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中华脑血管病杂志(电子版) ›› 2025, Vol. 19 ›› Issue (02) : 149 -154. doi: 10.3877/cma.j.issn.1673-9248.2025.02.010

综述

检测脑缺血再灌注损伤的探针及技术进展
庞淇丹1,2, 崔玮3, 唐涛3, 姜德春1, 李深3,()   
  1. 1. 100038 首都医科大学附属北京世纪坛医院药学部
    2. 100069 北京,首都医科大学药学院临床药学系
    3. 100038 首都医科大学附属北京世纪坛医院神经与精神科
  • 收稿日期:2024-08-02 出版日期:2025-04-01
  • 通信作者: 李深
  • 基金资助:
    国家自然科学基金项目(82371298)

Advances in probes and technologies for detecting cerebral ischemia-reperfusion injury

Qidan Pang1,2, Wei Cui3, Tao Tang3, Dechun Jiang1, Shen Li3,()   

  1. 1. Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
    2. Department of Clinical Pharmacy, College of Pharmacy, Capital Medical University, Beijing 100069, China
    3. Department of Neurology and Psychiatry, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
  • Received:2024-08-02 Published:2025-04-01
  • Corresponding author: Shen Li
引用本文:

庞淇丹, 崔玮, 唐涛, 姜德春, 李深. 检测脑缺血再灌注损伤的探针及技术进展[J/OL]. 中华脑血管病杂志(电子版), 2025, 19(02): 149-154.

Qidan Pang, Wei Cui, Tao Tang, Dechun Jiang, Shen Li. Advances in probes and technologies for detecting cerebral ischemia-reperfusion injury[J/OL]. Chinese Journal of Cerebrovascular Diseases(Electronic Edition), 2025, 19(02): 149-154.

缺血性脑卒中是严重危害人类健康的重大疾病。再灌注治疗是其最有效的治疗方法。然而,血流恢复常带来脑缺血再灌注损伤(CIRI),其发生机制复杂,加重了结构破坏和功能障碍。实时监测、早期预警和及时处理是减轻CIRI 的前提。因而,开发高敏感度和特异度的CIRI 检测探针和技术成为目前的研究热点。本文对用于CIRI 相关活性物质、线粒体状态和生物硫醇水平的检测探针和技术加以综述,为CIRI 的诊断和治疗提供依据,为脑保护策略的研发提供重要工具。

Ischemic stroke is a major global health challenge with profound impacts on human well-being.Reperfusion therapy represents the most effective intervention, yet successful blood flow restoration often triggers cerebral ischemia-reperfusion injury (CIRI), a complex pathological cascade that exacerbates structural damage and functional deficits.Real-time monitoring, early warning, and timely intervention are prerequisites for mitigating CIRI.Consequently, the development of highly sensitive and specific probes and technologies for CIRI detection has emerged as a research priority.This review systematically summarizes advances in molecular probes and analytical platforms targeting CIRI-related reactive species, mitochondrial dysfunction, and biothiol homeostasis.These innovations not only provide diagnostic and therapeutic insights for CIRI but also serve as critical tools for advancing neuroprotective strategies.

