基于STAIR原则的PSD-95靶向脑细胞保护剂在急性缺血性卒中中的研究进展

doi:10.3969/j.issn.1673-5765.2026.05.004

中国卒中杂志 ›› 2026, Vol. 21 ›› Issue (5): 543-552.DOI: 10.3969/j.issn.1673-5765.2026.05.004

基于STAIR原则的PSD-95靶向脑细胞保护剂在急性缺血性卒中中的研究进展

何丹丹^1，2，李姝雅^1，3，4

1北京 100070 首都医科大学附属北京天坛医院临床试验中心
2北京 100070 首都医科大学临床流行病学与临床试验学系
3北京 100070 神经系统疾病国家临床医学研究中心
4北京 100070 首都医科大学附属北京天坛医院神经病学中心

收稿日期:2026-02-16 修回日期:2026-04-18 接受日期:2026-05-02 出版日期:2026-05-20 发布日期:2026-05-20
通讯作者: 李姝雅 shuyali85@163.com
基金资助:
国家自然科学基金青年科学基金项目（B类）（82522025）

Research Progress of PSD-95-Targeted Brain Cytoprotective Agents in Acute Ischemic Stroke Based on STAIR Principles

HE Dandan^1,2, LI Shuya^1,3,4

1Department of Clinical Trial Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
2Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, Beijing 100070, China
3China National Clinical Research Center for Neurological Diseases, Beijing 100070, China
4Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China

Received:2026-02-16 Revised:2026-04-18 Accepted:2026-05-02 Online:2026-05-20 Published:2026-05-20
Contact: LI Shuya, E-mail: shuyali85@163.com

摘要/Abstract

摘要： 脑细胞保护是急性缺血性卒中再灌注治疗的重要补充策略。为打破脑细胞保护剂的临床转化困境，美国卒中治疗学术产业圆桌会议（stroke therapy academic industry roundtable，STAIR）于1999年成立，致力于建立卒中领域药物研发的系统化指导框架。自成立以来，STAIR不断完善针对脑细胞保护剂的研发策略及相关临床前实验、临床研究的系统性指导建议。突触后致密区95（postsynaptic density-95，PSD-95）因作用机制明确、靶点特异性高，已成为脑细胞保护领域的关键靶点之一。在STAIR原则的指导下，基于PSD-95靶点的脑细胞保护剂已完成了一系列临床前实验和临床研究。本文系统梳理STAIR原则指导脑细胞保护剂研发的要点，以及基于STAIR原则的PSD-95靶向药物临床前实验和临床研究的开展情况，总结其对缺血性卒中脑细胞保护作用的研究进展，以期为脑细胞保护剂的临床转化提供参考。

文章导读： 基于美国卒中治疗学术产业圆桌会议针对脑细胞保护治疗从临床前实验至临床研究的一系列建议和指导原则，以突触后致密区95为靶点的系列脑细胞保护剂研发已初见成效。这一规范、科学的研究策略有助于跨越脑细胞保护治疗领域的临床转化鸿沟，为进一步优化缺血性卒中治疗策略提供新的可能。

关键词: 急性缺血性卒中; 卒中治疗学术产业圆桌会议; 突触后致密区95; 脑细胞保护剂; 奈瑞奈肽; 洛贝米柳

Abstract: Brain cytoprotection serves as an important complementary strategy to reperfusion therapy in acute ischemic stroke. To overcome the challenges in the clinical translation of brain cytoprotective agents, the stroke therapy academic industry roundtable (STAIR) was established in 1999 in the United States with the aim of developing a systematic framework to guide drug research and development in stroke. Since its inception, STAIR has continuously refined strategy-specific recommendations for brain cytoprotective agents, providing structured guidance for preclinical experimentation and clinical research. Postsynaptic density protein-95 (PSD-95) has emerged as a key target in the brain cytoprotection field owing to its well-defined mechanisms and high target specificity. Under the guidance of STAIR principles, PSD-95-based brain cytoprotective agents have undergone a series of preclinical and clinical studies. This paper systematically reviews the key points of STAIR principles for the development of brain cytoprotective agents and summarizes the status of preclinical and clinical studies of PSD-95-targeting agents under STAIR guidance. It also outlines the research progress on the brain cytoprotective effects of these agents in acute ischemic stroke, thereby providing a reference for the clinical translation of brain cytoprotective agents.

