Skip to main content
SpringerLink
Log in

Attenuated Blood-Brain Barrier Dysfunction by XQ-1H Following Ischemic Stroke in Hyperlipidemic Rats

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Following ischemic stroke, blood-brain barrier (BBB) is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which exacerbates cerebral ischemic injury as a result. Here, we report that 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a novel analog of ginkgolide B, alleviates BBB breakdown in hyperlipidemic rats and protects endothelial cells against inflammatory response. Middle cerebral artery occlusion (MCAO) modeled ischemic stroke in rats. Before surgery, these rats were fed a cholesterol-rich diet to induce an experimental hyperlipidemic condition. Additionally, lipopolysaccharide (LPS) incubation with rat brain microvessel endothelial cells (rBMECs) was applied to mimic hyperlipidemia-induced inflammatory injury of BBB. The results indicated more severe infarct size, increased BBB permeability, excessive secretion of pro-inflammatory cytokines, and exaggerated inflammation infiltration of the brain in hyperlipidemic rats following MCAO when compared to rats fed with normal diet. XQ-1H protected BBB integrity, lessoned brain edema and inflammation penetration, downregulated MMP-9 and VCMA-1 expressions, and extenuated ischemic infarction. XQ-1H alleviated LPS-induced inflammatory response in rBMECs, characterized by promoting cell viability, inhibiting TNF-α, IL-1β, and IL-6 releasing, and downregulating NF-κB inflammatory signal and downstream proteins, such as VCAM-1 and iNOS. In conclusion, the present study shows that XQ-1H stabilizes BBB function following ischemic stroke in hyperlipidemic rats, and the possible mechanisms may be related to inflammation inhibition.

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

Access this article

Log in via an institution

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
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

BBB:

Blood-brain barrier

BWC:

Brain water content

CNS:

Central nervous system

EB:

Evans blue

ELISA:

Enzyme-linked immunosorbent assay

H/R:

Hypoxia and reoxygenation

IL-6:

Interleukin-6

IL-1β:

Interleukin-1β

iNOS:

Inducible nitric oxide synthase

I/R:

Ischemia/reperfusion

LPS:

Lipopolysaccharide

MCAO:

Middle cerebral artery occlusion

MMP-9:

Matrix metalloproteinase-9

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide

PAF:

Platelet activating factor

NF-κB:

Nuclear factor kappa-B

NO:

Nitric oxide

rBMECs:

Rat brain microvessel endothelial cells

TNF-α:

Tumor necrosis factor-α

TTC:

Triphenyltetrazolium chloride

VCAM-1:

Vascular cell adhesion molecule 1

XQ-1H:

10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate

References

  1. Tu JV (2010) Reducing the global burden of stroke: INTERSTROKE. Lancet 376:74–75

    Article  PubMed  Google Scholar 

  2. Sandoval KE, Witt KA (2008) Blood-brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis 32:200–219

    Article  CAS  PubMed  Google Scholar 

  3. Balami JS, Chen RL, Grunwald IQ, Buchan AM (2011) Neurological complications of acute ischaemic stroke. Lancet Neurol 10:357–371

    Article  PubMed  Google Scholar 

  4. Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD, Chan PH, Park TS (2005) Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol 289:H558–H568

    Article  CAS  PubMed  Google Scholar 

  5. Denes A, Ferenczi S, Kovacs KJ (2011) Systemic inflammatory challenges compromise survival after experimental stroke via augmenting brain inflammation, blood -brain barrier damage and brain oedema independently of infarct size. J Neuroinflammation 8:164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yang D, Li SY, Yeung CM, Chang RC, So KF, Wong D, Lo AC (2012) Lycium barbarum extracts protect the brain from blood-brain barrier disruption and cerebral edema in experimental stroke. PLoS One 7:e33596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. ElAli A, Doeppner TR, Zechariah A, Hermann DM (2011) Increased blood-brain barrier permeability and brain edema after focal cerebral ischemia induced by hyperlipidemia: role of lipid peroxidation and calpain-1/2, matrix metalloproteinase-2/9, and RhoA overactivation. Stroke 42:3238–3244

    Article  CAS  PubMed  Google Scholar 

  8. O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW (2006) 1,026 experimental treatments in acute stroke. Ann Neurol 59:467–477

    Article  PubMed  Google Scholar 

  9. Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C (2008) Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 371:117–125

    Article  CAS  PubMed  Google Scholar 

  10. Li W, Prakash R, Chawla D, Du W, Didion SP, Filosa JA, Zhang Q, Brann DW, Lima VV, Tostes RC, Ergul A (2013) Early effects of high-fat diet on neurovascular function and focal ischemic brain injury. Am J Physiol Regul Integr Comp Physiol 304:R1001–R1008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87:779–789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Engstrom G, Lind P, Hedblad B, Stavenow L, Janzon L, Lindgarde F (2002) Effects of cholesterol and inflammation-sensitive plasma proteins on incidence of myocardial infarction and stroke in men. Circulation 105:2632–2637