图1 荧光探针活体成像原理
表1 检测脑缺血再灌注损伤的各类探针技术总结及比较
1
Campbell B, De Silva DA, Macleod MR, et al.Ischaemic stroke [J].Nat Rev Dis Primers, 2019, 5(1): 70.
2
Feigin VL, Brainin M, Norrving B, et al.World Stroke Organization(WSO): Global Stroke Fact Sheet 2022 [J].Int J Stroke, 2022, 17(1):18-29.
3
Hankey GJ.Stroke [J].Lancet, 2017, 389(10069): 641-654.
4
Shin TH, Lee DY, Basith S, et al.Metabolome changes in cerebral ischemia [J].Cells, 2020, 9(7): 1630.
5
Chouchani ET, Pell VR, Gaude E, et al.Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS [J].Nature, 2014, 515(7527): 431-435.
6
Granger DN, Kvietys PR.Reperfusion injury and reactive oxygen species: the evolution of a concept [J].Redox Biol, 2015, 6: 524-551.
7
Lee KH, Cha M, Lee BH.Neuroprotective effect of antioxidants in the brain [J].Int J Mol Sci, 2020, 21(19): 7152.
8
Kang X, Li Y, Yin S, et al.Reactive species-activatable AIEgens for biomedical applications [J].Biosensors (Basel), 2022, 12(8): 646.
9
Kalogeris T, Baines CP, Krenz M, et al.Ischemia/reperfusion [J].Compr Physiol, 2016, 7(1): 113-170.
10
Chen Y, Shi X, Lu Z, et al.A fluorescent probe for hydrogen peroxide in vivo based on the modulation of intramolecular charge transfer [J].Anal Chem, 2017, 89(10): 5278-5284.
11
Dong B, Song X, Kong X, et al.Simultaneous near-infrared and twophoton in vivo imaging of H2O2 using a ratiometric fluorescent probe based on the unique oxidative rearrangement of oxonium [J].Adv Mater, 2016, 28(39): 8755-8759.
12
Guo H, Chen G, Gao M, et al.Imaging of endogenous hydrogen peroxide during the process of cell mitosis and mouse brain development with a near-infrared ratiometric fluorescent probe [J].Anal Chem, 2019, 91(1): 1203-1210.
13
Wang CK, Cheng J, Liang XG, et al.A H2O2-responsive theranostic probe for endothelial injury imaging and protection [J].Theranostics,2017, 7(15): 3803-3813.
14
Wang H, He Z, Yang Y, et al.Ratiometric fluorescence imaging of Golgi H2O2 reveals a correlation between Golgi oxidative stress and hypertension [J].Chem Sci, 2019, 10(47): 10876-10880.
15
Reja SI, Gupta M, Gupta N, et al.A lysosome targetable fluorescent probe for endogenous imaging of hydrogen peroxide in living cells [J].Chem Commun (Camb), 2017, 53(26): 3701-3704.
16
Zhu Y, Zhou T, Yang L, et al.Revelation of the dynamic progression of hypoxia-reoxygenation injury by visualization of the lysosomal hydrogen peroxide [J].Biochem Biophys Res Commun, 2017, 486(4):904-908.
17
Ye S, Hananya N, Green O, et al.A highly selective and sensitive chemiluminescent probe for real-time monitoring of hydrogen peroxide in cells and animals [J].Angew Chem Int Ed Engl,2020, 59(34): 14326-14330.
18
Tian D, Liu J, Wang S, et al.Selective imaging of hydrogen peroxide over peroxynitrite by a boronate-based fluorescent probe engineered via a doubly activated electrophilicity-increasing strategy [J].Sens Actuators B Chem, 2022, 368: 132149.
19
Wang J, Zhu Y, Yang L, et al.Early diagnosis of cerebral ischemia reperfusion injury and revelation of its regional development by a H3R receptor-directed probe [J].ACS Sens, 2021, 6(3): 1330-1338.
20
Fang C, Deng Q, Zhao K, et al.Fluorescent probe for investigating the mitochondrial viscosity and hydrogen peroxide changes in cerebral ischemia/reperfusion injury [J].Anal Chem, 2024, 96(8): 3436-3444.
21
Zhang B, Xu L, Zhou Y, et al.Synthesis and activity of a coumarinbased fluorescent probe for hydroxyl radical detection [J].Luminescence, 2020, 35(2): 305-311.