Key words: Acute ischemic stroke; Stroke therapy academic industry roundtable; Postsynaptic density protein-95; Brain cytoprotective agent; Nerinetide; Loberamisal

中图分类号:

何丹丹, 李姝雅. 基于STAIR原则的PSD-95靶向脑细胞保护剂在急性缺血性卒中中的研究进展[J]. 中国卒中杂志, 2026, 21(5): 543-552.

HE Dandan, LI Shuya. Research Progress of PSD-95-Targeted Brain Cytoprotective Agents in Acute Ischemic Stroke Based on STAIR Principles[J]. Chinese Journal of Stroke, 2026, 21(5): 543-552.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://www.chinastroke.org.cn/CN/10.3969/j.issn.1673-5765.2026.05.004

https://www.chinastroke.org.cn/CN/Y2026/V21/I5/543

参考文献

[1] GBD 2019 Stroke Collaborators. Global，regional，and national burden of stroke and its risk factors，1990-2019：a systematic analysis for the global burden of disease study 2019[J]. Lancet Neurol，2021，20（10）：795-820.
[2] PRABHAKARAN S，GONZALEZ N R，ZACHRISON K S，et al. 2026 guideline for the early management of patients with acute ischemic stroke：a guideline from the American Heart Association/American Stroke Association[J/OL]. Stroke，2026[2026-04-08]. https://doi.org/10.1161/STR.0000000000000513.
[3] OTITE F O，SAINI V，SUR N B，et al. Ten-year trend in age，sex，and racial disparity in tPA（alteplase）and thrombectomy use following stroke in the United States[J]. Stroke，2021，52（8）：2562-2570.
[4] ASIF K S，OTITE F O，DESAI S M，et al. Mechanical thrombectomy global access for stroke（MT-GLASS）：a mission thrombectomy（MT-2020 plus）study[J]. Circulation，2023，147（16）：1208-1220.
[5] FISHER M，SAVITZ S I. Pharmacological brain cytoprotection in acute ischaemic stroke—renewed hope in the reperfusion era[J]. Nat Rev Neurol，2022，18（4）：193-202.
[6] Stroke Therapy Academic Industry Roundtable（STAIR）. Recommendations for standards regarding preclinical neuroprotective and restorative drug development[J]. Stroke，1999，30（12）：2752-2758.
[7] ALBERS G W，BOGOUSSLAVSKY J，BOZIK M A，et al. Recommendations for clinical trial evaluation of acute stroke therapies—stroke therapy academic industry roundtable Ⅱ（STAIR-Ⅱ）[J]. Stroke，2001，32（7）：1598-1606.
[8] FISHER M，Stroke Therapy Academic Industry Roundtable. Recommendations for advancing development of acute stroke therapies：stroke therapy academic industry roundtable 3[J]. Stroke，2003，34（6）：1539-1546.
[9] FISHER M，ALBERS G W，DONNAN G A，et al. Enhancing the development and approval of acute stroke therapies：stroke therapy academic industry roundtable[J]. Stroke，2005，36（8）：1808-1813.
[10] FISHER M，HANLEY D F，HOWARD G，et al. Recommendations from the STAIR Ⅴ meeting on acute stroke trials，technology and outcomes[J]. Stroke，2007，38（2）：245-248.
[11] FISHER M，FEUERSTEIN G，HOWELLS D W，et al. Update of the stroke therapy academic industry roundtable preclinical recommendations[J]. Stroke，2009，40（6）：2244-2250.
[12] LEES K R，KHATRI P，STAIR Ⅸ Collaborators. Stroke treatment academic industry roundtable（STAIR）recommendations for individual data pooling analyses in stroke[J]. Stroke，2016，47（8）：2154-2159.
[13] SAVITZ S I，BARON J C，FISHER M，et al. Stroke treatment academic industry roundtable Ⅹ：brain cytoprotection therapies in the reperfusion era[J]. Stroke，2019，50（4）：1026-1031.
[14] LYDEN P，BUCHAN A，BOLTZE J，et al. Top priorities for cerebroprotective studies—a paradigm shift：report from STAIR Ⅺ[J]. Stroke，2021，52（9）：3063-3071.
