[go: up one dir, main page]
Skip to main content

Advertisement

SpringerLink
Log in

Baicalin Attenuates Blood-Brain Barrier Disruption and Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke Rats with Delayed t-PA Treatment: Involvement of ONOO−-MMP-9 Pathway

  • Original Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Tissue plasminogen activator (t-PA) has a restrictive therapeutic window within 4.5 h after ischemic stroke with the risk of hemorrhagic transformation (HT) and neurotoxicity when it is used beyond the time window. In the present study, we tested the hypothesis that baicalin, an active compound of medicinal plant, could attenuate HT in cerebral ischemia stroke with delayed t-PA treatment. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 4.5 h and then continuously received t-PA infusion (10 mg/kg) for 0.5 h and followed by 19-h reperfusion. Baicalin (50, 100, 150 mg/kg) was administrated via femoral vein at 4.5 h after MCAO cerebral ischemia. Delayed t-PA infusion significantly increased the mortality rate, induced HT, blood-brain barrier (BBB) damage, and apoptotic cell death in the ischemic brains and exacerbated neurological outcomes in cerebral ischemia-reperfusion rats at 24 h after MCAO cerebral ischemia. Co-treatment of baicalin significantly reduced the mortality rates, ameliorated the t-PA-mediated BBB disruption and HT. Furthermore, baicalin showed to directly scavenge peroxynitrite and inhibit MMP-9 expression and activity in the ischemic brains with the delayed t-PA treatment. Baicalin had no effect on the t-PA fibrinolytic function indicated by t-PA activity assay. Taken together, baicalin could attenuate t-PA-mediated HT and improve the outcomes of ischemic stroke treatment possibly via inhibiting peroxynitrite-mediated MMP-9 activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Heron M, Statistics V. Leading causes for 2007. National vital statistics reports Hyattsville, MD: National Center for Health Statistics 2011.

  2. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al. Heart disease and stroke statistics—2011 update. Circulation. 2011;123(4):e18–e209. https://doi.org/10.1161/CIR.0b013e3182009701.

    Article  PubMed  Google Scholar 

  3. Cheng NT, Kim AS. Intravenous thrombolysis for acute ischemic stroke within 3 hours versus between 3 and 4.5 hours of symptom onset. Neurohospitalist. 2015;5(3):101–9. https://doi.org/10.1177/1941874415583116.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kanazawa M, Takahashi T, Nishizawa M, Shimohata T. Therapeutic strategies to attenuate hemorrhagic transformation after tissue plasminogen activator treatment for acute ischemic stroke. J Atheroscler Thromb. 2017;24(3):240–53. https://doi.org/10.5551/jat.RV16006.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lees KR, Bluhmki E, Von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375(9727):1695–703. https://doi.org/10.1016/S0140-6736(10)60491-6.

    Article  PubMed  CAS  Google Scholar 

  6. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Executive summary: heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133(4):447–54. https://doi.org/10.1161/CIR.0000000000000366.

    Article  PubMed  Google Scholar 

  7. Bang OY, Buck BH, Saver JL, Alger JR, Yoon SR, Starkman S, et al. Prediction of hemorrhagic transformation after recanalization therapy using T2*-permeability magnetic resonance imaging. Ann Neurol. 2007;62(2):170–6. https://doi.org/10.1002/ana.21174.

    Article  PubMed  Google Scholar 

  8. Hamann GF, del Zoppo GJ, von Kummer R. Hemorrhagic transformation of cerebral infarction–possible mechanisms. Thromb Haemost. 1999;82(1):92–4.

    PubMed  Google Scholar 

  9. Hemorrhagic PEPF. MRI Detection of early blood-brain barrier disruption. Brain. 2008;39:1025–8.

    Google Scholar 

  10. Chen H, Guan B, Shen J. Targeting ONOO-/HMGB1/MMP-9 signaling cascades: potential for drug development from Chinese Medicine to attenuate ischemic brain injury and hemorrhagic transformation induced by thrombolytic treatment. Integr Med Int. 2016;3(1–2):32–52. https://doi.org/10.1159/000442468.

