Skip to content
2000
Volume 23, Issue 13
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

Background

L. (SO) is a traditional Chinese herbal medicine commonly used for inflammatory diseases. In ancient, SO is applied for stroke, but mechanisms have not been clear. The purpose is to investigate whether SO exerts neuroprotective effects by reducing microglia-related inflammatory injury after focal cerebral ischemia/reperfusion (I/R).

Methods

SO was extracted using 50% ethanol and quality control was performed by Waters ACQUITY-UPLC CLASS system. The focal cerebral I/R model was established in mice, neurological functions, weight loss and infarct volume was evaluated. Microglial status in penumbra was monitored by immunofluorescence staining and morphology. Mouse primary microglia was subjected to lipopolysaccharide stimulation for triggering inflammatory response, meanwhile microglia-neuron co-culture model was established . Apoptosis and pyroptosis for neurons were demonstrated using TUNEL assay, western blot and ELISA. Inflammatory cytokines were detected by qPCR and ELISA.

Results

SO treatment reduced infarct volume, improved neurological functions, lessened neuronal apoptosis and pyroptosis shown by increased Bcl-2/Bax ratio, decreased cleaved Caspase-3 and suppressed NLRP3/Caspase-1/GSDMD expression after I/R. Moreover, microglial status from pro-inflammation to anti-inflammation was characterized by morphological change and increasing percentage of CD206/Iba1 positive cells after SO treatment. Additionally, SO decreased TLR4 and nuclear-located p65 expression, suppressed IL-1β, IL-6, IL-18, and TNF-α, but increased IL-10 secretion both and .

Conclusion

SO reverses pro-inflammatory status of microglia as evidenced by suppression of TLR4/NF-κB cascade, down-regulation of pro-inflammatory cytokines and up-regulation of anti-inflammatory cytokines, which contributes to its neuroprotective against neuronal pyroptosis and apoptosis after ischemic stroke.

Loading

Article metrics loading...

/content/journals/cn/10.2174/011570159X349127241214045611
2025-04-25
2025-10-28
Loading full text...

Full text loading...