22
Tomizawa S, Imai H, Tsukada S, et al.The detection and quantification of highly reactive oxygen species using the novel HPF fluorescence probe in a rat model of focal cerebral ischemia [J].Neurosci Res,2005, 53(3): 304-313.
23
Kang Z, Jiang J, Tu Q, et al.Dual-Site chemosensor for monitoring·OH-cysteine redox in cells and in vivo [J].J Am Chem Soc, 2023,145(1): 507-515.
24
Abe K, Tonomura M, Ito M, et al.Imaging of reactive oxygen species in focal ischemic mouse brain using a radical trapping tracer [3H]hydromethidine [J].EJNMMI Res, 2015, 5(1): 115.
25
Setsukinai K, Urano Y, Kakinuma K, et al.Development of novel fluorescence probes that can reliably detect reactive oxygen species and distinguish specific species [J].J Biol Chem, 2003, 278(5): 3170-3175.
26
Abe K, Takai N, Fukumoto K, et al.In vivo imaging of reactive oxygen species in mouse brain by using [3H]hydromethidine as a potential radical trapping radiotracer [J].J Cereb Blood Flow Metab,2014, 34(12): 1907-1913.
27
Jie Z, Liu J, Shu M, et al.Detection strategies for superoxide anion: a review [J].Talanta, 2022, 236: 122892.
28
Zhang J, Li C, Zhang R, et al.A phosphinate-based near-infrared fluorescence probe for imaging the superoxide radical anion in vitro and in vivo [J].Chem Commun (Camb), 2016, 52(13): 2679-2682.
29
Hu JJ, Wong NK, Ye S, et al.Fluorescent probe HKSOX-1 for imaging and detection of endogenous superoxide in live cells and in vivo [J].J Am Chem Soc, 2015, 137(21): 6837-6843.
30
Shchepinova MM, Cairns AG, Prime TA, et al.MitoNeoD: a mitochondria-targeted superoxide probe [J].Cell Chem Biol, 2017,24(10): 1285-1298.e12.
31
Chen L, Cho MK, Wu D, et al.Two-photon fluorescence probe for selective monitoring of superoxide in live cells and tissues [J].Anal Chem, 2019, 91(22): 14691-14696.
32
Zhang W, Su D, Li P, et al.Two-photon fluorescence imaging of mitochondrial superoxide anion transport mediating liver ischemiareperfusion injury in mice [J].Chem Commun (Camb), 2019, 55(72):10740-10743.
33
Zhang W, Li P, Yang F, et al.Dynamic and reversible fluorescence imaging of superoxide anion fluctuations in live cells and in vivo [J].J Am Chem Soc, 2013, 135(40): 14956-14959.
34
Wang Y, Yamamoto S, Miyakawa A, et al.Intravital oxygen radical imaging in normal and ischemic rat cortex [J].Neurosurgery, 2010,67(1): 118-127, discussion 127-128.
35
Wang S, Liu J, Ju Z, et al.Simultaneous two-photon intravital imaging of viscosity and superoxide radical anion by a styrylpyridinium-based fluorescent probe [J].Sens Actuators B Chem, 2023, 381: 133470.
36
Chen S, Pan J, Gong Z, et al.Hypochlorous acid derived from microglial myeloperoxidase could mediate high-mobility group box 1 release from neurons to amplify brain damage in cerebral ischemiareperfusion injury [J].J Neuroinflammation, 2024, 21(1): 70.
37
Hu W, Qiang T, Li C, et al.Imaging of hypochlorous acid in mitochondria using an asymmetric near-infrared fluorescent probe with large stokes shift [J].Chem Sci, 2022, 13(37): 11140-11149.
38
Iadecola C, Anrather J.The immunology of stroke: from mechanisms to translation [J].Nat Med, 2011, 17(7): 796-808.
39
Xiong J, Wang W, Wang C, et al.Visualizing peroxynitrite in microvessels of the brain with stroke using an engineered highly specific fluorescent probe [J].ACS Sens, 2020, 5(10): 3237-3245.
40