    Article  Google Scholar 

  11. Chen HS, Qi SH, Shen JG. One-compound-multi-target: combination prospect of natural compounds with thrombolytic therapy in acute ischemic stroke. Curr Neuropharmacol. 2017;15(1):134–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Jickling GC, Liu D, Stamova B, Ander BP, Zhan X, Lu A, et al. Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab. 2014;34(2):185–99. https://doi.org/10.1038/jcbfm.2013.203.

    Article  PubMed  CAS  Google Scholar 

  13. Liu KJ, Rosenberg GA. Matrix metalloproteinases and free radicals in cerebral ischemia. Free Radic Biol Med. 2005;39(1):71–80.

    Article  CAS  Google Scholar 

  14. Pun PB, Lu J, Moochhala S. Involvement of ROS in BBB dysfunction. Free Radic Res. 2009;43(4):348–64. https://doi.org/10.1080/10715760902751902.

    Article  PubMed  CAS  Google Scholar 

  15. Yamashita T, Abe K. Therapeutic approaches to vascular protection in ischemic stroke. Acta Med Okayama. 2011;65(4):219–23. https://doi.org/10.18926/AMO/46846.

    Article  PubMed  CAS  Google Scholar 

  16. Gu Y, Dee CM, Shen J. Interaction of free radicals, matrix metalloproteinases and caveolin-1 impacts blood-brain barrier permeability. Front Biosci (Schol Ed). 2011;3(3):1216–31.

    Article  Google Scholar 

  17. Shen J, Ma S, Chan P, Lee W, Fung PC, Cheung RT, et al. Nitric oxide down-regulates caveolin-1 expression in rat brains during focal cerebral ischemia and reperfusion injury. J Neurochem. 2006;96(4):1078–89. https://doi.org/10.1111/j.1471-4159.2005.03589.x.

    Article  PubMed  CAS  Google Scholar 

  18. Gu Y, Zheng G, Xu M, Li Y, Chen X, Zhu W, et al. Caveolin-1 regulates nitric oxide-mediated matrix metalloproteinases activity and blood–brain barrier permeability in focal cerebral ischemia and reperfusion injury. J Neurochem. 2012;120(1):147–56. https://doi.org/10.1111/j.1471-4159.2011.07542.x.

    Article  PubMed  CAS  Google Scholar 

  19. Lakhan SE, Kirchgessner A, Tepper D, Leonard A. Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke. Front Neurol. 2013;4:32. https://doi.org/10.3389/fneur.2013.00032.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Groves JT. Peroxynitrite: reactive, invasive and enigmatic. Curr Opin Chem Biol. 1999;3(2):226–35. https://doi.org/10.1016/S1367-5931(99)80036-2.

    Article  PubMed  CAS  Google Scholar 

  21. Kuhn DM, Sakowski SA, Sadidi M, Geddes TJ. Nitrotyrosine as a marker for peroxynitrite-induced neurotoxicity: the beginning or the end of the end of dopamine neurons? J Neurochem. 2004;89(3):529–36. https://doi.org/10.1111/j.1471-4159.2004.02346.x.

    Article  PubMed  CAS  Google Scholar 

  22. Takizawa S, Fukuyama N, Hirabayashi H, Nakazawa H, Shinohara Y. Dynamics of nitrotyrosine formation and decay in rat brain during focal ischemia-reperfusion. J Cereb Blood Flow Metab. 1999;19(6):667–72. https://doi.org/10.1097/00004647-199906000-00010.

    Article  PubMed  CAS  Google Scholar 

  23. Takizawa S, Hirabayashi H, Fukuyama N, Nakazawa H, Shinohara Y. Peroxynitrite production in cerebral ischemia. Rinsho Shinkeigaku. 1999;39(12):1295–7.