References

  1. SainiV. GuadaL. YavagalD.R. Global epidemiology of stroke and access to acute Ischemic Stroke Interventions.Neurology202197Suppl. 2S6S1610.1212/WNL.0000000000012781 34785599
    [Google Scholar]
  2. EndresM. MoroM.A. NolteC.H. DamesC. BuckwalterM.S. MeiselA. Immune pathways in etiology, acute phase, and chronic sequelae of Ischemic Stroke.Circ. Res.202213081167118610.1161/CIRCRESAHA.121.319994 35420915
    [Google Scholar]
  3. QinC. ZhouL.Q. MaX.T. HuZ.W. YangS. ChenM. BoscoD.B. WuL.J. TianD.S. Dual functions of microglia in ischemic stroke.Neurosci. Bull.201935592193310.1007/s12264‑019‑00388‑3 31062335
    [Google Scholar]
  4. LuoL. LiuM. FanY. ZhangJ. LiuL. LiY. ZhangQ. XieH. JiangC. WuJ. XiaoX. WuY. Intermittent theta-burst stimulation improves motor function by inhibiting neuronal pyroptosis and regulating microglial polarization via TLR4/NFκB/] NLRP3 signaling pathway in cerebral ischemic mice.J. Neuroinflammation202219114110.1186/s12974‑022‑02501‑2 35690810
    [Google Scholar]
  5. VarS.R. ShettyA.V. GrandeA.W. LowW.C. CheeranM.C. Microglia and macrophages in neuroprotection, neurogenesis, and emerging therapies for stroke.Cells20211012355510.3390/cells10123555 34944064
    [Google Scholar]
  6. AnttilaJ.E. WhitakerK.W. WiresE.S. HarveyB.K. AiravaaraM. Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors.Prog. Neuropsychopharmacol. Biol. Psych.201779Pt A31410.1016/j.pnpbp.2016.07.003
    [Google Scholar]
  7. ParadaE. CasasA.I. Palomino-AntolinA. Gómez-RangelV. Rubio-NavarroA. Farré-AlinsV. Narros-FernandezP. Guerrero-HueM. MorenoJ.A. RosaJ.M. RodaJ.M. Hernández-GarcíaB.J. EgeaJ. Early toll‐like receptor 4 blockade reduces ROS and inflammation triggered by microglial pro-inflammatory phenotype in rodent and human brain ischaemia models.Br. J. Pharmacol.2019176152764277910.1111/bph.14703 31074003
    [Google Scholar]
  8. PanN. LuL. LiM. WangG. SunF. SunH. WenX. ChengJ. ChenJ. PangJ. LiuJ. GuanY. ZhaoL. ChenW. WangG. Xyloketal B alleviates cerebral infarction and neurologic deficits in a mouse stroke model by suppressing the ROS/TLR4/] NF-κB inflammatory signaling pathway.Acta Pharmacol. Sin.20173891236124710.1038/aps.2017.22 28552908
    [Google Scholar]
  9. CaiQ. ZhaoC. XuY. LinH. JiaB. HuangB. LinS. ChenD. JiaP. WangM. LinW. ZhangL. ChuJ. PengJ. Qingda granule alleviates cerebral ischemia/reperfusion injury by inhibiting TLR4/NF-κB/NLRP3 signaling in microglia.J. Ethnopharmacol.202432411771210.1016/j.jep.2024.117712 38184025
    [Google Scholar]
  10. WangN. LiuY. JiaC. GaoC. ZhengT. WuM. ZhangQ. ZhaoX. LiZ. ChenJ. WuC. Machine learning enables discovery of Gentianine targeting TLR4/NF-κB pathway to repair ischemic stroke injury.Pharmacol. Res.202117310591310.1016/j.phrs.2021.105913 34563661
    [Google Scholar]
  11. AlishahiM. FarzanehM. GhaedrahmatiF. NejabatdoustA. SarkakiA. KhoshnamS.E. NLRP3 inflammasome in ischemic stroke: As possible therapeutic target.Int. J. Stroke201914657459110.1177/1747493019841242 30940045
    [Google Scholar]
  12. XuQ. ZhaoB. YeY. LiY. ZhangY. XiongX. GuL. Relevant mediators involved in and therapies targeting the inflammatory response induced by activation of the NLRP3 inflammasome in ischemic stroke.J. Neuroinflammation202118112310.1186/s12974‑021‑02137‑8 34059091
    [Google Scholar]
  13. SunY. MaJ. LiD. LiP. ZhouX. LiY. HeZ. QinL. LiangL. LuoX. Interleukin-10 inhibits interleukin-1β production and inflammasome activation of microglia in epileptic seizures.J. Neuroinflammation20191616610.1186/s12974‑019‑1452‑1 30922332
    [Google Scholar]
  14. LiuZ. HermannD.M. DzyubenkoE. CaoG. CaoX. Editorial: Modulating microglia to enhance neuroplasticity for restoring brain function after stroke.Front. Cell. Neurosci.202317123243710.3389/fncel.2023.1232437 37426552
    [Google Scholar]
  15. TuoQ. ZhangS. LeiP. Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications.Med. Res. Rev.202242125930510.1002/med.21817 33957000
    [Google Scholar]
  16. LiZ. XiaoG. WangH. HeS. ZhuY. A preparation of Ginkgo biloba L. leaves extract inhibits the apoptosis of hippocampal neurons in post-stroke mice via regulating the expression of Bax/Bcl-2 and Caspase-3.J. Ethnopharmacol.202128011448110.1016/j.jep.2021.114481 34343651
    [Google Scholar]