    Article  CAS  PubMed  Google Scholar 

  13. Sleeman P, Patel NN, Lin H, Walkden GJ, Ray P, Welsh GI, Satchell SC, Murphy GJ (2013) High fat feeding promotes obesity and renal inflammation and protects against post cardiopulmonary bypass acute kidney injury in swine. Crit Care 17:R262

    Article  PubMed  PubMed Central  Google Scholar 

  14. Methia N, Andre P, Hafezi-Moghadam A, Economopoulos M, Thomas KL, Wagner DD (2001) ApoE deficiency compromises the blood brain barrier especially after injury. Mol Med 7:810–815

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Sun J, Li Y, Fang W, Mao L (2011) Therapeutic time window for treatment of focal cerebral ischemia reperfusion injury with XQ-1 h in rats. Eur J Pharmacol 666:105–110

    Article  CAS  PubMed  Google Scholar 

  16. Yang Q, Fang W, Lv P, Geng X, Li Y, Sha L (2012) Therapeutic neuroprotective effects of XQ-1H in a rat model of permanent focal cerebral ischemia. Pharmacology 89:1–6

    Article  CAS  PubMed  Google Scholar 

  17. Wei J, Fang W, Sha L, Han D, Zhang R, Hao X, Li Y (2013) XQ-1h suppresses neutrophils infiltration and oxidative stress induced by cerebral ischemia injury both in vivo and in vitro. Neurochem Res. 38:2542–2549

  18. Deng Y, Fang W, Li Y, Cen J, Fang F, Lv P, Gong S, Mao L (2009) Blood-brain barrier breakdown by PAF and protection by XQ-1H due to antagonism of PAF effects. Eur J Pharmacol 616:43–47

    Article  CAS  PubMed  Google Scholar 

  19. Rother J, Alberts MJ, Touze E, Mas JL, Hill MD, Michel P, Bhatt DL, Aichner FT, Goto S, Matsumoto M, Ohman EM, Okada Y, Uchiyama S, D’Agostino R, Hirsch AT, Wilson PW, Steg PG (2008) Risk factor profile and management of cerebrovascular patients in the REACH Registry. Cerebrovasc Dis 25:366–374

    Article  PubMed  Google Scholar 

  20. Burris RL, Ng HP, Nagarajan S (2013) Soy protein inhibits inflammation-induced VCAM-1 and inflammatory cytokine induction by inhibiting the NF-kappaB and AKT signaling pathway in apolipoprotein E-deficient mice. Eur J Nutr. 53(1):135–48. doi:10.1007/s00394-013-0509-7

  21. Fang W, Li Y, Cai Y, Kang K, Yan F, Liu G, Huang W (2007) Substituted tetrahydroisoquinoline compound B3 inhibited P-glycoprotein-mediated multidrug resistance in-vitro and in-vivo. J Pharm Pharmacol 59:1649–1655

    Article  CAS  PubMed  Google Scholar 

  22. Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91

    Article  CAS  PubMed  Google Scholar 

  23. Lv P, Fang W, Geng X, Yang Q, Li Y, Sha L (2011) Therapeutic neuroprotective effects of ginkgolide B on cortex and basal ganglia in a rat model of transient focal ischemia. Eur J Pharm Sci 44:235–240

    Article  CAS  PubMed  Google Scholar 

  24. Wei H, Yao X, Yang L, Wang S, Guo F, Zhou H, Marsicano G, Wang Q, Xiong L (2014) Glycogen synthase kinase-3beta is involved in electroacupuncture pretreatment via the cannabinoid CB1 receptor in ischemic stroke. Mol Neurobiol 49:326–336

    Article  CAS  PubMed  Google Scholar 

  25. Belayev L, Busto R, Zhao W, Ginsberg MD (1996) Quantitative evaluation of blood-brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res 739:88–96

    Article  CAS  PubMed  Google Scholar 

  26. Mdzinarishvili A, Kiewert C, Kumar V, Hillert M, Klein J (2007) Bilobalide prevents ischemia-induced edema formation in vitro and in vivo. Neuroscience 144:217–222

    Article  CAS  PubMed  Google Scholar 

  27. Garbuzova-Davis S, Haller E, Saporta S, Kolomey I, Nicosia SV, Sanberg PR (2007) Ultrastructure of blood-brain barrier and blood-spinal cord barrier in SOD1 mice modeling ALS. Brain Res 1157:126–137

    Article  CAS  PubMed  Google Scholar 

  28. Baatz H, Steinbauer M, Harris AG, Krombach F (1995) Kinetics of white blood cell staining by intravascular administration of rhodamine 6G. Int J Microcirc Clin Exp 15:85–91

    Article  CAS  PubMed  Google Scholar 

  29. Gaber MW, Yuan H, Killmar JT, Naimark MD, Kiani MF, Merchant TE (2004) An intravital microscopy study of radiation-induced changes in permeability and leukocyte-endothelial cell interactions in the microvessels of the rat pia mater and cremaster muscle. Brain Res Brain Res Protocol 13:1–10

    Article  CAS  Google Scholar 

  30. Yu H, Wang P, An P, Yixue X (2011) Recombinant human angiopoietin-1 ameliorates the expressions of ZO-1, occludin, VE-cadherin, and PKCalpha signaling after focal cerebral ischemia/reperfusion in rats. J Mol Neurosci. 46(1):236–47. doi: 10.1007/s12031-011-9584-5

  31. Fang W, Deng Y, Li Y, Shang E, Fang F, Lv P, Bai L, Qi Y, Yan F, Mao L (2010) Blood brain barrier permeability and therapeutic time window of Ginkgolide B in ischemia-reperfusion injury. Eur J Pharm Sci 39:8–14

    Article  CAS  PubMed  Google Scholar 

  32. Lindsberg PJ, Yue TL, Frerichs KU, Hallenbeck JM, Feuerstein G (1990) Evidence for platelet-activating factor as a novel mediator in experimental stroke in rabbits. Stroke 21:1452–1457

    Article  CAS  PubMed  Google Scholar 

  33. Latour LL, Kang DW, Ezzeddine MA, Chalela JA, Warach S (2004) Early blood-brain barrier disruption in human focal brain ischemia. Ann Neurol 56:468–477

    Article  PubMed  Google Scholar 

  34. Fang W, Geng X, Deng Y, Li Y, Shang E, Cen J, Lv P (2011) Platelet activating factor induces blood brain barrier permeability alteration in vitro. J Neuroimmunol 230:42–47

    Article  CAS  PubMed  Google Scholar 

  35. Jiang X, Guo M, Su J, Lu B, Ma D, Zhang R, Yang L, Wang Q, Ma Y, Fan Y (2012) Simvastatin blocks blood-brain barrier disruptions induced by elevated cholesterol both in vivo and in vitro. Int J Alzheimers Dis 2012:109324

    PubMed  PubMed Central  Google Scholar 

  36. Fung A, Vizcaychipi M, Lloyd D, Wan Y, Ma D (2012) Central nervous system inflammation in disease related conditions: mechanistic prospects. Brain Res 1446:144–155

    Article  CAS  PubMed  Google Scholar 

  37. Pan W, Kastin AJ (2002) TNFalpha transport across the blood-brain barrier is abolished in receptor knockout mice. Exp Neurol 174:193–200

    Article  CAS  PubMed  Google Scholar 

  38. Chen B, Liao WQ, Xu N, Xu H, Wen JY, Yu CA, Liu XY, Li CL, Zhao SM, Campbell W (2009) Adiponectin protects against cerebral ischemia-reperfusion injury through anti-inflammatory action. Brain Res 1273:129–137

    Article  CAS  PubMed  Google Scholar 

  39. Weiss N, Miller F, Cazaubon S, Couraud PO (2009) The blood-brain barrier in brain homeostasis and neurological diseases. Biochim Biophys Acta 1788:842–857

    Article  CAS  PubMed  Google Scholar 

  40. Ghanim H, Abuaysheh S, Sia CL, Korzeniewski K, Chaudhuri A, Fernandez-Real JM, Dandona P (2009) Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Diabetes Care 32:2281–2287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bannerman DD, Sathyamoorthy M, Goldblum SE (1998) Bacterial lipopolysaccharide disrupts endothelial monolayer integrity and survival signaling events through caspase cleavage of adherens junction proteins. J Biol Chem 273:35371–35380

    Article  CAS  PubMed  Google Scholar 

  42. Selvaraj SK, Periandythevar P, Prasadarao NV (2007) Outer membrane protein A of Escherichia coli K1 selectively enhances the expression of intercellular adhesion molecule-1 in brain microvascular endothelial cells. Microbes Infect 9:547–557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ulbrich H, Eriksson EE, Lindbom L (2003) Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease. Trends Pharmacol Sci 24:640–647

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation of China (Program No. 81202974), Natural Science Foundation of Jiangsu Province of China (Program No. BK2011625), Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. JKGQ201108), Fundamental Research Funds for the Central Universities (No. JKPZ2013018), Qing Lan Project, “333” Project, and Priority Academic Program Development of Jiangsu Higher Education Institutions.

Conflict of Interest

The authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China

    Weirong Fang, Lan Sha, Nandani Darshika Kodithuwakku, Jie Wei, Rui Zhang, Dan Han & Yunman Li

  2. Jiangsu Kefeiping Pharmaceutical Company Limited, Number 12, Nanjing Qianbanshanyuan, Jiangsu, 210016, People’s Republic of China

    Lishun Mao

  3. Department of Physiology, School of Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, Jiangsu, 210009, People’s Republic of China

    Yunman Li

Authors
  1. Weirong Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lan Sha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nandani Darshika Kodithuwakku
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jie Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dan Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lishun Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yunman Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yunman Li.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fang, W., Sha, L., Kodithuwakku, N.D. et al. Attenuated Blood-Brain Barrier Dysfunction by XQ-1H Following Ischemic Stroke in Hyperlipidemic Rats. Mol Neurobiol 52, 162–175 (2015). https://doi.org/10.1007/s12035-014-8851-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8851-1

Keywords

Search

Navigation