    PubMed  CAS  Google Scholar 

  24. Suzuki M, Tabuchi M, Ikeda M, Tomita T. Concurrent formation of peroxynitrite with the expression of inducible nitric oxide synthase in the brain during middle cerebral artery occlusion and reperfusion in rats. Brain Res. 2002;951(1):113–20. https://doi.org/10.1016/S0006-8993(02)03145-1.

    Article  PubMed  CAS  Google Scholar 

  25. Chen HS, Chen XM, Feng JH, Liu KJ, Qi SH, Shen JG. Peroxynitrite decomposition catalyst reduces delayed thrombolysis-induced hemorrhagic transformation in ischemia-reperfused rat brains. CNS Neurosci Ther. 2015;21(7):585–90. https://doi.org/10.1111/cns.12406.

    Article  PubMed  CAS  Google Scholar 

  26. Romanos E, Planas AM, Amaro S, Chamorro Á. Uric acid reduces brain damage and improves the benefits of rt-PA in a rat model of thromboembolic stroke. J Cereb Blood Flow Metab. 2007;27(1):14–20. https://doi.org/10.1038/sj.jcbfm.9600312.

    Article  PubMed  CAS  Google Scholar 

  27. Amaro S, Urra X, Gomez-Choco M, Obach V, Cervera A, Vargas M, et al. Uric acid levels are relevant in patients with stroke treated with thrombolysis. Stroke. 2011;42(1 Suppl):S28–32. https://doi.org/10.1161/STROKEAHA.110.596528.

    Article  PubMed  CAS  Google Scholar 

  28. Lee S-H, Heo SH, Kim J-H, Lee D, Lee JS, Kim YS, et al. Effects of uric acid levels on outcome in severe ischemic stroke patients treated with intravenous recombinant tissue plasminogen activator. Eur Neurol. 2014;71(3–4):132–9. https://doi.org/10.1159/000355020.

    Article  PubMed  CAS  Google Scholar 

  29. Liu X, Liu M, Chen M, Ge Q-M, Pan S-M. Serum uric acid is neuroprotective in Chinese patients with acute ischemic stroke treated with intravenous recombinant tissue plasminogen activator. J Stroke Cerebrovasc Dis. 2015;24(5):1080–6. https://doi.org/10.1016/j.jstrokecerebrovasdis.2015.01.011.

    Article  PubMed  Google Scholar 

  30. Chuanyun L, Yanshu P, Xu J. Effects of Huangqin (dried root of Scutellaria baicalensis) and Zhizi (dried fruit of Gardenia jasminoides) used in combination on ischemic cascade reaction in the rat model of focal cerebral ischemia and reperfusion. J Beijing Univ Tradit Chin Med. 2002;25(6):31–3.

    Google Scholar 

  31. Singh DP, Chopra K. Flavocoxid, dual inhibitor of cyclooxygenase-2 and 5-lipoxygenase, exhibits neuroprotection in rat model of ischaemic stroke. Pharmacol Biochem Behav. 2014;120:33–42. https://doi.org/10.1016/j.pbb.2014.02.006.

    Article  PubMed  CAS  Google Scholar 

  32. Tu X-K, Yang W-Z, Liang R-S, Shi S-S, Chen J-P, Chen C-M, et al. Effect of baicalin on matrix metalloproteinase-9 expression and blood–brain barrier permeability following focal cerebral ischemia in rats. Neurochem Res. 2011;36(11):2022.

    Article  PubMed  CAS  Google Scholar 

  33. Zhu H, Wang Z, Xing Y, Gao Y, Ma T, Lou L, et al. Baicalin reduces the permeability of the blood–brain barrier during hypoxia in vitro by increasing the expression of tight junction proteins in brain microvascular endothelial cells. J Ethnopharmacol. 2012;141(2):714–20. https://doi.org/10.1016/j.jep.2011.08.063.

    Article  PubMed  CAS  Google Scholar 

  34. Xu M, Chen X, Gu Y, Peng T, Yang D, Chang RC-C, et al. Baicalin can scavenge peroxynitrite and ameliorate endogenous peroxynitrite-mediated neurotoxicity in cerebral ischemia-reperfusion injury. J Ethnopharmacol. 2013;150(1):116–24. https://doi.org/10.1016/j.jep.2013.08.020.

    Article  PubMed  CAS  Google Scholar 

  35. Liu W, Hendren J, Qin X-J, Liu KJ. Normobaric hyperoxia reduces the neurovascular complications associated with delayed tissue plasminogen activator treatment in a rat model of focal cerebral ischemia. Stroke. 2009;40(7):2526–31. https://doi.org/10.1161/STROKEAHA.108.545483.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Korninger C, Collen D. Studies on the specific fibrinolytic effect of human extrinsic (tissue-type) plasminogen activator in human blood and in various animal species in vitro. Thromb Haemost. 1981;46(2):561–5.

    Article  PubMed  CAS  Google Scholar 

  37. Xue X, Qu X-J, Yang Y, Sheng X-H, Cheng F, Jiang E-N, et al. Baicalin attenuates focal cerebral ischemic reperfusion injury through inhibition of nuclear factor κB p65 activation. Biochem Biophys Res Commun. 2010;403(3):398–404. https://doi.org/10.1016/j.bbrc.2010.11.042.

    Article  PubMed  CAS  Google Scholar 

  38. Qiu J, Niu X, Dong J, Wang D, Wang J, Li H, et al. Baicalin protects mice from Staphylococcus aureus pneumonia via inhibition of the cytolytic activity of α-hemolysin. J Infect Dis. 2012;206(2):292–301. https://doi.org/10.1093/infdis/jis336.

    Article  PubMed  CAS  Google Scholar 

  39. Thiyagarajan M, Kaul CL, Sharma SS. Neuroprotective efficacy and therapeutic time window of peroxynitrite decomposition catalysts in focal cerebral ischemia in rats. Br J Pharmacol. 2004;142(5):899–911. https://doi.org/10.1038/sj.bjp.0705811.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Fagan SC, Lapchak PA, Liebeskind DS, Ishrat T, Ergul A. Recommendations for preclinical research in hemorrhagic transformation. Transl Stroke Res. 2013;4(3):322–7. https://doi.org/10.1007/s12975-012-0222-5.

    Article  PubMed  Google Scholar 

  41. Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE, et al. Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke. 2001;32(11):2682–8. https://doi.org/10.1161/hs1101.098367.

    Article  PubMed  CAS  Google Scholar 

  42. Naderi V, Khaksari M, Abbasi R, Maghool F. Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors α and β following traumatic brain injury. Iran J Basic Med Sci. 2015;18(2):138–44.

    PubMed  PubMed Central  Google Scholar 

  43. Liu W, Sood R, Chen Q, Sakoglu U, Hendren J, Çetin Ö, et al. Normobaric hyperoxia inhibits NADPH oxidase-mediated matrix metalloproteinase-9 induction in cerebral microvessels in experimental stroke. J Neurochem. 2008;107(5):1196–205. https://doi.org/10.1111/j.1471-4159.2008.05664.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. García-Yébenes I, Sobrado M, Zarruk JG, Castellanos M, de la Ossa NP, Dávalos A, et al. A mouse model of hemorrhagic transformation by delayed tissue plasminogen activator administration after in situ thromboembolic stroke. Stroke. 2011;42(1):196–203. https://doi.org/10.1161/STROKEAHA.110.600452.

    Article  PubMed  CAS  Google Scholar 

  45. Gao L, Chen X, Peng T, Yang D, Wang Q, Lv Z, et al. Caveolin-1 protects against hepatic ischemia/reperfusion injury through ameliorating peroxynitrite-mediated cell death. Free Radic Biol Med. 2016;95:209–15. https://doi.org/10.1016/j.freeradbiomed.2016.03.023.