[15] DEMCHUK A M，ALBERS G W，NOGUEIRA R G. STAIR Ⅹ：trial design considerations and additional populations to expand indications for endovascular treatment[J]. Stroke，2019，50（6）：1605-1611.
[16] WECHSLER L R，ADEOYE O，ALEMSEGED F，et al. Most promising approaches to improve stroke outcomes：the stroke treatment academic industry roundtable Ⅻ workshop[J]. Stroke，2023，54（12）：3202-3213.
[17] SAVITZ S I，SAMANIEGO E A，LIEBESKIND D S，et al. Updated priorities for cerebroprotection trials[J]. Stroke，2026，57（3）：829-836.
[18] UGALDE-TRIVIÑO L，DÍAZ-GUERRA M. PSD-95：an effective target for stroke therapy using neuroprotective peptides[J/OL]. Int J Mol Sci，2021，22（22）：12585[2026-04-10]. https://doi.org/10.3390/ijms222212585.
[19] LYDEN P D，LAMB J，KOTHARI S，et al. Differential effects of hypothermia on neurovascular unit determine protective or toxic results：toward optimized therapeutic hypothermia[J]. J Cereb Blood Flow Metab，2019，39（9）：1693-1709.
[20] LAPCHAK P A. Emerging therapies：pleiotropic multi-target drugs to treat stroke victims[J]. Transl Stroke Res，2011，2（2）：129-135.
[21] EILERTSEN G，ORMSTAD H，KIRKEVOLD M. Experiences of poststroke fatigue：qualitative meta-synthesis[J]. J Adv Nurs，2013，69（3）：514-525.
[22] MICHIELSEN H J，DE VRIES J，VAN HECK G L. Psychometric qualities of a brief self-rated fatigue measure：the fatigue assessment scale[J]. J Psychosom Res，2003，54（4）：345-352.
[23] SATTLER R，XIONG Z，LU W Y，et al. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein[J]. Science，1999，284（5421）：1845-1848.
[24] ADAMEC E，MOHAN P，VONSATTEL J P，et al. Calpain activation in neurodegenerative diseases：confocal immunofluorescence study with antibodies specifically recognizing the active form of calpain 2[J]. Acta Neuropathol，2002，104（1）：92-104.
[25] PICÓN-PAGÈS P，GARCIA-BUENDIA J，MUÑOZ F J. Functions and dysfunctions of nitric oxide in brain[J]. Biochim Biophys Acta Mol Basis Dis，2019，1865（8）：1949-1967.
[26] CHRISTOPHERSON K S，HILLIER B J，LIM W A，et al. PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain[J]. J Biol Chem，1999，274（39）：27467-27473.
[27] ZHENG H Y，DING Y R，GUO F Y，et al. The novel PSD-95 inhibitor BXOS110 provides neuroprotection in acute ischemic stroke[J/OL]. Neuropharmacology，2026，288：110845[2026-04-10]. https://doi.org/10.1016/j.neuropharm.2026.110845.
[28] WANG J C，LIANG R G，ZHANG L，et al. Development of cell-permeable and plasma-stable peptidomimetic inhibitors against PSD-95/nNOS interaction as potential anti-ischemic stroke agents[J/OL]. Eur J Med Chem，2025，299：118062[2026-04-10]. https://doi.org/10.1016/j.ejmech.2025.118062.
[29] SOMMER J B，BACH A，MALÁ H，et al. In vitro and in vivo effects of a novel dimeric inhibitor of PSD-95 on excitotoxicity and functional recovery after experimental traumatic brain injury[J]. Eur J Neurosci，2017，45（2）：238-248.
[30] FERNANDES E F A，PALNER M，RAVAL N R，et al. Development of peptide-based probes for molecular imaging of the postsynaptic density in the brain[J]. J Med Chem，2024，67（14）：11975-11988.
[31] AARTS M，LIU Y T，LIU L D，et al. Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions[J]. Science，2002，298（5594）：846-850.
[32] COOK D J，TEVES L，TYMIANSKI M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain[J]. Nature，2012，483（7388）：213-217.
[33] BACH A，CLAUSEN B H，MØLLER M，et al. A high-affinity，dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage[J]. Proc Natl Acad Sci U S A，2012，109（9）：3317-3322.
