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Protective Effect of Luteolin in Experimental Ischemic Stroke: Upregulated SOD1, CAT, Bcl-2 and Claudin-5, Down-Regulated MDA and Bax Expression

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Abstract

Luteolin recently has been proved to elicit a vanity of biological effects through its antioxidant and anti-apoptosis properties. Oxidative and apoptosis damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. The aim of this study was to evaluate the neuroprotective effects of luteolin and the underlying mechanisms in cerebral ischemia. Focal cerebral ischemia was induced in adult male Sprague–Dawley rats by permanent middle cerebral artery occlusion (pMCAO). Luteolin was injected intraperitoneally at different doses of 10 or 25 mg/kg immediately after pMCAO. Experiment 1, luteolin’s neuroprotective effect was analyzed. Neurological deficits, brain water content and infarct volume were evaluated at 24 and 72 h after pMCAO. SOD1, Bcl-2, and Bax expression were measured by immunohistochemistry, western blot and reverse transcription-polymerase chain reaction. Experiment 2, luteolin’s anti-oxidative activities were evaluated. SOD1, CAT activities, and MDA content were measured by spectrophotometer. Experiment 3, the influence of luteolin on claudin-5 was detected. Compared with MCAO group, luteolin significantly increased the activities of SOD1, CAT, Bcl-2 and claudin-5 (P < 0.05), decreased the levels of MDA and Bax (P < 0.05), and alleviated the neurological deficits, infarct volume and brain water content (P < 0.05). The results indicated that luteolin protected the brain from ischemic damage, and this effect may be through reduction of oxidative stress and apoptosis, and upregulation of the expressions of claudin-5.

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References

  1. Fiskum G, Rosenthal RE, Vereczki V, Martin E, Hoffman GE, Chinopoulos C, Kowaltowski A (2004) Protection against ischemic brain injury by inhibition of mitochondrial oxidative stress. J Bioenerg Biomembr 36:347–352

    Article  PubMed  CAS  Google Scholar 

  2. Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3:205–214

    Article  PubMed  CAS  Google Scholar 

  3. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62

    Article  PubMed  CAS  Google Scholar 

  4. Schettler V, Methe H, Staschinsky D, Schuff-Werner P, Müller GA, Wieland E (1999) Review: the oxidant/antioxidant balance during regular low density lipoprotein apheresis. Ther Apher 3:219–226

    PubMed  CAS  Google Scholar 

  5. Loh KP, Qi J, Tan BK, Liu XH, Wei BG, Zhu YZ (2010) Leonurine protects middle cerebral artery occluded rats through antioxidant effect and regulation of mitochondrial function. Stroke 41:2661–2668

    Article  PubMed  CAS  Google Scholar 

  6. Greenlund LJ, Deckwerth TL, Johnson EM Jr (1995) Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death. Neuron 14:303–315

    Article  PubMed  CAS  Google Scholar 

  7. Wattanapitayakul SK, Bauer JA (2001) Oxidative pathways in cardiovascular disease: roles, mechanisms, and therapeutic implications. Pharmacol Ther 89:187–206

    Article  PubMed  CAS  Google Scholar 

  8. Choi BM, Lim DW, Lee JA, Gao SS, Kwon DY, Kim BR (2008) Luteolin suppresses cisplatin-induced apoptosis in auditory cells: possible mediation through induction of heme oxygenase-1 expression. J Med Food 11:230–236

    Article  PubMed  CAS  Google Scholar 

  9. Seelinger G, Merfort I, Schempp CM (2008) Anti-oxidant, anti-inflammatory and anti-allergic activities of Luteolin. Planta Med 74:1667–1677

    Article  PubMed  CAS  Google Scholar 

  10. Coleta M, Campos MG, Cotrim MD, Lima TC, Cunha AP (2008) Assessment of luteolin (3′,4′,5,7-tetrahydroxyflavone) neuropharmacological activity. Behav Brain Res 189:75–82

    Article  PubMed  CAS  Google Scholar 

  11. Tsai FS, Peng WH, Wang WH, Wu CR, Hsieh CC, Lin YT, Feng IC, Hsieh MT (2007) Effects of luteolin on learning acquisition in rats: involvement of the central cholinergic system. Life Sci 80:1692–1698

    Article  PubMed  CAS  Google Scholar 

  12. Zhao G, Zang SY, Jiang ZH, Chen YY, Ji XH, Lu BF, Wu JH, Qin GW, Guo LH (2011) Postischemic administration of liposome-encapsulated luteolin prevents against ischemia-reperfusion injury in a rat middle cerebral artery occlusion model. J Nutr Biochem 22:929–936

    Article  PubMed  CAS  Google Scholar 

  13. Qiao H, Zhang X, Zhu C, Dong L, Wang L, Zhang X, Xing Y, Wang C, Ji Y, Cao X (2012) Luteolin downregulates TLR4, TLR5, NF-κB and p-p38MAPK expression, upregulates the p-ERK expression, and protects rat brains against focal ischemia. Brain Res 1448:71–81

