Journal of Neural Transmission

, Volume 120, Issue 8, pp 1217–1223 | Cite as

Cerebroprotective potential of resveratrol through anti-oxidant and anti-inflammatory mechanisms in rats

  • Prabhakar OrsuEmail author
  • B. V. S. N. Murthy
  • Annapurna Akula
Neurology and Preclinical Neurological Studies - Original Article


Oxidative stress and inflammation are two important pathological mechanisms involved in cerebral ischemia and reperfusion injury. In pathological conditions such as cerebral infarction, the free radical production is greater than that of elimination by endogenous anti-oxidant system, by this undesirable effect brain is highly injured. Resveratrol is reported to have anti-oxidant and anti-inflammatory, athero-protective activities. Therefore, the aim of the present study is to evaluate the therapeutic potential of resveratrol against cerebral infarction induced by ischemia and reperfusion injury in Wistar rats. Bi-common carotid occlusion followed by 4 h reperfusion model was used to induce cerebral infarction. Percent infarction, oxidative stress markers (malondialdehyde, catalase, superoxide dismutase) and inflammatory markers (myeloperoxidase, TNF-α, IL-6, ICAM-1 and IL-10) were measured. TNF-α, IL-6, IL-10, and intracellular adhesive molecule-I (ICAM-1) levels were quantified by enzyme-linked immunosorbent assay (ELISA). Resveratrol produced significant dose-dependent reduction in percent cerebral infarct volume. At resveratrol 20 mg/kg dose, there was a significant reduction in oxidative stress and inflammatory markers like malondialdehyde, TNF-α, IL-6, myeloperoxidase and ICAM-I and in contrast there was a significant increase in anti-oxidants and anti-inflammatory markers like superoxide dismutase, catalase and IL-10 levels. Resveratrol showed significant cerebroprotective action mediated by anti-oxidant and anti-inflammatory mechanisms.


Resveratrol Ischemia–reperfusion Antioxidant Anti-inflammatory ICAM-I 


Conflict of interest

Not applicable.