[34] BACH A，CLAUSEN B H，KRISTENSEN L K，et al. Selectivity，efficacy and toxicity studies of UCCB01-144，a dimeric neuroprotective PSD-95 inhibitor[J/OL]. Neuropharmacology，2019，150：101-111[2026-04-10]. https://doi.org/10.1016/j.neuropharm.2019.02.035.
[35] SUN H S，DOUCETTE T A，LIU Y T，et al. Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat[J]. Stroke，2008，39（9）：2544-2553.
[36] HILL M D，GOYAL M，MENON B K，et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke（ESCAPE-NA1）：a multicentre，double-blind，randomised controlled trial[J]. Lancet，2020，395（10227）：878-887.
[37] MAYOR-NUNEZ D，JI Z X，SUN X J，et al. Plasmin-resistant PSD-95 inhibitors resolve effect-modifying drug-drug interactions between alteplase and nerinetide in acute stroke[J/OL]. Sci Transl Med，2021，13（588）：eabb1498[2026-04-10]. https://doi.org/10.1126/scitranslmed.abb1498.
[38] HILL M D，MARTIN R H，MIKULIS D，et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair（ENACT）：a phase 2，randomised，double-blind，placebo-controlled trial[J]. Lancet Neurol，2012，11（11）：942-950.
[39] HILL M D，GOYAL M，DEMCHUK A M，et al. Efficacy and safety of nerinetide in acute ischaemic stroke in patients undergoing endovascular thrombectomy without previous thrombolysis（ESCAPE-NEXT）：a multicentre，double-blind，randomised controlled trial[J]. Lancet，2025，405（10478）：560-570.
[40] CHRISTENSON J，HILL M D，SWARTZ R H，et al. Efficacy and safety of intravenous nerinetide initiated by paramedics in the field for acute cerebral ischaemia within 3 h of symptom onset（FRONTIER）：a phase 2，multicentre，randomised，double-blind，placebo-controlled study[J]. Lancet，2025，405（10478）：571-582.
[41] TYMIANSKI M，HILL M D，GOYAL M，et al. Safety and efficacy of nerinetide in patients with acute ischaemic stroke enrolled in the early window：a post-hoc meta-analysis of individual patient data from three randomised trials[J]. Lancet Neurol，2025，24（3）：208-217.
[42] WEI W，LIU W L，DU S B，et al. A compound mitigates cancer pain and chemotherapy-induced neuropathic pain by dually targeting nNOS-PSD-95 interaction and GABAA receptor[J]. Neurotherapeutics，2021，18（4）：2436-2448.
[43] WU H Y，HUANG Z Q，WANG X，et al. Preclinical evaluation of ZL006-05，a new antistroke drug with fast-onset antidepressant and anxiolytic effects[J]. Stroke Vasc Neurol，2023，8（6）：463-474.
[44] LI J，ZHANG L，XU C，et al. A pain killer without analgesic tolerance designed by co-targeting PSD-95-nNOS interaction and α2-containning GABAARs[J]. Theranostics，2021，11（12）：5970-5985.
[45] FENG B Y，LI H，XU S H，et al. Loberamisal injection for the treatment of acute ischaemic stroke：a multicentre，randomised，double-blind，placebo-controlled phase Ⅱ clinical trial[J/OL]. Stroke Vasc Neurol，2025：svn-2025-4581[2026-04-10]. https://doi.org/10.1136/svn-2025-004581.
[46] LI S Y，WANG X C，FENG B Y，et al. Loberamisal for acute ischaemic stroke（LAIS）：a multicentre，randomised，double-blind，parallel，placebo-controlled phase Ⅲ clinical trial[J/OL]. Stroke Vasc Neurol，2025：svn-2025-4582[2026-04-10]. https://doi.org/10.1136/svn-2025-004582.
[47] AYUSO-DOLADO S，ESTEBAN-ORTEGA G M，VIDAURRE Ó G，et al. A novel cell-penetrating peptide targeting calpain-cleavage of PSD-95 induced by excitotoxicity improves neurological outcome after stroke[J]. Theranostics，2021，11（14）：6746-6765.