Xing L, Wang B, Li J, et al.A fluorogenic ONOO--triggered carbon monoxide donor for mitigating brain ischemic damage [J].J Am Chem Soc, 2022, 144(5): 2114-2119.
41
Liu Y, Ai K, Ji X, et al.Comprehensive insights into the multiantioxidative mechanisms of melanin nanoparticles and their application to protect brain from injury in ischemic stroke [J].J Am Chem Soc, 2017, 139(2): 856-862.
42
Yang X, Wang Z, Huang H, et al.A targeted activatable NIR-IIb nanoprobe for highly sensitive detection of ischemic stroke in a photothrombotic stroke model [J].Adv Healthc Mater, 2021, 10(5):e2001544.
43
Yu TF, Wang K, Yin L, et al.A molecular probe carrying antitropomyosin 4 for early diagnosis of cerebral ischemia/reperfusion injury [J].Neural Regen Res, 2023, 18(6): 1321-1324.
44
Esterbauer H, Schaur RJ, Zollner H.Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes [J].Free Radic Biol Med, 1991, 11(1): 81-128.
45
Su D, Zhang R, Wang X, et al.Shedding light on lysosomal malondialdehyde affecting vitamin B12 transport during cerebral ischemia/reperfusion injury [J].J Am Chem Soc, 2023, 145(41):22609-22619.
46
Nakamura A, Sakai S, Taketomi Y, et al.PLAGZE mediated lipid metabolism triggers brain-autonomous neural repair after ischemic stroke [J].Neuron, 2023, 111(19): 2995-3010.e9.
47
苏迪.原位荧光成像研究氧化应激相关分子在缺血再灌注损伤中的调控作用 [D].济南: 山东师范大学, 2023.
48
Su D, Li P, Wang X, et al.Observing malondialdehyde-mediated signaling pathway in cerebral ischemia reperfusion injury with a specific nanolight [J].Anal Chem, 2020, 92(3): 2748-2755.
49
Haroon E, Miller AH.Rewiring the brain: Inflammation's impact on glutamate and neural networks in depression [J].Neuropsychopharmacology, 2024, 50(1): 312-313.
50
Kumar Saini S, Singh D.Mitochondrial mechanisms in cerebral ischemia-reperfusion injury: unravelling the intricacies [J].Mitochondrion, 2024, 77: 101883.
51
Dieteren CE, Gielen SC, Nijtmans LG, et al.Solute diffusion is hindered in the mitochondrial matrix [J].Proc Natl Acad Sci U S A,2011, 108(21): 8657-8662.
52
Palikaras K, Lionaki E, Tavernarakis N.Mechanisms of mitophagy in cellular homeostasis, physiology and pathology [J].Nat Cell Biol,2018, 20(9): 1013-1022.
53
Li X, Hu Y, Li X, et al.Mitochondria-immobilized near-infrared ratiometric fluorescent pH probe to evaluate cellular mitophagy [J].Anal Chem, 2019, 91(17): 11409-11416.
54
Cheng F, Qiang T, Ren L, et al.Observation of inflammation-induced mitophagy during stroke by a mitochondria-targeting two-photon ratiometric probe [J].Analyst, 2021, 146(8): 2632-2637.
55
Lei P, Li M, Dong C, et al.Multifunctional mitochondria-targeting near-infrared fluorescent probe for viscosity, ONOO-, mitophagy, and bioimaging [J].ACS Biomater Sci Eng, 2023, 9(6): 3581-3589.
56
Li M, Huang Y, Song S, et al.A bifunctional fluorescence probe for dual-channel detecting of mitochondrial viscosity and endogenous/exogenous peroxynitrite [J].Bioorg Chem, 2022, 119: 105484.
57
Baruah M, Jana A, Pareek N, et al.A ratiometric fluorescent probe for hypochlorite and lipid droplets to monitor oxidative stress [J].Biosensors (Basel), 2023, 13(6): 662.
58
Hu W, Qiang T, Chai L, et al.Simultaneous tracking of autophagy and oxidative stress during stroke with an ICT-TBET integrated ratiometric two-photon platform [J].Chem Sci, 2022, 13(18): 5363-5373.
59
Kaushik R, Nehra N, Novakova V, et al.Near-infrared probes for biothiols (cysteine, homocysteine, and glutathione): a comprehensive review [J].ACS Omega, 2023, 8(1): 98-126.