  17. XianM. CaiJ. ZhengK. LiuQ. LiuY. LinH. LiangS. WangS. Aloe-emodin prevents nerve injury and neuroinflammation caused by ischemic stroke via the PI3K/AKT/mTOR and NF-κB pathway.Food Funct.202112178056806710.1039/D1FO01144H 34286782
    [Google Scholar]
  18. PuigB. BrennaS. MagnusT. Molecular communication of a dying neuron in stroke.Int. J. Mol. Sci.2018199283410.3390/ijms19092834 30235837
    [Google Scholar]
  19. MaoR. ZongN. HuY. ChenY. XuY. Neuronal death mechanisms and therapeutic strategy in ischemic stroke.Neurosci. Bull.202238101229124710.1007/s12264‑022‑00859‑0 35513682
    [Google Scholar]
  20. XiaoB. LiJ. QiaoZ. YangS. KwanH.Y. JiangT. ZhangM. XiaQ. LiuZ. SuT. Therapeutic effects of Siegesbeckia orientalis L. and its active compound luteolin in Rheumatoid arthritis: network pharmacology, molecular docking and experimental validation.J. Ethnopharmacol.202331711685210.1016/j.jep.2023.116852 37390879
    [Google Scholar]
  21. GuoH. ZhangY. ChengB.C. FuX. ZhuP. ChenJ. ChanY. YinC. WangY. HossenM. AminA. TseA.K. YuZ. An ethanolic extract of the aerial part of Siegesbeckia orientalis L. inhibits the production of inflammatory mediators regulated by AP-1, NF-κB and IRF3 in LPS-stimulated RAW 264.7 cells.Biosci. Trends201812333033710.5582/bst.2018.01103 30012916
    [Google Scholar]
  22. NguyenT.D. ThuongP.T. HwangI.H. HoangT.K.H. NguyenM.K. NguyenH.A. NaM. Anti-hyperuricemic, anti-inflammatory and analgesic effects of Siegesbeckia orientalis L. Resulting from the fraction with high phenolic content.BMC Complement. Altern. Med.201717119110.1186/s12906‑017‑1698‑z 28376775
    [Google Scholar]
  23. ChuJ.M.T. XiongW. LinghuK.G. LiuY. ZhangY. ZhaoG.D. IrwinM.G. WongG.T.C. YuH. Siegesbeckia orientalis l. extract attenuates postoperative cognitive dysfunction, systemic inflammation, and neuroinflammation.Exp. Neurobiol.201827656457310.5607/en.2018.27.6.564 30636906
    [Google Scholar]
  24. LinghuK.G. XiongS.H. ZhaoG.D. ZhangT. XiongW. ZhaoM. ShenX.C. XuW. BianZ. WangY. YuH. Sigesbeckia orientalis L. extract alleviated the collagen type ii–induced arthritis through inhibiting multi-target-mediated synovial hyperplasia and inflammation.Front. Pharmacol.20201154791310.3389/fphar.2020.547913 32982752
    [Google Scholar]
  25. ChuJ.M.T. AbulimitiA. WongB.S.H. ZhaoG.D. XiongS.H. ZhaoM.M. WangY. ChenY. WangJ. ZhangY. ChangR.C.C. YuH. WongG.T.C. Sigesbeckia orientalis l. derived active fraction ameliorates perioperative neurocognitive disorders through alleviating hippocampal neuroinflammation.Front. Pharmacol.20221384663110.3389/fphar.2022.846631 35370714
    [Google Scholar]
  26. ZhouZ. ZhangY. HanF. ChenZ. ZhengY. Umbelliferone protects against cerebral ischemic injury through selective autophagy of mitochondria.Neurochem. Int.202316510552010.1016/j.neuint.2023.105520 36933866
    [Google Scholar]
  27. HanQ.Y. ZhangH. ZhangX. HeD.S. WangS.W. CaoX. DaiY.T. XuY. HanL.J. DL‐3‐n‐butylphthalide preserves white matter integrity and alleviates cognitive impairment in mice with chronic cerebral hypoperfusion.CNS Neurosci. Ther.20192591042105310.1111/cns.13189 31334611
    [Google Scholar]
  28. ManiskasM.E. RobertsJ.M. TruemanR. LearoydA.E. GormanA. FraserJ.F. BixG.J. Intra-arterial nitroglycerin as directed acute treatment in experimental ischemic stroke.J. Neurointerv. Surg.2018101293310.1136/neurintsurg‑2016‑012793 28031354
    [Google Scholar]
  29. AlamriF.F. ShoyaibA.A. BiggersA. JayaramanS. GuindonJ. KaramyanV.T. Applicability of the grip strength and automated von Frey tactile sensitivity tests in the mouse photothrombotic model of stroke.Behav. Brain Res.201833625025510.1016/j.bbr.2017.09.008 28893552
    [Google Scholar]
  30. LiuP. LiH. DongM. GuX. XuS. XiaS. BaoX. XuY. CaoX. Infiltrating myeloid cell-derived properdin markedly promotes microglia-mediated neuroinflammation after ischemic stroke.J. Neuroinflammation202320126010.1186/s12974‑023‑02946‑z 37951917
    [Google Scholar]
  31. ZhangZ. QinP. DengY. MaZ. GuoH. GuoH. HouY. WangS. ZouW. SunY. MaY. HouW. The novel estrogenic receptor GPR30 alleviates ischemic injury by inhibiting TLR4-mediated microglial inflammation.J. Neuroinflammation201815120610.1186/s12974‑018‑1246‑x 30001721
    [Google Scholar]
  32. YangC. GongS. ChenX. WangM. ZhangL. ZhangL. HuC. Analgecine regulates microglia polarization in ischemic stroke by inhibiting NF-κB through the TLR4 MyD88 pathway.Int. Immunopharmacol.20219910793010.1016/j.intimp.2021.107930 34229178
    [Google Scholar]
