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Effect of Propofol Post-treatment on Blood–Brain Barrier Integrity and Cerebral Edema After Transient Cerebral Ischemia in Rats

Neurochemical Research volume 38, pages 2276–2286 (2013)Cite this article

Abstract

Although propofol has been reported to offer neuroprotection against cerebral ischemia injury, its impact on cerebral edema following ischemia is not clear. The objective of this investigation is to evaluate the effects of propofol post-treatment on blood–brain barrier (BBB) integrity and cerebral edema after transient cerebral ischemia and its mechanism of action, focusing on modulation of aquaporins (AQPs), matrix metalloproteinases (MMPs), and hypoxia inducible factor (HIF)-1α. Cerebral ischemia was induced in male Sprague–Dawley rats (n = 78) by occlusion of the right middle cerebral artery for 1 h. For post-treatment with propofol, 1 mg kg−1 min−1 of propofol was administered for 1 h from the start of reperfusion. Nineteen rats undergoing sham surgery were also included in the investigation. Edema and BBB integrity were assessed by quantification of cerebral water content and extravasation of Evans blue, respectively, following 24 h of reperfusion. In addition, the expression of AQP-1, AQP-4, MMP-2, and MMP-9 was determined 24 h after reperfusion and the expression of HIF-1α was determined 8 h after reperfusion. Propofol post-treatment significantly reduced cerebral edema (P < 0.05) and BBB disruption (P < 0.05) compared with the saline-treated control. The expression of AQP-1, AQP-4, MMP-2, and MMP-9 at 24 h and of HIF-1α at 8 h following ischemia/reperfusion was significantly suppressed in the propofol post-treatment group (P < 0.05). Propofol post-treatment attenuated cerebral edema after transient cerebral ischemia, in association with reduced expression of AQP-1, AQP-4, MMP-2, and MMP-9. The decreased expression of AQPs and MMPs after propofol post-treatment might result from suppression of HIF-1α expression.

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References

  1. Chalela JA, Merino JG, Warach S (2004) Update on stroke. Curr Opin Neurol 17:447–451

    PubMed  Article  Google Scholar 

  2. Zador Z, Stiver S, Wang V, Manley G (2009) Role of aquaporin-4 in cerebral edema and stroke. Handb Exp Pharmacol 190:159–170

    PubMed  Article  CAS  Google Scholar 

  3. Pluta R (2005) Pathological opening of the blood-brain barrier to horseradish peroxidase and amyloid precursor protein following ischemia-reperfusion brain injury. Chemotherapy 51:223–226

    PubMed  Article  CAS  Google Scholar 

  4. Pluta R, Lossinsky AS, Wisniewski HM, Mossakowski MJ (1994) Early blood-brain barrier changes in the rat following transient complete cerebral ischemia induced by cardiac arrest. Brain Res 633:41–52

    PubMed  Article  CAS  Google Scholar 

  5. Zelenina M (2010) Regulation of brain aquaporins. Neurochem Int 57:468–488

    PubMed  Article  CAS  Google Scholar 

  6. Kim JH, Lee YW, Park KA, Lee WT, Lee JE (2010) Agmatine attenuates brain edema through reducing the expression of aquaporin-1 after cerebral ischemia. J Cereb Blood Flow Metab 30:943–949

    PubMed  Article  CAS  Google Scholar 

  7. Zheng Y, Lan Y, Tang H, Zhu S (2008) Propofol pretreatment attenuates aquaporin-4 over-expression and alleviates cerebral edema after transient focal brain ischemia reperfusion in rats. Anesth Analg 107:2009–2016

    PubMed  Article  CAS  Google Scholar 

  8. Rosenberg GA, Yang Y (2007) Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus 22:E4

    PubMed  Article  Google Scholar 

  9. Heo JH, Lucero J, Abumiya T, Koziol JA, Copeland BR, del Zoppo GJ (2009) Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab 19:624–633

    Google Scholar 

  10. Nagle DG, Zhou Y (2006) Natural product-derived small molecule activators of hypoxia-inducible factor-1 (HIF-1). Curr Pharm Des 12:2673–2688

    PubMed  Article  CAS  Google Scholar 

  11. Lee J, Bae S, Jeong J, Kim S, Kim K (2004) Hypoxia-inducible factor (HIF-1) α: its protein stability and biological functions. Exp Mol Med 36:1–12

    PubMed  Article  Google Scholar 

  12. Higashida T, Peng C, Li J, Dornbos D III, Teng K, Li X, Kinni H, Guthikonda M, Ding Y (2011) Hypoxia-inducible factor-1α contributes to brain edema after stroke by regulating aquaporins and glycerol distribution in brain. Curr Neurovasc Res 8:44–51

