{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:05:14Z","timestamp":1790057114228,"version":"4.0.1"},"reference-count":101,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ischemic stroke is a leading cause of long-term disability and mortality worldwide. Despite substantial advances in reperfusion therapy, effective neuroprotective strategies remain limited. Sinomenine, a bioactive alkaloid derived from plants of the Menispermaceae family, has shown neuroprotective effects in preclinical models of ischemic stroke. However, the available preclinical evidence has not been systematically quantified, and the relationship between sinomenine dosage and therapeutic efficacy remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Eight electronic databases were searched from inception to 30 March 2026. The risk of bias, reporting quality, and translational readiness were assessed using the SYRCLE risk-of-bias tool, the ARRIVE 2.0 guidelines, and the Stroke Therapy Academic Industry Roundtable criteria, respectively. Data synthesis and quantitative analyses were performed with RevMan 5.3 and Stata 17.0. Subgroup and sensitivity analyses were conducted for outcomes with high heterogeneity. Additionally, dose-response curves were fitted using restricted cubic spline models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>This meta-analysis included 15 studies. In animal models of ischemic stroke, sinomenine significantly reduced cerebral infarct volume, improved neurological function score (NFS), and preserved blood-brain barrier (BBB) integrity. Sinomenine also downregulated neuroinflammation-related biomarkers, enhanced superoxide dismutase (SOD) activity, and modulated apoptosis-related marker levels. RCS analysis suggested nonlinear dose-response relationships between sinomenine dosage and cerebral infarct volume, NFS, and brain water content. Subgroup analyses revealed that animal strain, comorbidity status, experimental blinding, drug dosage, and timing of administration may influence effect sizes. Trim-and-fill analysis showed that the pooled standardized mean difference (SMD) for cerebral infarct volume attenuated from \u22123.02 (95% CI [-3.96, \u22122.08]) to \u22121.97 (95% CI [-2.93, \u22121.01]) after adjustment, whereas that for NFS attenuated from \u22121.57 (95% CI [-2.18, \u22120.97]) to \u22121.06 (95% CI [-1.72, \u22120.40]).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In animal models, sinomenine may mitigate ischemic stroke injury through multiple pathways, with the efficacy following nonlinear dose-response relationships, suggesting its potential as an adjunctive neuroprotective intervention warranting further investigation. However, given the methodological limitations of the included studies, these findings should be interpreted cautiously. To facilitate clinical translation, future studies should incorporate more rigorous and standardized experimental designs to strengthen the evidence base and validate its therapeutic potential.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD420261359581<\/jats:ext-link>\n                      , identifier CRD420261359581.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1926226","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:39:03Z","timestamp":1790055543000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuroprotective effects and mechanistic insights of sinomenine in ischemic stroke: a systematic review and meta-analysis of preclinical animal studies"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaoqun","family":"Li","sequence":"first","affiliation":[{"name":"Third Clinical Medical College of Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xuanwu Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xuanwu Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinzuo","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xuanwu Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningyu","family":"Xue","sequence":"additional","affiliation":[{"name":"Third Clinical Medical College of Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Fan","sequence":"additional","affiliation":[{"name":"Third Clinical Medical College of Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xuanwu Hospital of Capital Medical University","place":["Beijing, China"]},{"name":"Department of Chinese Medicine, Xuanwu Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1007\/s11910-023-01282-2","article-title":"Neuroinflammation in acute ischemic and hemorrhagic stroke","volume":"23","author":"Alsbrook","year":"2023","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"148589","DOI":"10.1016\/j.ijbiomac.2025.148589","article-title":"Neuronal nitric oxide synthase (nNOS) uncoupling in ischemic stroke: mechanisms of oxidative\/nitrosative stress and opportunities for neuroprotection: a review","volume":"332","author":"Anwar","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"302","DOI":"10.3870\/j.issn.1672-8009.2018.05.008","article-title":"Effects of sinomenine on hypoxia-induced neuronal injury and endoplasmic reticulum stress autophagy","volume":"15","author":"Bai","year":"2018","journal-title":"J. Med. Mol. Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/j.jclinepi.2014.04.008","article-title":"Lack of blinding of outcome assessors in animal model experiments implies risk of observer bias","volume":"67","author":"Bello","year":"2014","journal-title":"J. Clin. Epidemiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"647","DOI":"10.3892\/etm.2021.10079","article-title":"Sinomenine activation of Nrf2 signaling prevents inflammation and cerebral injury in a mouse model of ischemic stroke","volume":"21","author":"Bi","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1161\/strokeaha.122.036946","article-title":"Neuroinflammation, stroke, blood-brain barrier dysfunction, and imaging modalities","volume":"53","author":"Candelario-Jalil","year":"2022","journal-title":"Stroke"},{"key":"B7","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1007\/s00281-022-00943-7","article-title":"Inflammatory responses after ischemic stroke","volume":"44","author":"DeLong","year":"2022","journal-title":"Semin. Immunopathol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"115772","DOI":"10.1016\/j.bcp.2023.115772","article-title":"Spatial and temporal mapping of neuron-microglia interaction modes in acute ischemic stroke","volume":"216","author":"Dou","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3892\/ijmm.2025.5544","article-title":"Molecular mechanisms of programmed cell death and potential targeted pharmacotherapy in ischemic stroke","volume":"56","author":"Duan","year":"2025","journal-title":"Int. J. Mol. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1007\/s10571-017-0469-1","article-title":"Sinomenine protects PC12 neuronal cells against H(2)O(2)-induced cytotoxicity and oxidative stress via a ROS-dependent Up-regulation of endogenous antioxidant system","volume":"37","author":"Fan","year":"2017","journal-title":"Cell Mol. Neurobiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1016\/s1474-4422(23)00277-6","article-title":"Pragmatic solutions to reduce the global burden of stroke: a world stroke organization-lancet neurology commission","volume":"22","author":"Feigin","year":"2023","journal-title":"Lancet Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/s1474-4422(24)00369-7","article-title":"Global, regional, and national burden of stroke and its risk factors, 1990-2021: a systematic analysis for the global burden of disease study 2021","volume":"23","author":"Feigin","year":"2024","journal-title":"Lancet Neurol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1177\/17474930241308142","article-title":"World stroke organization: global stroke fact sheet 2025","volume":"20","author":"Feigin","year":"2025","journal-title":"Int. J. Stroke"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2752","DOI":"10.1161\/01.Str.30.12.2752","article-title":"Recommendations for standards regarding preclinical neuroprotective and restorative drug development","volume":"30","author":"Feinklestein","year":"1999","journal-title":"Stroke"},{"key":"B15","doi-asserted-by":"publisher","first-page":"806","DOI":"10.3969\/j.issn.1008-0805.2010.04.015","article-title":"Effect of sinomenine on the expression of cyclooxygenase-2 and the permeability of the blood-brain barrier following cerebral ischemic reperfusion injury in rats","volume":"21","author":"Feng","year":"2010","journal-title":"Lishizhen Med. Mater Med. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1038\/s41582-021-00605-6","article-title":"Pharmacological brain cytoprotection in acute ischaemic stroke - renewed hope in the reperfusion era","volume":"18","author":"Fisher","year":"2022","journal-title":"Nat. Rev. Neurol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.1161\/strokeaha.108.541128","article-title":"Update of the stroke therapy academic industry roundtable preclinical recommendations","volume":"40","author":"Fisher","year":"2009","journal-title":"Stroke"},{"key":"B18","doi-asserted-by":"publisher","first-page":"3445","DOI":"10.2147\/dddt.S56071","article-title":"Animal models of ischemic stroke and their application in clinical research","volume":"9","author":"Fluri","year":"2015","journal-title":"Drug Des. Devel Ther."