    Article  PubMed  CAS  Google Scholar 

  46. Peng T, Chen X, Gao L, Zhang T, Wang W, Shen J, et al. A rationally designed rhodamine-based fluorescent probe for molecular imaging of peroxynitrite in live cells and tissues. Chem Sci. 2016;7(8):5407–13. https://doi.org/10.1039/C6SC00012F.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Watanabe T, Okuda Y, Nonoguchi N, Zhao MZ, Kajimoto Y, Furutama D, et al. Postischemic intraventricular administration of FGF-2 expressing adenoviral vectors improves neurologic outcome and reduces infarct volume after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2004;24(11):1205–13. https://doi.org/10.1097/01.WCB.0000136525.75839.41.

    Article  PubMed  CAS  Google Scholar 

  48. Ding R, Feng L, He L, Chen Y, Wen P, Fu Z, et al. Peroxynitrite decomposition catalyst prevents matrix metalloproteinase-9 activation and neurovascular injury after hemoglobin injection into the caudate nucleus of rats. Neuroscience. 2015;297:182–93. https://doi.org/10.1016/j.neuroscience.2015.03.065.

    Article  PubMed  CAS  Google Scholar 

  49. Suofu Y, Clark J, Broderick J, Wagner KR, Tomsick T, Sa Y, et al. Peroxynitrite decomposition catalyst prevents matrix metalloproteinase activation and neurovascular injury after prolonged cerebral ischemia in rats. J Neurochem. 2010;115(5):1266–76. https://doi.org/10.1111/j.1471-4159.2010.07026.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Wang P, Cao Y, Yu J, Liu R, Bai B, Qi H, et al. Baicalin alleviates ischemia-induced memory impairment by inhibiting the phosphorylation of CaMKII in hippocampus. Brain Res. 2016;1642:95–103. https://doi.org/10.1016/j.brainres.2016.03.019.

    Article  PubMed  CAS  Google Scholar 

  51. Rosenberg GA, Yang Y. Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus. 2007;22(5):1–9. https://doi.org/10.3171/foc.2007.22.5.5.

    Article  Google Scholar 

  52. Yang Y, Rosenberg GA. MMP-mediated disruption of claudin-5 in the blood–brain barrier of rat brain after cerebral ischemia. Methods Mol Biol. 2011;762:333–45. https://doi.org/10.1007/978-1-61779-185-7_24.

  53. Castellanos M, Sobrino T, Millán M, García M, Arenillas J, Nombela F, et al. Serum cellular fibronectin and matrix metalloproteinase-9 as screening biomarkers for the prediction of parenchymal hematoma after thrombolytic therapy in acute ischemic stroke. Stroke. 2007;38(6):1855–9. https://doi.org/10.1161/STROKEAHA.106.481556.

    Article  PubMed  CAS  Google Scholar 

  54. Tang G, Yang G-Y. Aquaporin-4: a potential therapeutic target for cerebral edema. Int J Mol Sci. 2016;17(10):1413. https://doi.org/10.3390/ijms17101413.

    Article  PubMed Central  CAS  Google Scholar 

  55. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87(1):315–424. https://doi.org/10.1152/physrev.00029.2006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Virág L, Szabo E, Gergely P, Szabo C. Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. Toxicol Lett. 2003;140:113–24.

    Article  PubMed  CAS  Google Scholar 

  57. Zheng W-X, Cao X-L, Wang F, Wang J, Ying T-Z, Xiao W, et al. Baicalin inhibiting cerebral ischemia/hypoxia-induced neuronal apoptosis via MRTF-A-mediated transactivity. Eur J Pharmacol. 2015;767:201–10. https://doi.org/10.1016/j.ejphar.2015.10.027.

    Article  PubMed  CAS  Google Scholar 

  58. Zheng W-X, Wang F, Cao X-L, Pan H-Y, Liu X-Y, Hu X-M, et al. Baicalin protects PC-12 cells from oxidative stress induced by hydrogen peroxide via anti-apoptotic effects. Brain Inj. 2014;28(2):227–34. https://doi.org/10.3109/02699052.2013.860469.