  1. Aebi H (1974) Catalase: methods in enzymatic analysis Vol.II (ed.H.U.Bergmer) 673–84Google Scholar
  2. Aggarwal BB, Bhardwai A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y (2004) Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res 24(5A):2783–27840PubMedGoogle Scholar
  3. Alarcon de la Lastra C, Villegas I (2007) Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans 35:1156–1160CrossRefPubMedGoogle Scholar
  4. Andrabi SA, Spina MG, Lorenz P, Ebmeyer U, Wolf G, Horn TF (2004) Oxyresveratrol (trans-2, 3′, 4, 5′- tetrahydroxystilbene) is neuroprotective and inhibits the apoptotic cell death in transient cerebral ischemia. Brain Res 1017:98–107CrossRefPubMedGoogle Scholar
  5. Ban JY, Cho SO, Choi SH, Ju HS, Kim JY, Bae K, Song KS, Seong YH (2008) Neuroprotective effect of Smilacis chinae rhizome on NMDA-induced neurotoxicity in vitro and focal cerebral ischemia in vivo. J Pharmacol Sci 106(1):68–77CrossRefPubMedGoogle Scholar
  6. Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H (1986) Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17:472–476CrossRefPubMedGoogle Scholar
  7. Bruning CA, Prigol M, Luchese C, Jesse CR, Duarte MM, Roman SS, Nogueria CW (2012) Protective effect of diphenyl diselenide on ischemia and reperfusion-induced cerebral injury: involvement of oxidative stress and pro-inflammatory cytokines. Neurochem Res (Epub ahead of print)Google Scholar
  8. Chanvitayapongs S, Draczynska LB, Sun AY (1997) Amelioration of oxidative stress by antioxidant and resveratrol in PC12 cells. Neuroreport 8:1499–1502CrossRefPubMedGoogle Scholar
  9. Dawn B (2007) Resveratrol: ready for prime time? J Mol Cell Cardiol 42(3):484–486CrossRefPubMedGoogle Scholar
  10. Del Zoppo GJ (1997) Microvascular responses to cerebral ischemia/inflammation. Ann NY Acad Sci 823:132–147CrossRefPubMedGoogle Scholar
  11. Della-Morte D, Dave KR, DeFazio RA, Bao YC, Raval AP, Perez-Pinzon MA (2009) Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience 159:993–1002CrossRefPubMedGoogle Scholar
  12. Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 371:1612–1623CrossRefPubMedGoogle Scholar
  13. Frank PG, Lisanti MP (2008) ICAM-1: role in inflammation and in the regulation of vascular permeability. Am J Physiol Heart Circ Physiol 295(3):H926–H927CrossRefPubMedGoogle Scholar
  14. Hakim J (1993) Reactive oxygen species and inflammation. CR Seances Soc Biol Fil 187(3):286–295Google Scholar
  15. Iwasaki Y, Ito S, Suzuki M, Nagahori T, Yamamato T, Konno H (1989) Forebrain ischemia induced by temporary bilateral common carotid occlusion in normotensive rats. J Neurol Sci 90:155–165CrossRefPubMedGoogle Scholar
  16. Juhasz B, Varga B, Gesztelyi R, Kemeny-Beke A, Zsuga J, Tosaki A (2010) Resveratrol: a multifunctional cytoprotective molecule. Curr Pharm Biotechnol 11(8):810–818CrossRefPubMedGoogle Scholar
  17. Kakkar P, Das B, Viswanathan PN (1984) A modified spectrophotometric assay of superoxide dismutase. Ind J Bio Chem Biophys 21(2):130–132Google Scholar
  18. Kaste M (1997) Current therapeutic options for brain ischemia. Neurology 49:s56–s59CrossRefPubMedGoogle Scholar
  19. Keller JN, Kindy MS, Holtsberg FW et al (1998) Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J Neurosci 18(2):687–697PubMedGoogle Scholar
  20. Khan M, Siphon B, Jatana M, Giri S, Gilg AG, Sekhon C, Singh AK (2004) Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J Neurosci Res 76(4):519–527CrossRefPubMedGoogle Scholar
  21. Kim HK (1997) Experimental models of cerebral ischemia. Acta Anaesthesiol Scand Suppl 111:91–92PubMedGoogle Scholar
  22. Kumar P, Padi SS, Naidu PS, Kumar A (2006) Effect of resveratrol on 3-nitropropionic acid-induced biochemical and behavioral changes: possible neuroprotective mechanisms. Behav Pharmacol 17:485–492CrossRefPubMedGoogle Scholar
  23. Lakhan SE, Kirchgessner A, Hfer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7:97CrossRefPubMedGoogle Scholar
  24. Lanzillotta A, Sarnico I, Ingrassia R et al (2010) The acetylation of RelA in Lys310 dictates the NF-κB-dependent response in post-ischemic injury. Cell Death Dis 1:e96CrossRefPubMedGoogle Scholar
  25. Lapi D, Vagnani S, Pignataro G, Esposito E, Paterni M, Colantuoni A (2012) Rat Pial microvascular responses to transient bilateral common carotid artery occlusion and reperfusion: Quercetin’s mechanism of action. Front Physiol 3:99PubMedGoogle Scholar
  26. Liu N, Chen R, Du H, Wang J, Zhang Y, Wen J (2009) Expression of IL-10 and TNF-alpha in rats with cerebral infarction after transplantation with mesenchymal stem cells. Cell Mol Immunol 6:207–213CrossRefPubMedGoogle Scholar
  27. Liu C, Shi Z, Fan L, Chen Z, Wang K, Wang B (2011) Resveratrol improves neuron protection and functional recovery in rat model of spinal cord injury. Brain Res 1374:100–109CrossRefPubMedGoogle Scholar
  28. Markus MA, Morris BJ (2008) Resveratrol in prevention and treatment of common clinical conditions of aging. Clin Interv Aging 3(2):331–339PubMedGoogle Scholar
  29. Mohagheghi F, Khalaj L, Ahmadiani A, