Skip to main content

Advertisement

Log in

Curcumin Ameliorates the Permeability of the Blood–Brain Barrier During Hypoxia by Upregulating Heme Oxygenase-1 Expression in Brain Microvascular Endothelial Cells

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Curcumin (Cur) is a major active component of the food flavor turmeric isolated from the powdered dry rhizome of Curcuma longa Linn., which has been used in traditional Chinese medicine to ameliorate intracerebral ischemic damage and reduce brain edema. However, the effects of Cur on the disruption of the blood–brain barrier (BBB) induced by brain ischemia are still unclear. The effects of Cur on the disruption of BBB and changes of tight junction (TJ) proteins induced by oxygen glucose deprivation (OGD) were studied in BBB in vitro. The transendothelial electrical resistance and the flux of horseradish peroxidase in BBB in vitro were measured. The expression and localization of the TJ proteins occludin and zonula occludens-1 (ZO-1) were evaluated by Western blots and immunofluorescence microscopy. The protein levels of heme oxygenase-1 (HO-1) were also analyzed via Western blots. Cur attenuated OGD-induced disruption of paracellular permeability and increased the expression of HO-1 protein in rat brain microvascular endothelial cells (RBMECs). After administration of OGD, the expression of occludin and ZO-1 proteins was restored by Cur, and this effect was blocked by a HO-1 inhibitor, zinc protoporphyrin (ZnPP). Cur protects RBMECs against OGD-induced disruption of TJ and barrier dysfunction via the HO-1 pathway. We propose that Cur is capable of improving the barrier function of BBB under ischemic conditions and this beneficial effect might be reversed by a HO-1 inhibitor, ZnPP.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Al Ahmad A, Gassmann M, Ogunshola OO (2012) Involvement of oxidative stress in hypoxia-induced blood–brain barrier breakdown. Microvasc Res 84:222–225

    Article  PubMed  CAS  Google Scholar 

  • Araujo JA, Zhang M, Yin F (2012) Heme oxygenase-1, oxidation, inflammation, and atherosclerosis. Front Pharmacol 3:119

    Article  PubMed  Google Scholar 

  • Balbuena P, Li W, Ehrich M (2011) Assessments of tight junction proteins occludin, claudin 5 and scaffold proteins ZO1 and ZO2 in endothelial cells of the rat blood–brain barrier: cellular responses to neurotoxicants malathion and lead acetate. Neurotoxicology 32:58–67

    Article  PubMed  CAS  Google Scholar 

  • Bhaskaran N, Shukla S, Kanwal R, Srivastava JK, Gupta S (2012) Induction of heme oxygenase-1 by chamomile protects murine macrophages against oxidative stress. Life Sci 90:1027–1033

    Article  PubMed  CAS  Google Scholar 

  • Chen YB, Li CG, Xu CS (2005) Curcumin for the protection and treatment of cerebral vascular disease. Chin J Integr Med Cardio-Cerebrovasc Dis 3:631–633

    Google Scholar 

  • Coisne C, Engelhardt B (2011) Tight junctions in brain barriers during central nervous system inflammation. Antioxid Redox Signal 15:1285–1303

    Article  PubMed  CAS  Google Scholar 

  • Das L, Vinayak M (2012) Anti-carcinogenic action of curcumin by activation of antioxidant defence system and inhibition of NF-κB signalling in lymphoma-bearing mice. Biosci Rep 32:161–170

    Article  PubMed  CAS  Google Scholar 

  • Farkas AE, Capaldo CT, Nusrat A (2012) Regulation of epithelial proliferation by tight junction proteins. Ann N Y Acad Sci 1258:115–124

    Article  PubMed  CAS  Google Scholar 

  • Gandapu U, Chaitanya RK, Kishore G, Reddy RC, Kondapi AK (2011) Curcumin-loaded apotransferrin nanoparticles provide efficient cellular uptake and effectively inhibit HIV-1 replication in vitro. PLoS One 6:e23388

    Article  PubMed  CAS  Google Scholar 

  • Gerjevic LN, Lu S, Chaky JP, Harrison-Findik DD (2011) Regulation of heme oxygenase expression by alcohol, hypoxia and oxidative stress. World J Biol Chem 2:252–260

    Article  PubMed  Google Scholar 

  • González-Mariscal L, Betanzos A, Nava P, Jaramillo BE (2003) Tight junction proteins. Prog Biophys Mol Biol 81:1–44

    Article  PubMed  Google Scholar 

  • Hao XE, Wang XG, Li N, Wang SP, Zhang XJ, Li GM (2002) The effect of the compound curcumin capsule on focal cerebral ischemia in rats. Shandong J Tradit Chin Med 7:427–429

    Google Scholar 

  • Jiang J, Wang W, Sun YJ, Hu M, Li F, Zhu DY (2007) Neuroprotective effect of curcumin on focal cerebral ischemic rats by preventing blood–brain barrier damage. Eur J Pharmacol 561:54–62

    Article  PubMed  CAS  Google Scholar 

  • Kaur C, Ling EA (2008) Blood brain barrier in hypoxic-ischemic conditions. Curr Neurovasc Res 5:71–81

    Article  PubMed  CAS  Google Scholar 

  • Kim SJ, Park JG, Lee SM (2012) Protective effect of heme oxygenase-1 induction against hepatic injury in alcoholic steatotic liver exposed to cold ischemia/reperfusion. Life Sci 90:169–176