  33. LingY. JinL. MaQ. HuangY. YangQ. ChenM. ShouQ. Salvianolic acid A alleviated inflammatory response mediated by microglia through inhibiting the activation of TLR2/4 in acute cerebral ischemia-reperfusion.Phytomedicine20218715356910.1016/j.phymed.2021.153569 33985878
    [Google Scholar]
  34. LiuM. XuZ. WangL. ZhangL. LiuY. CaoJ. FuQ. LiuY. LiH. LouJ. HouW. MiW. MaY. Cottonseed oil alleviates ischemic stroke injury by inhibiting the inflammatory activation of microglia and astrocyte.J. Neuroinflammation202017127010.1186/s12974‑020‑01946‑7 32917229
    [Google Scholar]
  35. HuaF. TangH. WangJ. PruntyM.C. HuaX. SayeedI. SteinD.G. TAK-242, an antagonist for Toll-like receptor 4, protects against acute cerebral ischemia/reperfusion injury in mice.J. Cereb. Blood Flow Metab.201535453654210.1038/jcbfm.2014.240 25586141
    [Google Scholar]
  36. ChenW.F. ShihY.H. LiuH.C. ChengC.I. ChangC.I. ChenC.Y. LinI.P. LinM.Y. LeeC.H. 6-methoxyflavone suppresses neuroinflammation in lipopolysaccharide- stimulated microglia through the inhibition of TLR4/MyD88/p38 MAPK/NF-κB dependent pathways and the activation of HO-1/NQO-1 signaling.Phytomedicine20229915402510.1016/j.phymed.2022.154025 35272244
    [Google Scholar]
  37. GaoL. DongQ. SongZ. ShenF. ShiJ. LiY. NLRP3 inflammasome: A promising target in ischemic stroke.Inflamm. Res.2017661172410.1007/s00011‑016‑0981‑7 27576327
    [Google Scholar]
  38. HuJ. ZengC. WeiJ. DuanF. LiuS. ZhaoY. TanH. The combination of Panax ginseng and Angelica sinensis alleviates ischemia brain injury by suppressing NLRP3 inflammasome activation and microglial pyroptosis.Phytomedicine20207615325110.1016/j.phymed.2020.153251 32531700
    [Google Scholar]
  39. XuP. HongY. XieY. YuanK. LiJ. SunR. ZhangX. ShiX. LiR. WuJ. LiuX. HuW. SunW. TREM-1 exacerbates neuroinflammatory injury via NLRP3 inflammasome-mediated pyroptosis in experimental subarachnoid hemorrhage.Transl. Stroke Res.202112464365910.1007/s12975‑020‑00840‑x 32862402
    [Google Scholar]
  40. RanY. SuW. GaoF. DingZ. YangS. YeL. ChenX. TianG. XiJ. LiuZ. Curcumin ameliorates white matter injury after ischemic stroke by inhibiting microglia/macrophage pyroptosis through NF‐κ B suppression and NLRP3 inflammasome inhibition.Oxid. Med. Cell. Longev.202120211155212710.1155/2021/1552127 34630845
    [Google Scholar]
  41. LiQ. DaiZ. CaoY. WangL. Caspase-1 inhibition mediates neuroprotection in experimental stroke by polarizing M2 microglia/] macrophage and suppressing NF-κB activation.Biochem. Biophys. Res. Commun.2019513247948510.1016/j.bbrc.2019.03.202 30979498
    [Google Scholar]
  42. QiJ.P. WuA.P. WangD.S. WangL.F. LiS.X. XuF.L. Correlation between neuronal injury and Caspase-3 after focal ischemia in human hippocampus.Chin. Med. J. (Engl.)20041171015071512 15498374
    [Google Scholar]
  43. BiW. BaoK. ZhouX. DengY. LiX. ZhangJ. LanX. ZhaoJ. LuD. XuY. CenY. CaoR. XuM. ZhongW. ZhuL. PSMC5 regulates microglial polarization and activation in LPS-induced cognitive deficits and motor impairments by interacting with TLR4.J. Neuroinflammation202320127710.1186/s12974‑023‑02904‑9 38001534
    [Google Scholar]
  44. XuS.Y. JiaJ.Q. SunM. BaoX.Y. XiaS.N. ShuS. LiuP. JiS. YeL. CaoX. XuY. QHRD106 ameliorates ischemic stroke injury as a long-acting tissue kallikrein preparation.iScience202326710726810.1016/j.isci.2023.107268 37496671
    [Google Scholar]
  45. CalabreseV. MancusoC. CalvaniM. RizzarelliE. ButterfieldD.A. Giuffrida StellaA.M. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity.Nat. Rev. Neurosci.200781076677510.1038/nrn2214 17882254
    [Google Scholar]
  46. CalabreseV. CorneliusC. Dinkova-KostovaA.T. CalabreseE.J. MattsonM.P. Cellular stress responses, the hormesis paradigm, and vitagenes: Novel targets for therapeutic intervention in neurodegenerative disorders.Antioxid. Redox Signal.201013111763181110.1089/ars.2009.3074 20446769
    [Google Scholar]
  47. Di RosaG. BrunettiG. ScutoM. Trovato SalinaroA. CalabreseE.J. CreaR. Schmitz-LinneweberC. CalabreseV. SaulN. Healthspan enhancement by olive polyphenols in C. elegans wild type and Parkinson’s Models.Int. J. Mol. Sci.20202111389310.3390/ijms21113893 32486023
    [Google Scholar]
/content/journals/cn/10.2174/011570159X349127241214045611
Loading
/content/journals/cn/10.2174/011570159X349127241214045611
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test