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  15. 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 

  16. Khatibi NH, Jadhav V, Charles S, Chiu J, Buchholz J, Tang J, Zhang JH (2011) Capsaicin pre-treatment provides neurovascular protection against neonatal hypoxic-ischemic brain injury in rats. Acta Neurochir Suppl 111:225–230

    Article  PubMed  Google Scholar 

  17. Ahmad A, Khan MM, Hoda MN, Raza SS, Khan MB, Javed H, Ishrat T, Ashafaq M, Ahmad ME, Safhi MM, Islam F (2011) Quercetin protects against oxidative stress associated damages in a rat model of transient focal cerebral ischemia and reperfusion. Neurochem Res 36:1360–1371

    Article  PubMed  CAS  Google Scholar 

  18. Wang J, Zhao Y, Liu C, Jiang C, Zhao C, Zhu Z (2011) Progesterone inhibits inflammatory response pathways after permanent middle cerebral artery occlusion in rats. Mol Med Report 4:319–324

    PubMed  CAS  Google Scholar 

  19. Hatashita S, Hoff JT, Salamat SM (1988) Ischemic brain edema and the osmotic gradient between blood and brain. J Cereb Blood Flow Metab 8:552–559

    Article  PubMed  CAS  Google Scholar 

  20. Bederson JB, Pitts LH, Germano SM, Nishimura MC, Davis RL, Bartkowski HM (1986) Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke 17:1304–1308

    Article  PubMed  CAS  Google Scholar 

  21. Tatlisumak T, Carano RA, Takano K, Opgenorth TJ, Sotak CH, Fisher M (1998) A novel endothelin antagonist, A-127722, attenuates ischemic lesion size in rats with temporary middle cerebral artery occlusion: a diffusion and perfusion MRI study. Stroke 29:850–857

    Article  PubMed  CAS  Google Scholar 

  22. Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79:1431–1568

    PubMed  CAS  Google Scholar 

  23. Ikeda K, Negishi H, Yamori Y (2003) Antioxidant nutrients and hypoxia/ischemia brain injury in rodents. Toxicology 189:55–61

    Article  PubMed  CAS  Google Scholar 

  24. Simonyi A, Wang Q, Miller RL, Yusof M, Shelat PB, Sun AY, Sun GY (2005) Polyphenols in cerebral ischemia: novel targets for neuroprotection. Mol Neurobiol 31:135–148

    Article  PubMed  CAS  Google Scholar 

  25. Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21:2–14

    Article  PubMed  CAS  Google Scholar 

  26. Lin AM, Chen CF, Ho LT (2002) Neuroprotective effect of intermittent hypoxia on iron-induced oxidative injury in rat brain. Exp Neurol 176:328–335

    Article  PubMed  CAS  Google Scholar 

  27. Suzuki M, Takeuchi H, Kakita T, Unno M, Katayose Y, Matsuno S (2000) The involvement of the intracellular superoxide production system in hepatic ischemia-reperfusion injury. In vivo and in vitro experiments using transgenic mice manifesting excessive Cu-Zn SOD activity. Free Radic Biol Med 29:756–763

    Article  PubMed  CAS  Google Scholar 

  28. Szeto HH (2006) Mitochondria-targeted peptide antioxidants: novel neuropro-tective agents. AAPS J 8:E521–E531

    Article  PubMed  CAS  Google Scholar 

  29. Powanda DD, Chang TM (2002) Cross-linked polyhemoglobin-superoxide dismutase-catalase supplies oxygen without causing blood-brain barrier disruption or brain edema in a rat model of transient global brain ischemia-reperfusion. Artif Cells Blood Substit Immobil Biotechnol 30:23–37

    Article  PubMed  CAS  Google Scholar 

  30. Chan PH, Kawase M, Murakami K, Chen SF, Li Y, Calagui B, Reola L, Carlson E, Epstein CJ (1998) Overexpression of SOD1 in transgenic rats protects vulnerable neurons against ischemic damage after global cerebral ischemia and reperfusion. J Neurosci 18:8292–8299

    PubMed  CAS  Google Scholar 

  31. Kofler J, Hurn PD, Traystman RJ (2005) SOD1 overexpression and female sex exhibit region-specific neuroprotection after global cerebral ischemia due to cardiac arrest. J Cereb Blood Flow Metab 25:1130–1137

    Article  PubMed  CAS  Google Scholar 

  32. Nishi T, Maier CM, Hayashi T, Saito A, Chan PH (2005) Superoxide dismutase 1 overexpression reduces MCP-1 and MIP-1 alpha expression after transient focal cerebral ischemia. J Cereb Blood Flow Metab 25:1312–1324

    Article  PubMed  CAS  Google Scholar 

  33. Ji H, Zhang X, Du Y, Liu H, Li S, Li L (2012) Polydatin modulates inflammation by decreasing NF-κB activation and oxidative stress by increasing Gli1, Ptch1, SOD1 expression and ameliorates blood-brain barrier permeability for its neuroprotective effect in pMCAO rat brain. Brain Res Bull 87:50–59

    Article  PubMed  CAS  Google Scholar 

  34. Chelikani P, Fita I, Loewen PC (2004) Diversity of structures and properties among catalases. Cell Mol Life Sci 61:192–208

    Article  PubMed  CAS  Google Scholar 

  35. Wang GG, Lu XH, Li W, Zhao X, Zhang C (2011) Protective effects of luteolin on diabetic nephropathy in STZ-induced diabetic rats. Evid Based Complement Alternat Med 2011:323171

    PubMed  Google Scholar 

  36. Liu R, Meng F, Zhang L, Liu A, Qin H, Lan X, Li L, Du G (2011) Luteolin isolated from the medicinal plant Elsholtzia rugulosa (Labiatae) prevents copper-mediated toxicity in β-amyloid precursor protein Swedish mutation overexpressing SH-SY5Y cells. Molecules 16:2084–2096

    Article  PubMed  CAS  Google Scholar 

  37. Rump AF, Schüssler M, Acar D, Cordes A, Ratke R, Theisohn M, Rösen R, Klaus W, Fricke U (1995) Effects of different inotropes with antioxidant properties on acute regional myocardial ischemia in isolated rabbit hearts. Gen Pharmacol 26:603–611

    Article  PubMed  CAS  Google Scholar 

  38. Qiusheng Z, Yuntao Z, Rongliang Z, Dean G, Changling L (2005) Effects of verbascoside and luteolin on oxidative damage in brain of heroin treated mice. Pharmazie 60:539–543

    PubMed  Google Scholar 

  39. Broughton BR, Reutens DC, Sobey CG (2009) Apoptotic mechanisms after cerebral ischemia. Stroke 40:e331–e339

    Article  PubMed  Google Scholar 

  40. Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656

    Article  PubMed  CAS  Google Scholar 

  41. Srivastava M, Ahmad N, Gupta S, Mukhtar H (2001) Involvement of Bcl-2 and Bax in photodynamic therapy-mediated apoptosis. Antisense Bcl-2 oligonucleotide sensitizes RIF 1 cells to photodynamic therapy apoptosis. J Biol Chem 276:15481–15488

    Article  PubMed  CAS  Google Scholar 

  42. Budihardjo I, Oliver H, Lutter M, Luo X, Wang X (1999) Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 15:269–290

    Article  PubMed  CAS  Google Scholar 

  43. Wang X (2001) The expanding role of mitochondria in apoptosis. Genes Dev 15:2922–2933

    PubMed  CAS  Google Scholar 

  44. Sun D, Huang J, Zhang Z, Gao H, Li J, Shen M, Cao F, Wang H (2012) Luteolin limits infarct size and improves cardiac function after myocardium ischemia/reperfusion injury in diabetic rats. PLoS ONE 7:e33491

    Article  PubMed  CAS  Google Scholar 

  45. Fang F, Li D, Pan H, Chen D, Qi L, Zhang R, Sun H (2011) Luteolin inhibits apoptosis and improves cardiomyocyte contractile function through the PI3K/Akt pathway in simulated ischemia/reperfusion. Pharmacology 88:149–158

    Article  PubMed  CAS  Google Scholar 

  46. Mark KS, Davis TP (2002) Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation. Am J Physiol Heart Circ Physiol 282:H1485–H1494

    PubMed  CAS  Google Scholar 

  47. Petito CK (1979) Early and latemechanisms of increased vascular permeability following experimental cerebral infarction. J Neuropathol Exp Neurol 38:222–234

    Article  PubMed  CAS  Google Scholar 

  48. Kahles T, Luedike P, Endres M, Galla HJ, Steinmetz H, Busse R, Neumann-Haefelin T, Brandes RP (2007) NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke 38:3000–3006

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was funded by Hebei Province (Grant no. C2010000564 and no. 10276104D); we thank technicians Ruichun Liu and Hongran Wu for their technical assistance, and Prof. Yansu Guo M.D. PhD. and Prof. Weisong Duan M.D. PhD. for providing valuable suggestions.

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Correspondence to Xiangjian Zhang.

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Huimin Qiao and Lipeng Dong are co-first authors.

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Qiao, H., Dong, L., Zhang, X. et al. Protective Effect of Luteolin in Experimental Ischemic Stroke: Upregulated SOD1, CAT, Bcl-2 and Claudin-5, Down-Regulated MDA and Bax Expression. Neurochem Res 37, 2014–2024 (2012). https://doi.org/10.1007/s11064-012-0822-1

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  • DOI: https://doi.org/10.1007/s11064-012-0822-1

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