    Article  PubMed  Google Scholar 

  59. Hou J, Wang J, Zhang P, Li D, Zhang C, Zhao H, et al. Baicalin attenuates proinflammatory cytokine production in oxygen–glucose deprived challenged rat microglial cells by inhibiting TLR4 signaling pathway. Int Immunopharmacol. 2012;14(4):749–57. https://doi.org/10.1016/j.intimp.2012.10.013.

    Article  PubMed  CAS  Google Scholar 

  60. Shi X, Fu Y, Zhang S, Ding H, Chen J. Baicalin attenuates subarachnoid hemorrhagic brain injury by modulating blood-brain barrier disruption, inflammation, and oxidative damage in mice. Oxidative Med Cell Longev. 2017;2017:1–9. https://doi.org/10.1155/2017/1401790.

    Article  Google Scholar 

  61. Tu X-K, Yang W-Z, Shi S-S, Chen Y, Wang C-H, Chen C-M, et al. Baicalin inhibits TLR2/4 signaling pathway in rat brain following permanent cerebral ischemia. Inflammation. 2011;34(5):463–70.

    Article  PubMed  CAS  Google Scholar 

  62. Bai Y, Xu G, Xu M, Li Q, Qin X. Inhibition of Src phosphorylation reduces damage to the blood-brain barrier following transient focal cerebral ischemia in rats. Int J Mol Med. 2014;34(6):1473–82. https://doi.org/10.3892/ijmm.2014.1946.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Cui L, Zhang X, Yang R, Liu L, Wang L, Li M, et al. Baicalein is neuroprotective in rat MCAO model: role of 12/15-lipoxygenase, mitogen-activated protein kinase and cytosolic phospholipase A2. Pharmacol Biochem Behav. 2010;96(4):469–75. https://doi.org/10.1016/j.pbb.2010.07.007.

    Article  PubMed  CAS  Google Scholar 

  64. Yigitkanli K, Zheng Y, Pekcec A, Lo EH, van Leyen K. Increased 12/15-lipoxygenase leads to widespread brain injury following global cerebral ischemia. Transl Stroke Res. 2017;8(2):194–202. https://doi.org/10.1007/s12975-016-0509-z.

    Article  PubMed  CAS  Google Scholar 

  65. van Leyen K, Kim HY, Lee S-R, Jin G, Arai K, Lo EH. Baicalein and 12/15-lipoxygenase in the ischemic brain. Stroke. 2006;37(12):3014–8. https://doi.org/10.1161/01.STR.0000249004.25444.a5.

    Article  PubMed  CAS  Google Scholar 

  66. Jin G, Arai K, Murata Y, Wang S, Stins MF, Lo EH, et al. Protecting against cerebrovascular injury: contributions of 12/15-lipoxygenase to edema formation after transient focal ischemia. Stroke. 2008;39(9):2538–43. https://doi.org/10.1161/STROKEAHA.108.514927.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Lee JH, Lee SR. The effect of baicalein on hippocampal neuronal damage and metalloproteinase activity following transient global cerebral ischaemia. Phytother Res. 2012;26(11):1614–9. https://doi.org/10.1002/ptr.4644.

    Article  PubMed  CAS  Google Scholar 

  68. Liu Y, Zheng Y, Karatas H, Wang X, Foerch C, Lo EH, et al. 12/15-Lipoxygenase inhibition or knockout reduces warfarin-associated hemorrhagic transformation after experimental stroke. Stroke. 2017;48(2):445–51. https://doi.org/10.1161/STROKEAHA.116.014790.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Karatas H, Jung JE, Lo E, van Leyen K. Inhibiting 12/15-lipoxygenase to treat acute stroke in permanent and tPA induced thrombolysis models. Brain Res. 1678;2018:123–8.

    Google Scholar 

  70. Zhang Y, Wang H, Li J, Jimenez DA, Levitan ES, Aizenman E, et al. Peroxynitrite-induced neuronal apoptosis is mediated by intracellular zinc release and 12-lipoxygenase activation. J Neurosci. 2004;24(47):10616–27. https://doi.org/10.1523/JNEUROSCI.2469-04.2004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Huang H, Zhang Y, Yang R, Tang X. Determination of baicalin in rat cerebrospinal fluid and blood using microdialysis coupled with ultra-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B. 2008;874(1):77–83. https://doi.org/10.1016/j.jchromb.2008.09.005.

    Article  CAS  Google Scholar 

  72. Zeng M-F, Pan L-M, Zhu H-X, Zhang Q-C, Guo L-W. Comparative pharmacokinetics of baicalin in plasma after oral administration of Huang-Lian-Jie-Du-Tang or pure baicalin in MCAO and sham-operated rats. Fitoterapia. 2010;81(6):490–6. https://doi.org/10.1016/j.fitote.2010.01.004.

    Article  PubMed  CAS  Google Scholar 

  73. Tu X-K, Yang W-Z, Shi S-S, Wang C-H, Chen C-M. Neuroprotective effect of baicalin in a rat model of permanent focal cerebral ischemia. Neurochem Res. 2009;34(9):1626–34.

    Article  PubMed  CAS  Google Scholar 

  74. Zhou Q-B, Jin Y-L, Jia Q, Zhang Y, Li L-Y, Liu P, et al. Baicalin attenuates brain edema in a rat model of intracerebral hemorrhage. Inflammation. 2014;37(1):107–15. https://doi.org/10.1007/s10753-013-9717-9.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Mr. Chong Gao and Ms. Jinghan Feng, Dr. Lei Zhao and Dr. Hao Wu for assistance in the immunofluorescence study and animal study.

Funding

This work was supported by Hong Kong General Research Fund (GRF No. 17102915, GRF No. 17118717), Research Grant Council, Hong Kong SAR; Health and Medical Research Fund, Hong Kong SAR (No. 13142901); AoE/P-705/16 Areas of Excellence Scheme, RGC, Hong Kong SAR; SIRI/04/04/2015/06 Shenzhen Basic Research Plan Project; National Natural Science Foundation of China (No. 81671164); and Natural Science Foundation of the Jiangsu Higher Education Institutions of China (No. 13KJA310005).

Author information

Authors and Affiliations

  1. School of Chinese Medicine, The University of Hong Kong, Sassoon Road, Pokfulam, Hong Kong SAR, People’s Republic of China

    Hansen Chen, Binghe Guan, Xingmiao Chen & Jiangang Shen

  2. The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Hong Kong SAR, China

    Hansen Chen, Binghe Guan, Xingmiao Chen & Jiangang Shen

  3. Department of Core Facility, The People’s Hospital of Bao-an Shenzhen, Shenzhen Shi, China

    Xi Chen

  4. The 8th People’s Hospital of Shenzhen, The Affiliated Bao-an Hospital of Southern Medical University, Shenzhen, 518000, China

    Xi Chen

  5. Department of Neurology, Huizhou First Hospital, Huizhou, Guangdong Province, China

    Caiming Li & Jinhua Qiu

  6. Morningside Laboratory for Chemical Biology and Department of Chemistry, The University of Hong Kong, Hong Kong SAR, China

    Dan Yang

  7. Department of Pharmaceutical Sciences, College of Pharmacy, The University of New Mexico, Albuquerque, NM, 87131, USA

    Ke Jian Liu

  8. Research Center for Biochemistry and Molecular Biology and Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, 221000, People’s Republic of China

    Suhua Qi

Authors
  1. Hansen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Binghe Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xingmiao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Caiming Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jinhua Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ke Jian Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Suhua Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jiangang Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Suhua Qi or Jiangang Shen.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

Animal experimental protocols were conducted in accordance with the national and institutional guidelines on ethics and biosafety, which were approved and regulated by the Committee on the Use of Live Animals in Teaching and Research (CULATR), HKU.