},{"key":"B19","doi-asserted-by":"publisher","first-page":"5796","DOI":"10.3390\/ijms23105796","article-title":"The development of novel drug treatments for stroke patients: a review","volume":"23","author":"Frank","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jep.2013.04.002","article-title":"Xiaoxuming decoction for acute ischemic stroke: a systematic review and meta-analysis","volume":"148","author":"Fu","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"104633","DOI":"10.1016\/j.dib.2019.104633","article-title":"Exploratory study data for determining the adverse effects of sinomenine plus Gabapentin or ligustrazine hydrochloride and the pharmacokinetic insights of sinomenine in plasma and CNS tissue","volume":"27","author":"Gao","year":"2019","journal-title":"Data Brief."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2350821","DOI":"10.1080\/21688370.2024.2350821","article-title":"Hyperglycaemia perturbs blood-brain barrier integrity through its effects on endothelial cell characteristics and function","volume":"13","author":"Hashmat","year":"2025","journal-title":"Tissue Barriers"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2820","DOI":"10.1016\/s0140-6736(24)00642-1","article-title":"Stroke","volume":"403","author":"Hilkens","year":"2024","journal-title":"Lancet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1015035","DOI":"10.3389\/fphar.2022.1015035","article-title":"Potential therapeutic effects and pharmacological evidence of sinomenine in central nervous system disorders","volume":"13","author":"Hong","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/1471-2288-14-43","article-title":"SYRCLE's risk of bias tool for animal studies","volume":"14","author":"Hooijmans","year":"2014","journal-title":"BMC Med. Res. Methodol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"103185","DOI":"10.1016\/j.redox.2024.103185","article-title":"Developing targeted antioxidant nanomedicines for ischemic penumbra: novel strategies in treating brain ischemia-reperfusion injury","volume":"73","author":"Hou","year":"2024","journal-title":"Redox Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"540","DOI":"10.3390\/molecules29020540","article-title":"Bioactivities and mechanisms of action of sinomenine and its derivatives: a comprehensive review","volume":"29","author":"Hou","year":"2024","journal-title":"Molecules"},{"key":"B28","doi-asserted-by":"publisher","first-page":"3245","DOI":"10.1007\/s00204-022-03368-1","article-title":"Sex-related differences in safety profiles, pharmacokinetics and tissue distribution of sinomenine hydrochloride in rats","volume":"96","author":"Huang","year":"2022","journal-title":"Arch. Toxicol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e3001873","DOI":"10.1371\/journal.pbio.3001873","article-title":"A qualitative study of the barriers to using blinding in in vivo experiments and suggestions for improvement","volume":"20","author":"Karp","year":"2022","journal-title":"PLoS Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1007\/s11033-025-10686-x","article-title":"Molecular and biological approach to ischemia\/reperfusion in diabetes conditions","volume":"52","author":"Kilic","year":"2025","journal-title":"Mol. Biol. Rep."},{"key":"B31","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.freeradbiomed.2023.08.004","article-title":"Hyperglycemia exacerbates ischemic stroke not through increased generation of hydrogen peroxide","volume":"208","author":"Kotova","year":"2023","journal-title":"Free Radic. Biol. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"108999","DOI":"10.1016\/j.pharmthera.2026.108999","article-title":"NETosis in ischemic stroke: mechanisms, implications, and therapeutic prospects","volume":"281","author":"Krishnamoorthy","year":"2026","journal-title":"Pharmacol. Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1038\/jcbfm.2009.255","article-title":"Effects of AMP-Activated protein kinase in cerebral ischemia","volume":"30","author":"Li","year":"2010","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.3969\/j.issn.1004-745X.2008.08.045","article-title":"Effects of sinomenine on prostaglandin E2 content and the permeability of the blood-brain barrier following cerebral ischemia reperfusion injury in rats","volume":"17","author":"Li","year":"2008","journal-title":"JETCM"},{"key":"B35","first-page":"436","article-title":"Effect mechanism of neuroprotection of sinomenine on rats with cerebral ischemia-reperfusion","volume":"22","author":"Li","year":"2009","journal-title":"J. Clin. Neurol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2558","DOI":"10.3969\/j.issn.1671-8348.2010.19.006","article-title":"Mechanism of neuroprotective effect of sinomenine after focal cerebral ischemia reperfusion injury in rats","volume":"39","author":"Li","year":"2010","journal-title":"Chongqing Med. J."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2159","DOI":"10.1111\/bph.16267","article-title":"From mundane to classic: Sinomenine as a multi-therapeutic agent","volume":"182","author":"Li","year":"","journal-title":"Br. J. Pharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1677685","DOI":"10.3389\/fmed.2025.1677685","article-title":"Sinomenine in cerebral ischemia: mechanisms, delivery strategies, and the emerging multifunctional biomaterials of the bone-brain axis","volume":"12","author":"Li","year":"","journal-title":"Front. Med. (Lausanne)"},{"key":"B39","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1113\/ep093135","article-title":"Neuroprotective effects of sinomenine and metformin in diabetic stroke: role of NLRP3\/caspase-1 and mitophagy","volume":"111","author":"Li","year":"2026","journal-title":"Exp. Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3969\/j.issn.1008-1836.1999.01.003","article-title":"The effects of sinomenine on rat behavior and the range of cerebral infarction after focal brain ischemia-reperfusion","volume":"27","author":"Liang","year":"1999","journal-title":"Acad. J. Guangzhou Med. Univ."},{"key":"B41","doi-asserted-by":"publisher","first-page":"2465","DOI":"10.2174\/1570159x21666230718104634","article-title":"The relationship of astrocytes and microglia with different stages of ischemic stroke","volume":"21","author":"Liang","year":"2023","journal-title":"Curr. Neuropharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"108541","DOI":"10.1016\/j.pharmthera.2023.108541","article-title":"Signaling pathways in brain ischemia: mechanisms and therapeutic implications","volume":"251","author":"Lin","year":"2023","journal-title":"Pharmacol. Ther."},{"key":"B43","doi-asserted-by":"publisher","first-page":"30","DOI":"10.3969\/j.issn.1672-2779.2020.01.012","article-title":"An exploration of pathogenic wind in stroke disorders","volume":"18","author":"Liu","year":"2020","journal-title":"Chin. Med. Mod. Distance Educ. China"},{"key":"B44","doi-asserted-by":"publisher","first-page":"3197","DOI":"10.1016\/j.lfs.2005.05.054","article-title":"The pharmacokinetics and tissue distribution of sinomenine in rats and its protein binding ability in vitro","volume":"77","author":"Liu","year":"2005","journal-title":"Life Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2283","DOI":"10.2174\/1570159x21666230717144752","article-title":"Neuroprotective strategies for stroke by natural products: advances and perspectives","volume":"21","author":"Liu","year":"2023","journal-title":"Curr. Neuropharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"108721","DOI":"10.1016\/j.pharmthera.2024.108721","article-title":"Potential application of natural compounds in ischaemic stroke: focusing on the mechanisms underlying \u201clysosomocentric\u201d dysfunction of the autophagy-lysosomal pathway","volume":"263","author":"Liu","year":"2024","journal-title":"Pharmacol. Ther."},{"key":"B47","doi-asserted-by":"publisher","first-page":"116186","DOI":"10.1016\/j.bcp.2024.116186","article-title":"The role of oxidative stress in blood-brain barrier disruption during ischemic stroke: antioxidants in clinical trials","volume":"228","author":"Lochhead","year":"2024","journal-title":"Biochem. Pharmacol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1508","DOI":"10.1038\/aps.2010.122","article-title":"HPLC and LC-MS analysis of sinomenine and its application in pharmacokinetic studies in rats","volume":"31","author":"Long","year":"2010","journal-title":"Acta Pharmacol. Sin."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1007\/s12264-022-00859-0","article-title":"Neuronal death mechanisms and therapeutic strategy in ischemic stroke","volume":"38","author":"Mao","year":"2022","journal-title":"Neurosci. Bull."},{"key":"B50","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1007\/s12975-022-01082-9","article-title":"Translating animal models of ischemic stroke to the human condition","volume":"14","author":"Matur","year":"2023","journal-title":"Transl. Stroke Res."},{"key":"B51","doi-asserted-by":"publisher","first-page":"632","DOI":"10.3390\/cimb48060632","article-title":"Transient middle cerebral artery occlusion in rats as a nonclinical model of ischemic stroke: a systematic review","volume":"48","author":"Mendes","year":"2026","journal-title":"Curr. Issues Mol. Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1002\/ame2.12166","article-title":"Preclinical animal studies in ischemic stroke: challenges and some solutions","volume":"4","author":"Narayan","year":"2021","journal-title":"Anim. Model Exp. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1016\/s0140-6736(24)01410-7","article-title":"Endovascular management of acute stroke","volume":"404","author":"Nguyen","year":"2024","journal-title":"Lancet"},{"key":"B54","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1136\/jnis-2022-019382","article-title":"Reocclusion after successful endovascular treatment in acute ischemic stroke: systematic review and meta-analysis","volume":"15","author":"Oliveira","year":"2023","journal-title":"J. Neurointerv Surg."},{"key":"B55","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"Bmj"},{"key":"B56","doi-asserted-by":"publisher","first-page":"110323","DOI":"10.1016\/j.cellsig.2022.110323","article-title":"Targeting AMPK signaling in ischemic\/reperfusion injury: from molecular mechanism to pharmacological interventions","volume":"94","author":"Paskeh","year":"2022","journal-title":"Cell Signal"},{"key":"B57","doi-asserted-by":"publisher","first-page":"113518","DOI":"10.1016\/j.expneurol.2020.113518","article-title":"Emerging neuroprotective strategies for the treatment of ischemic stroke: an overview of clinical and preclinical studies","volume":"335","author":"Paul","year":"2021","journal-title":"Exp. Neurol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.3390\/biom14091130","article-title":"The influence of oxidative stress markers in patients with ischemic stroke","volume":"14","author":"Pawluk","year":"2024","journal-title":"Biomolecules"},{"key":"B59","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1161\/strokeaha.124.049013","article-title":"Cerebral infarct growth: pathophysiology, pragmatic assessment, and clinical implications","volume":"56","author":"Pensato","year":"2025","journal-title":"Stroke"},{"key":"B60","doi-asserted-by":"publisher","first-page":"2237","DOI":"10.1161\/strokeaha.126.055331","article-title":"Redefining the cerebral ischemic core-penumbra-oligemia continuum","volume":"57","author":"Pensato","year":"2026","journal-title":"Stroke"},{"key":"B61","doi-asserted-by":"publisher","first-page":"e3000410","DOI":"10.1371\/journal.pbio.3000410","article-title":"The ARRIVE guidelines 2.0: updated guidelines for reporting animal research","volume":"18","author":"Percie du Sert","year":"2020","journal-title":"PLoS Biol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1742-2094-4-23","article-title":"Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase","volume":"4","author":"Qian","year":"2007","journal-title":"J. Neuroinflammation"},{"key":"B63","doi-asserted-by":"crossref","first-page":"140","DOI":"10.14715\/cmb\/2018.64.10.23","article-title":"Sinomenine relieves oxygen and glucose deprivation-induced microglial activation via inhibition of the SP1\/miRNA-183-5p\/I\u03baB-\u03b1 signaling pathway","volume":"64","author":"Qin","year":"2018","journal-title":"Cell Mol. Biol. (Noisy-le-grand)"},{"key":"B64","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1016\/j.intimp.2016.09.024","article-title":"The neuroprotection of sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling","volume":"40","author":"Qiu","year":"","journal-title":"Int. Immunopharmacol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1186\/s12974-016-0739-8","article-title":"Sinomenine activates astrocytic dopamine D2 receptors and alleviates neuroinflammatory injury via the CRYAB\/STAT3 pathway after ischemic stroke in mice","volume":"13","author":"Qiu","year":"","journal-title":"J. Neuroinflammation"},{"key":"B66","doi-asserted-by":"publisher","first-page":"1411307","DOI":"10.3389\/fneur.2024.1411307","article-title":"Blood-based protein biomarkers during the acute ischemic stroke treatment window: a systematic review","volume":"15","author":"Rahmig","year":"2024","journal-title":"Front. Neurol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1177\/01410768221100970","article-title":"The role of systematic reviews in identifying the limitations of preclinical animal research, 2000-2022: part 2","volume":"115","author":"Ritskes-Hoitinga","year":"2022","journal-title":"J. R. Soc. Med."},{"key":"B68","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1007\/s00281-022-00961-5","article-title":"Role of alarmins in poststroke inflammation and neuronal repair","volume":"45","author":"Sakai","year":"2023","journal-title":"Semin. Immunopathol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"305","DOI":"10.3390\/biom14030305","article-title":"Understanding the pathophysiology of ischemic stroke: the basis of current therapies and opportunity for new ones","volume":"14","author":"Salaudeen","year":"2024","journal-title":"Biomolecules"},{"key":"B70","doi-asserted-by":"publisher","first-page":"h831","DOI":"10.1136\/bmj.h831","article-title":"Standard deviation or the standard error of the mean","volume":"350","author":"Sedgwick","year":"2015","journal-title":"Bmj"},{"key":"B71","doi-asserted-by":"publisher","first-page":"e1000344","DOI":"10.1371\/journal.pbio.1000344","article-title":"Publication bias in reports of animal stroke studies leads to major overstatement of efficacy","volume":"8","author":"Sena","year":"2010","journal-title":"PLoS Biol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"3251","DOI":"10.1007\/s10571-023-01382-0","article-title":"The pathological mechanism of neuronal autophagy-lysosome dysfunction after ischemic stroke","volume":"43","author":"Shi","year":"2023","journal-title":"Cell Mol. Neurobiol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"807658","DOI":"10.3389\/fneur.2021.807658","article-title":"Adhesion of leukocytes to cerebral venules precedes neuronal cell death and is sufficient to trigger tissue damage after cerebral ischemia","volume":"12","author":"Sienel","year":"2021","journal-title":"Front. Neurol."},{"key":"B74","doi-asserted-by":"publisher","first-page":"1360014","DOI":"10.3389\/fcell.2024.1360014","article-title":"Role of autophagy in ischemic stroke: insights from animal models and preliminary evidence in the human disease","volume":"12","author":"Stanzione","year":"2024","journal-title":"Front. Cell Dev. Biol."},{"key":"B75","doi-asserted-by":"publisher","first-page":"107695","DOI":"10.1016\/j.pharmthera.2020.107695","article-title":"Natural medicine in neuroprotection for ischemic stroke: challenges and prospective","volume":"216","author":"Tao","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"B76","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1016\/s1474-4422(22)00519-1","article-title":"Thrombolysis for acute ischaemic stroke: current status and future perspectives","volume":"22","author":"Tsivgoulis","year":"2023","journal-title":"Lancet Neurol."},{"key":"B77","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1007\/s10495-019-01556-6","article-title":"Apoptosis regulation in the penumbra after ischemic stroke: expression of pro- and antiapoptotic proteins","volume":"24","author":"Uzdensky","year":"2019","journal-title":"Apoptosis"},{"key":"B78","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1258\/002367706775404426","article-title":"Experimental stroke: ischaemic lesion volume and oedema formation differ among rat strains (A comparison between wistar and sprague-dawley rats using MRI)","volume":"40","author":"Walberer","year":"2006","journal-title":"Lab. Anim."},{"key":"B79","doi-asserted-by":"publisher","first-page":"110227","DOI":"10.1016\/j.intimp.2023.110227","article-title":"A review on pharmacokinetics of sinomenine and its anti-inflammatory and immunomodulatory effects","volume":"119","author":"Wang","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"1613679","DOI":"10.3389\/fphar.2025.1613679","article-title":"Research progress in treatment of rheumatoid arthritis with sinomenine and related formulations based on different administration routes","volume":"16","author":"Wang","year":"2025","journal-title":"Front. Pharmacol."},{"key":"B81","doi-asserted-by":"publisher","first-page":"109048","DOI":"10.1016\/j.celrep.2021.109048","article-title":"Reactive astrocytes facilitate vascular repair and remodeling after stroke","volume":"35","author":"Williamson","year":"2021","journal-title":"Cell Rep."},{"key":"B82","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.3969\/j.issn.1005-9202.2010.11.032","article-title":"Effect of sinomenine on expression of Bcl-2 and caspase-3 after cerebral ischemia-reperfusion injury in diabetic rats","volume":"30","author":"Wu","year":"","journal-title":"Chin. J. Gerontol."},{"key":"B83","doi-asserted-by":"publisher","first-page":"527","DOI":"10.3969\/j.issn.1008-0805.2010.03.008","article-title":"Effect of sinomenine on the contents of MCP-1 and TNF-\u03b1 after cerebral ischemic reperfusion injury in diabetic rats","volume":"21","author":"Wu","year":"","journal-title":"Lishizhen Med. Mater Med. Res."},{"key":"B84","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.1111\/j.1476-5381.2011.01487.x","article-title":"Sinomenine protects against ischaemic brain injury: involvement of co-inhibition of acid-sensing ion channel 1a and L-type calcium channels","volume":"164","author":"Wu","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"102842","DOI":"10.1016\/j.arr.2025.102842","article-title":"Bidirectional regulation of neuronal autophagy in ischemic stroke: mechanisms and therapeutic potential","volume":"111","author":"Wu","year":"2025","journal-title":"Ageing Res. Rev."