    PubMed  Article  CAS  Google Scholar 

  13. Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA (1999) Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell 4:915–924

    PubMed  Article  CAS  Google Scholar 

  14. Valable S, Montaner J, Bellail A, Berezowski V, Brillault J, Cecchelli R, Divoux D, Mackenzie ET, Bernaudin M, Roussel S, Petit E (2005) VEGF-induced BBB permeability is associated with an MMP-9 activity increase in cerebral ischemia: both effects decreased by Ang-1. J Cereb Blood Flow Metab 25:1491–1504

    PubMed  Article  CAS  Google Scholar 

  15. Wang H, Luo M, Li C, Wang G (2011) Propofol post-conditioning induced long-term neuroprotection and reduced internalization of AMPAR GluR2 subunit in a rat model of focal cerebral ischemia/reperfusion. J Neurochem 119:210–219

    PubMed  Article  CAS  Google Scholar 

  16. Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X, Zhang S (2008) Ischemic post-conditioning protects brain and reduces inflammation in a rat model of focal cerebral ischemia/reperfusion. J Neurochem 105:1737–1745

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  18. Hunter AJ, Hatcher J, Virley D, Nelson P, Irving E, Hadingham SJ, Parsons AA (2000) Functional assessments in mice and rats after focal stroke. Neuropharmacology 39:806–816

    PubMed  Article  CAS  Google Scholar 

  19. Belayev L, Alonso OF, Busto R, Zhao W, Ginsberg MD (1996) Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke 27:1616–1622

    PubMed  Article  CAS  Google Scholar 

  20. Kamada H, Yu F, Nito C, Chan PH (2007) Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/reperfusion in rats: relation to blood-brain barrier dysfunction. Stroke 38:1044–1049

    PubMed  Article  CAS  Google Scholar 

  21. Yeh S, Ou L, Gean P, Hung J, Chang W (2011) Selective inhibition of early—but not late—expressed HIF-1α is neuroprotective in rats after focal ischemic brain damage. Brain Pathol 21:249–262

    PubMed  Article  CAS  Google Scholar 

  22. Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6:159–163

    PubMed  Article  CAS  Google Scholar 

  23. Zeng X, Asmaro K, Ren C, Gao M, Peng C, Ding JY, Fredrickson V, Ji X, Ding Y (2012) Acute ethanol treatment reduces blood–brain barrier dysfunction following ischemia/reperfusion injury. Brain Res 1437:127–133

    PubMed  Article  CAS  Google Scholar 

  24. Badaut J, Brunet JF, Grollimund L, Hamou MF, Magistretti PJ, Villemure JG, Regli L (2003) Aquaporin 1 and aquaporin 4 expression in human brain after subarachnoid hemorrhage and in peritumoral tissue. Acta Neurochir Suppl 86:495–498

    PubMed  CAS  Google Scholar 

  25. Suzuki R, Okuda M, Asai J, Nagashima G, Itokawa H, Matsunaga A, Fujimoto T, Suzuki T (2006) Astrocytes co-express aquaporin-1, -4, and vascular endothelial growth factor in brain edema tissue associated with brain contusion. Acta Neurochir Suppl 96:398–401

    PubMed  Article  CAS  Google Scholar 

  26. Satoh J, Tabunoki H, Yamamura T, Arima K, Konno H (2007) Human astrocytes express aquaporin-1 and aquaporin-4 in vitro and in vivo. Neuropathology 27:245–256

    PubMed  Article  Google Scholar 

  27. Zhu S, Xiong X, Zheng Y, Pan C (2009) Propofol inhibits aquaporin 4 expression through a protein kinase C-dependent pathway in an astrocyte model of cerebral ischemia/reoxygenation. Anesth Analg 109:1493–1499

    PubMed  Article  CAS  Google Scholar 

  28. Zhang ZG, Zhang L, Tsang W, Soltanian-Zadeh H, Morris D, Zhang R, Goussev A, Powers C, Yeich T, Chopp M (2002) Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. J Cereb Blood Flow Metab 22:379–392

    PubMed  Article  CAS  Google Scholar 

  29. Chen C, Hu Q, Yan J, Lei J, Qin L, Shi X, Luan L, Yang L, Wang K, Han J, Nanda A, Zhou C (2007) Multiple effects of 2ME2 and D609 on the cortical expression of HIF-1α and apoptotic genes in a middle cerebral artery occlusion-induced focal ischemia rat model. J Neurochem 102:1831–1841