Electronic Supplementary Material

Supplementary Figure 1

Baicalin inhibited AQP4 expression in ischemic brains with delayed t-PA treatment. A, representative immunoblotting of AQP4 in ischemic brains; B, statistical analysis of AQP4 expression; * or & p < 0.05, ** or ## p < 0.01, n = 4. (JPEG 45 kb)

High resolution image (TIFF 939 kb)

Supplementary Figure 2

baicalin scavenged peroxynitrite in human neuroblastoma SHSY-5Y cells treated with oxygen and glucose deprivation (OGD) plus tissue plasminogen activator (t-PA), or treated with peroxynitrite donor SIN-1. A, SHSY-5Y cells were subjected to OGD 6 h plus reoxygenation 2 h, with or without t-PA treatment. t-PA was dissolved in DMEM medium and treated at a dosage of 20 μg/ml. Baicalin was given at a concentration of 10 uM; B, Normal SHSY-5Y cells was incubated with peroxynitrite donor SIN-1 (500 uM) at 37 °C for 4 h, with or without baicalin (10 uM). Peroxynitrite was detected with specific probe HK-Yellow AM with red fluorescence. (JPEG 40 kb)

High resolution image (TIFF 2412 kb)

Supplementary Figure 3

Baicalin protected brain microvascular endothelial b.End3 cells viability against oxygen and glucose deprivation (OGD) injury. b.End3 was subjected to OGD 5 h plus reoxygenation 19 h. Baicalin was given during reperfusion at 10 uM. Cell viability was determined by MTT assay. **** p < 0.0001, ## p < 0.01, &&& p < 0.001, n = 3. (JPEG 32 kb)

High resolution image (TIFF 782 kb)

Supplementary Figure 4

baicalin did not induce cell death at 100 uM in brain microvascular endothelial b.End3 cells and neuroblastoma SH-SY5Y cells. b. End3 or SH-SY5Y cells were incubated with baicalin at 10 uM or 100 uM for 24 h. Cell viability was determined after treated for 24 h via MTT assay. (JPEG 34 kb)

High resolution image (TIFF 798 kb)

Supplementary Figure 5

baicalin did not induce cell shrinkage at 100 uM in brain microvascular endothelial b.End3 cells and neuroblastoma SH-SY5Y cells. b.End3 or SH-SY5Y cells were incubated with baicalin at 10 uM or 100 uM for 24 h. Cell morphology was observed by optical microscope. (JPEG 250 kb)

High resolution image (TIFF 13281 kb)

Supplementary Figure 6

baicalin inhibited the 3-NT signaling in ischemic brains with delayed t-PA treatment, which partially co-localized with neuron marker MAP2. Co-staining of 3-NT and MAP2 was performed in ischemic brain tissues to observe the 3-NT production in the neurons. Green signal stands for MAP2 positive; Pink signal stands for 3-NT positive; blue signal represents nucleus (DAPI positive); white color stands for overlap of MAPs2 and 3-NT signal. n = 3 (JPEG 135 kb)

High resolution image (TIFF 4367 kb)

Supplementary Figure 7

3-NT did not co-localize with astrocyte marker GFAP in ischemic brains with delayed t-PA treatment. Ischemic brain tissues were stained with GFAP antibody and 3-NT antibody, and results revealed no significant overlap of these two signal. Green signal stands for GFAP positive, pink signal stands for 3-NT positive, the blue signal represents nucleus (DAPI positive). n = 3 (JPEG 69 kb)

High resolution image (TIFF 3900 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, H., Guan, B., Chen, X. et al. Baicalin Attenuates Blood-Brain Barrier Disruption and Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke Rats with Delayed t-PA Treatment: Involvement of ONOO−-MMP-9 Pathway. Transl. Stroke Res. 9, 515–529 (2018). https://doi.org/10.1007/s12975-017-0598-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-017-0598-3

Keywords

Search

Navigation