基于STAIR原则的PSD-95靶向脑细胞保护剂在急性缺血性卒中中的研究进展

Research Progress of PSD-95-Targeted Brain Cytoprotective Agents in Acute Ischemic Stroke Based on STAIR Principles

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

[1]	何丹丹, 李俭, 王春娟, 李姝雅. 我国急性缺血性卒中脑细胞保护剂基础实验与临床研究的挑战与突破[J]. 中国卒中杂志, 2026, 21(5): 517-524.
[2]	程希玥, 赵璟妍, 王春娟. 依达拉奉右莰醇在急性缺血性卒中脑细胞保护中的研究进展[J]. 中国卒中杂志, 2026, 21(5): 526-532.
[3]	杨千千, 张眉扬, 陆瑶, 周东杨, 王正一蕾, 单舒乙, 刘晨辉, 王伊龙, 管玲. 米诺环素在急性缺血性卒中中的抗神经炎症与脑细胞保护研究进展：从机制到临床证据[J]. 中国卒中杂志, 2026, 21(5): 533-542.
[4]	陈壮壮, 徐柳, 王楠星, 张眉扬, 姬若冰, 杨沫, 刘向荣, 王伊龙. 经颅骨骨髓途径递送脑细胞保护剂的研究与展望[J]. 中国卒中杂志, 2026, 21(5): 553-560.
[5]	李汶逸, 姜季委, 任琦玮, 王琳琳, 赵敏, 徐俊. 载脂蛋白E基因多态性与卒中后认知功能变化的相关性研究[J]. 中国卒中杂志, 2026, 21(5): 577-584.
[6]	刘元昊, 吴磊, 杨欢, 朱佳颖, 李亚哲. 不同取栓装置在急性缺血性卒中治疗中的有效性与安全性：1项回顾性比较研究[J]. 中国卒中杂志, 2026, 21(4): 463-470.
[7]	欧茹, 刘益民, 徐智坚, 黄文纯. 血管源性腔隙灶对急性缺血性卒中患者生命健康状况的动态影响[J]. 中国卒中杂志, 2026, 21(3): 312-319.
[8]	李荔, 段振晖, 高爱华, 潘宋斌. 老年急性缺血性卒中患者衰弱指数、营养风险与静脉溶栓后院内感染风险的相关性分析及预测模型构建[J]. 中国卒中杂志, 2026, 21(3): 331-337.
[9]	张自立, 赵颖, 孟珩, 徐安定. 急性缺血性卒中血管内治疗后无效再通预测研究进展[J]. 中国卒中杂志, 2026, 21(3): 378-386.
[10]	姚莉, 吴川杰. 2026美国心脏学会/美国卒中学会急性缺血性卒中患者早期管理指南血管内治疗要点与解读[J]. 中国卒中杂志, 2026, 21(2): 234-239.
[11]	何丹丹, 许淑红, 李姝雅. 急性缺血性卒中标准时间窗内新型静脉溶栓药物临床研究及展望[J]. 中国卒中杂志, 2026, 21(1): 24-29.
[12]	黄旭阳, 李润辉. 替奈普酶与阿替普酶治疗急性缺血性卒中短期神经功能恢复比较：线性混合效应模型分析[J]. 中国卒中杂志, 2026, 21(1): 31-37.
[13]	何丹丹, 冯宝玉, 刘改芬, 谷鸿秋, 李姝雅. 中性粒细胞与淋巴细胞比值对急性缺血性卒中静脉溶栓患者预后的预测价值：基于3项随机对照试验的个体患者数据分析[J]. 中国卒中杂志, 2026, 21(1): 38-47.
[14]	赵敏, 冯宝玉, 何丹丹, 王维聪, 李姝雅. 瑞替普酶与阿替普酶治疗急性缺血性卒中合并心律失常患者的有效性及安全性比较[J]. 中国卒中杂志, 2026, 21(1): 48-54.
[15]	何丹丹, 李姝雅. 急性缺血性卒中静脉溶栓中外周血炎症指标与预后的研究进展[J]. 中国卒中杂志, 2026, 21(1): 55-64.