    Article  PubMed  CAS  Google Scholar 

  • Kunwar A, Sandur SK, Krishna M, Priyadarsini KI (2009) Curcumin mediates time and concentration dependent regulation of redox homeostasis leading to cytotoxicity in macrophage cells. Eur J Pharmacol 611:8–16

    Article  PubMed  CAS  Google Scholar 

  • Lee JC, Kinniry PA, Arguiri E, Serota M, Kanterakis S, Chatterjee S, Solomides CC, Javvadi P, Koumenis C, Cengel KA, Christofidou-Solomidou M (2010) Dietary curcumin increases antioxidant defenses in lung, ameliorates radiation-induced pulmonary fibrosis, and improves survival in mice. Radiat Res 173:590–601

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Sun XJ, Liu J, Kang ZM, Deng XM (2011) Heme oxygenase-1 could mediate the protective effects of hyperbaric oxygen preconditioning against hepatic ischemia-reperfusion injury in rats. Clin Exp Pharmacol Physiol 38:675–682

    Article  PubMed  Google Scholar 

  • Liu WY, Wang ZB, Zhang LC, Wei X, Li L (2012) Tight junction in blood–brain barrier: an overview of structure, regulation, and regulator substances. CNS Neurosci Ther doi: 10.1111/j.1755-5949.2012.00340.x

  • Luo F, Huang R, Yang YJ, Yu XH (2003) Protective effect and mechanism of pretreatment with curcumin on infectious brain edema in rats. Zhonghua Er Ke Za Zhi 41:940–944

    PubMed  Google Scholar 

  • McNally SJ, Harrison EM, Ross JA, Garden OJ, Wigmore SJ (2007) Curcumin induces heme oxygenase 1 through generation of reactive oxygen species, p38 activation and phosphatase inhibition. Int J Mol Med 19:165–172

    PubMed  CAS  Google Scholar 

  • Motterlini R, Foresti R, Bassi R, Green CJ (2000) Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Radic Biol Med 28:1303–1312

    Article  PubMed  CAS  Google Scholar 

  • Panchal HD, Vranizan K, Lee CY, Ho J, Ngai J, Timiras PS (2008) Early anti-oxidative and anti-proliferative curcumin effects on neuroglioma cells suggest therapeutic targets. Neurochem Res 33:1701–1710

    Article  PubMed  CAS  Google Scholar 

  • Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD (2006) Blood–brain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol 1:223–236

    Article  PubMed  Google Scholar 

  • Preston E, Foster DO (1997) Evidence for pore-like opening of the blood–brain barrier following forebrain ischemia in rats. Brain Res 761:4–10

    Article  PubMed  CAS  Google Scholar 

  • Pun PB, Lu J, Moochhala S (2003) Involvement of ROS in BBB dysfunction. Free Radic Res 43:348–364

    Article  Google Scholar 

  • Reed JR, Huber WJ 3rd, Backes WL (2010) Human heme oxygenase-1 efficiently catabolizes heme in the absence of biliverdin reductase. Drug Metab Dispos 38:2060–2066

    Article  PubMed  CAS  Google Scholar 

  • Rosenberg GA (2012) Neurological diseases in relation to the blood–brain barrier. J Cereb Blood Flow Metab 32:1139–1151

    Article  PubMed  CAS  Google Scholar 

  • Scott PA, Bicknell R (1993) The isolation and culture of microvascular endothelium. J Cell Sci 105(Pt 2):269–273

    PubMed  Google Scholar 

  • Wang N, Wang G, Hao J, Ma J, Wang Y, Jiang X, Jiang H (2012) Curcumin ameliorates hydrogen peroxide-induced epithelial barrier disruption by upregulating heme oxygenase-1 expression in human intestinal epithelial cells. Dig Dis Sci 57:1792–1801

    Article  PubMed  CAS  Google Scholar 

  • Xie H, Xue YX, Liu LB, Liu YH, Wang P (2012) Role of RhoA/ROCK signaling in endothelial-monocyte-activating polypeptide II opening of the blood-tumor barrier: role of RhoA/ROCK signaling in EMAP II opening of the BTB. J Mol Neurosci 46(3):666–676

    Google Scholar 

  • Yang Y, Rosenberg GA (2011) Blood–brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke 42:3323–3328

    Article  PubMed  CAS  Google Scholar 

  • Yang G, Cao H, Zeng YM (2005) The protective effect of curcumin on cerebral ischemia reperfusion injury. Foreign Medical Sciences. Anesthesiol Resuscitation 3:157–160

    Google Scholar 

  • Yang C, Zhang X, Fan H, Liu Y (2009) Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. Brain Res 1282:133–141

    Article  PubMed  CAS  Google Scholar 

  • Zhao J, Zhao Y, Zheng W, Lu Y, Feng G, Yu S (2008) Neuroprotective effect of curcumin on transient focal cerebral ischemia in rats. Brain Res 1229:224–232

    Article  PubMed  CAS  Google Scholar 

  • Zhu H, Wang Z, Xing Y, Gao Y, Ma T, Lou L, Lou J, Gao Y, Wang S, Wang YJ (2012) 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. Ethnopharmacol 141:714–720

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Science Foundation for China (no. 81100924).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yan-ting Gu.

Additional information

Yan-feng Wang and Yan-ting Gu contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, Yf., Gu, Yt., Qin, Gh. et al. Curcumin Ameliorates the Permeability of the Blood–Brain Barrier During Hypoxia by Upregulating Heme Oxygenase-1 Expression in Brain Microvascular Endothelial Cells. J Mol Neurosci 51, 344–351 (2013). https://doi.org/10.1007/s12031-013-9989-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-013-9989-4

Keywords

Navigation