},{"key":"B86","first-page":"1","article-title":"Pharmacology of sinomenine, an anti-rheumatic alkaloid from Sinomenium acutum","volume":"30","author":"Yamasaki","year":"1976","journal-title":"Acta Med. Okayama"},{"key":"B87","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1016\/j.jstrokecerebrovasdis.2016.02.023","article-title":"Therapeutic effect analysis of sinomenine on rat cerebral ischemia-reperfusion injury","volume":"25","author":"Yang","year":"2016","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"B88","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s40478-025-01950-z","article-title":"Sinomenine alleviates neuroinflammation in chronic cerebral hypoperfusion by promoting M2 microglial polarization and inhibiting neuronal pyroptosis via exosomal miRNA-223-3p","volume":"13","author":"Yang","year":"","journal-title":"Acta Neuropathol. Commun."},{"key":"B89","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s13041-025-01244-4","article-title":"Microglia-astrocyte crosstalk following ischemic stroke","volume":"18","author":"Yang","year":"","journal-title":"Mol. Brain"},{"key":"B90","doi-asserted-by":"publisher","first-page":"1613464","DOI":"10.3389\/fphar.2025.1613464","article-title":"Cerebral ischemia-reperfusion injury: mechanisms and promising therapies","volume":"16","author":"Yang","year":"","journal-title":"Front. Pharmacol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"41","DOI":"10.3969\/j.issn.1000-484X.2019.01.008","article-title":"Sinomenine ameliorates cerebral ischemic injury of MCAO rats by inhibiting ischemia induced-abnormal autophagy","volume":"35","author":"Yin","year":"2019","journal-title":"Chin. J. Immunol."},{"key":"B92","doi-asserted-by":"publisher","first-page":"749113","DOI":"10.3389\/fcvm.2021.749113","article-title":"Sinomenine in cardio-cerebrovascular diseases: potential therapeutic effects and pharmacological evidences","volume":"8","author":"Zhang","year":"2021","journal-title":"Front. Cardiovasc Med."},{"key":"B93","doi-asserted-by":"publisher","first-page":"3525","DOI":"10.1007\/s11064-022-03697-8","article-title":"Cell death mechanisms in cerebral ischemia-reperfusion injury","volume":"47","author":"Zhang","year":"2022","journal-title":"Neurochem. Res."},{"key":"B94","doi-asserted-by":"publisher","first-page":"1581320","DOI":"10.3389\/fphar.2025.1581320","article-title":"Edaravone dexborneol protected neurological function by targeting NRF2\/ARE and NF-\u03baB\/AIM2 pathways in cerebral ischemia\/reperfusion injury","volume":"16","author":"Zhang","year":"2025","journal-title":"Front. Pharmacol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.3109\/13880209.2012.656847","article-title":"Sinomenium acutum: a review of chemistry, pharmacology, pharmacokinetics, and clinical use","volume":"50","author":"Zhao","year":"2012","journal-title":"Pharm. Biol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.3390\/biom14091181","article-title":"Multi-target and multi-phase adjunctive cerebral protection for acute ischemic stroke in the reperfusion era","volume":"14","author":"Zhao","year":"2024","journal-title":"Biomolecules"},{"key":"B97","doi-asserted-by":"publisher","first-page":"121793","DOI":"10.1016\/j.jep.2026.121793","article-title":"Botany, ethnopharmacology, phytochemistry, pharmacological activities, toxicity, quality control, clinical application and novel preparations of sinomenii caulis: an updated review","volume":"368","author":"Zhen","year":"2026","journal-title":"J. Ethnopharmacol."},{"key":"B98","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.3969\/j.issn.1008-0805.2009.07.012","article-title":"Effect of sinomenine on expression of P-selectin and ICAM-1 following cerebral ischemic reperfusion injury in diabetic rats","volume":"20","author":"Zhou","year":"","journal-title":"Lishizhen Med. Mater Med. Res."},{"key":"B99","doi-asserted-by":"publisher","first-page":"763","DOI":"10.3969\/j.issn.1004-745X.2009.05.052","article-title":"Effect of sinomenine on expression of Bcl-2 and bax following cerebral ischemic reperfusion injury in diabetic rats","volume":"18","author":"Zhou","year":"","journal-title":"JETCM"},{"key":"B100","doi-asserted-by":"publisher","first-page":"6246","DOI":"10.2174\/0109298673323738240830055548","article-title":"Research, development and pharmacological activity of sinomenine and its derivatives","volume":"32","author":"Zong","year":"2025","journal-title":"Curr. Med. Chem."},{"key":"B101","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1007\/s13311-023-01377-1","article-title":"Hemorrhagic conversion of acute ischemic stroke","volume":"20","author":"Zubair","year":"2023","journal-title":"Neurotherapeutics"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1926226\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:39:13Z","timestamp":1790055553000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1926226\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":101,"alternative-id":["10.3389\/fphar.2026.1926226"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1926226","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]},"article-number":"1926226"}}