute coronary syndrome: a prospective cohort study [J]. JAMA Intern Med, 2013, 173(12): 1150-1151.
59 GrahamC, LewisS, ForbesJ, et al. The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis [J]. Trials, 2017, 18(1): 627.

[1]	邵伟婷, 雷江华. 反应中断再定向干预孤独症谱系障碍儿童刻板语言的效果：Scoping综述[J]. 《中国康复理论与实践》, 2024, 30(1): 10-20.
[2]	王航宇, 葛可可, 范永红, 都丽露, 邹敏, 封磊. 基于ICD-11和ICF主动式音乐疗法改善认知障碍老年人认知功能的系统综述[J]. 《中国康复理论与实践》, 2024, 30(1): 36-43.
[3]	闻嘉宁, 金秋艳, 张琦, 李杰, 司琦. 认知参与型身体活动对发展儿童青少年执行功能的效果：基于ICF的系统综述[J]. 《中国康复理论与实践》, 2024, 30(1): 44-53.
[4]	葛可可, 范永红, 王航宇, 都丽露, 李长江, 邹敏. 失眠老年人正念干预健康效益的系统综述[J]. 《中国康复理论与实践》, 2024, 30(1): 54-60.
[5]	陈珺雯, 陈谦, 陈程, 李淑月, 刘玲玲, 吴存书, 龚翔, 鲁俊, 许光旭. 改良八段锦身体活动对脑卒中患者心肺功能、运动功能和日常生活活动能力的效果[J]. 《中国康复理论与实践》, 2024, 30(1): 74-80.
[6]	张婧雅, 邹敏, 孙宏伟, 孙昌隆, 朱峻同. 听障儿童青少年焦虑或抑郁情绪心理干预效果的系统综述[J]. 《中国康复理论与实践》, 2023, 29(9): 1004-1011.
[7]	王俊宇, 杨永, 袁逊, 谢婷, 庄洁. 高强度间歇训练对健康儿童青少年执行功能效果的系统综述[J]. 《中国康复理论与实践》, 2023, 29(9): 1012-1020.
[8]	魏晓微, 杨剑, 魏春艳. 特殊教育学校孤独症谱系障碍儿童参与适应性瑜伽活动的心理与行为效益的系统综述[J]. 《中国康复理论与实践》, 2023, 29(9): 1021-1028.
[9]	杨亚茹, 杨剑. 基于WHO-HPS架构学校身体活动相关健康服务及其健康效益：系统综述的系统综述[J]. 《中国康复理论与实践》, 2023, 29(9): 1040-1047.
[10]	史佳伟, 李凌宇, 杨浩杰, 王琴潞, 邹海欧. 预康复对全膝关节置换术后患者的有效性：系统综述的系统综述[J]. 《中国康复理论与实践》, 2023, 29(9): 1057-1064.
[11]	孙藤方, 任梦婷, 杨琳, 王耀霆, 王红雨, 闫兴洲. 高压氧治疗联合重复外周磁刺激干预脑卒中患者踝运动功能和平衡能力的效果[J]. 《中国康复理论与实践》, 2023, 29(8): 875-881.
[12]	王亚楠, 刘西花. 脑卒中偏瘫患者主观和客观平衡功能测量的相关性及预测效能[J]. 《中国康复理论与实践》, 2023, 29(8): 890-895.
[13]	蒋长好, 黄辰, 高晓妍, 戴元富, 赵国明. 神经反馈训练对老年人认知功能效果的系统综述[J]. 《中国康复理论与实践》, 2023, 29(8): 903-909.
[14]	魏晓微, 杨剑, 魏春艳, 贺启令. 学校环境下适应性体育课程促进智力与发展性残疾儿童心理运动发展的系统综述[J]. 《中国康复理论与实践》, 2023, 29(8): 910-918.
[15]	王海云, 王寅, 周信杰, 何爱群. 基于“中枢-外周-中枢”理论的经颅直流电刺激结合针刺干预脑卒中患者中枢及上肢功能的效果[J]. 《中国康复理论与实践》, 2023, 29(8): 919-925.