    PubMed  Article  CAS  Google Scholar 

  30. Weis S, Shintani S, Weber A, Kirchmair R, Wood M, Cravens A, McSharry H, Iwakura A, Yoon YS, Himes N, Burstein D, Doukas J, Soll R, Losordo D, Cheresh D (2004) Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. J Clin Invest 113:885–894

    PubMed  CAS  Google Scholar 

  31. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27:697–709

    PubMed  Article  CAS  Google Scholar 

  32. Candelario-Jalil E, Yang Y, Rosenberg GA (2009) Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 158:983–994

    PubMed  Article  CAS  Google Scholar 

  33. Rosenberg GA, Estrada EY, Dencoff JE (1998) Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke 29:2189–2195

    PubMed  Article  CAS  Google Scholar 

  34. Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, Fini ME, Lo EH (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci 21:7724–7732

    PubMed  CAS  Google Scholar 

  35. Kanazawa M, Igarashi H, Kawamura K, Takahashi T, Kakita A, Takahashi H, Nakada T, Nishizawa M, Shimohata T (2011) Inhibition of VEGF signaling pathway attenuates hemorrhage after tPA treatment. J Cereb Blood Flow Metab 31:1461–1474

    PubMed  Article  CAS  Google Scholar 

  36. Ding JY, Kreipke CW, Speirs SL, Schafer P, Schafer S, Rafols JA (2009) Hypoxia-inducible factor-1α signaling in aquaporin upregulation after traumatic brain injury. Neurosci Lett 453:68–72

    PubMed  Article  CAS  Google Scholar 

  37. Baranova O, Miranda LF, Pichiule P, Dragatsis I, Johnson RS, Chavez JC (2007) Neuron-specific inactivation of the hypoxia inducible factor 1α increases brain injury in a mouse model of transient focal cerebral ischemia. J Neurosci 27:6320–6332

    PubMed  Article  CAS  Google Scholar 

  38. Helton R, Cui J, Scheel JR, Ellison JA, Ames C, Gibson C, Blouw B, Ouyang L, Dragatsis I, Zeitlin S, Johnson RS, Lipton SA, Barlow C (2005) Brain-specific knock-out of hypoxia-inducible factor-1α reduces rather than increases hypoxic-ischemic damage. J Neurosci 25:4099–4107

    PubMed  Article  CAS  Google Scholar 

  39. Takabuchi S, Hirota K, Nishi K, Oda S, Oda T, Shingu K, Takabayashi A, Adachi T, Semenza GL, Fukuda K (2004) The intravenous anesthetic propofol inhibits hypoxia-inducible factor 1 activity in an oxygen tension-dependent manner. FEBS Lett 577:434–438

    PubMed  Article  CAS  Google Scholar 

  40. Tanaka T, Takabuchi S, Nishi K, Oda S, Wakamatsu T, Daijo H, Fukuda K, Hirota K (2010) The intravenous anesthetic propofol inhibits lipopolysaccharide-induced hypoxia-inducible factor 1 activation and suppresses the glucose metabolism in macrophages. J Anesth 24:54–60

    PubMed  Article  Google Scholar 

  41. Yeh CH, Cho W, So EC, Chu CC, Lin MC, Wang JJ, Hsing CH (2011) Propofol inhibits lipopolysaccharide-induced lung epithelial cell injury by reducing hypoxia-inducible factor-1α expression. Br J Anaesth 106:590–599

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by the “Dongwha Holdings” Faculty Research ssistance Program of Yonsei University College of Medicine for 2012 (6-2012-0050).

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Authors and Affiliations

  1. Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea

    Jae Hoon Lee, Seo Kyung Shin, Jeong Min Kim, So Yeon Kim & Bon-Nyeo Koo

  2. Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea

    Hui Song Cui

  3. Department of Anatomy, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea

    Jong Eun Lee

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  1. Jae Hoon Lee
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Correspondence to Jong Eun Lee or Bon-Nyeo Koo.

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Lee, J.H., Cui, H.S., Shin, S.K. et al. Effect of Propofol Post-treatment on Blood–Brain Barrier Integrity and Cerebral Edema After Transient Cerebral Ischemia in Rats. Neurochem Res 38, 2276–2286 (2013). https://doi.org/10.1007/s11064-013-1136-7

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  • DOI: https://doi.org/10.1007/s11064-013-1136-7

Keywords

  • Blood–brain barrier
  • Cerebral edema
  • Cerebral ischemia
  • Propofol