60
Yang Y, Ma M, Shen L, et al.A fluorescent probe for investigating the role of biothiols in signaling pathways associated with cerebral ischemia-reperfusion injury [J].Angew Chem Int Ed Engl, 2023,62(40): e202310408.
61
Yang Y, Zhou T, Jin M, et al.Thiol-chromene "click" reaction triggered self-immolative for NIR visualization of thiol Flux in physiology and pathology of living cells and mice [J].J Am Chem Soc, 2020, 142(3):1614-1620.
62
Kannan N, Nguyen LV, Makarem M, et al.Glutathione-dependent and-independent oxidative stress-control mechanisms distinguish normal human mammary epithelial cell subsets [J].Proc Natl Acad Sci U S A,2014, 111(21): 7789-7794.
63
Kalogeris T, Bao Y, Korthuis RJ.Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning [J].Redox Biol, 2014, 2: 702-714.
64
Zhang X, Huang Y, Han X, et al.Evaluating the protective effects of mitochondrial glutathione on cerebral ischemia/reperfusion injury via near-infrared fluorescence imaging [J].Anal Chem, 2019, 91(22):14728-14736.
65
Han Y, Li X, Li D, et al.Selective, rapid, and ratiometric fluorescence sensing of homocysteine in live neurons via a reaction-kinetics/sequence-differentiation strategy based on a small molecular probe [J].ACS Sens, 2022, 7(4): 1036-1044.
66
Stipanuk MH.Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine [J].Annu Rev Nutr, 2004,24: 539-577.
67
Sun J, Hu Z, Zhang S, et al.A novel chemiluminescent probe based on 1,2-dioxetane scaffold for imaging cysteine in living mice [J].ACS Sens, 2019, 4(1): 87-92.
68
Ge C, Shen F, Yin Y, et al.A novel NIR fluorescence probe with cysteine-activated structure for specific detection of cysteine and its application in vitro and in vivo [J].Talanta, 2021, 223(Pt 2): 121758.
69
Long Y, Liu J, Tian D, et al.Cooperation of ESIPT and ICT processes in the designed 2-(2'-Hydroxyphenyl)benzothiazole derivative: a nearinfrared two-photon fluorescent probe with a large stokes shift for the detection of cysteine and its application in biological environments [J].Anal Chem, 2020, 92(20): 14236-14243.
70
Kolluru GK, Shen X, Bir SC, et al.Hydrogen sulfide chemical biology: pathophysiological roles and detection [J].Nitric Oxide,2013, 35: 5-20.
71
Kimura H, Shibuya N, Kimura Y.Hydrogen sulfide is a signaling molecule and a cytoprotectant [J].Antioxid Redox Signal, 2012, 17(1):45-57.
72
Zhao XJ, Li YT, Jiang YR, et al.A novel "turn-on" mitochondriatargeting near-infrared fluorescent probe for H2S detection and in living cells imaging [J].Talanta, 2019, 197: 326-333.
73
Cai S, Liu C, He S, et al.Mitochondria-targeted fluorescent probe for imaging endogenous hydrogen sulfide in cellular antioxidant stress [J].Anal Methods, 2020, 12(42): 5061-5067.
74
Ji A, Fan Y, Ren W, et al.A sensitive near-infrared fluorescent sensor for mitochondrial hydrogen sulfide [J].ACS Sens, 2018, 3(5): 992-997.
75
Orlando A, Franceschini F, Muscas C, et al.A comprehensive review on raman spectroscopy applications [J].Chemosensors, 2021, 9: 262.
76
Jensen M, Liu S, Stepula E, et al.Opto-lipidomics of tissues [J].Adv Sci (Weinh), 2024, 11(14): e2302962.
77
Liu M, Mu J, Gong W, et al.In Vitro diagnosis and visualization of cerebral ischemia/reperfusion injury in rats and protective effects of ferulic acid by raman biospectroscopy and machine learning [J].ACS Chem Neurosci, 2023, 14(1): 159-169.
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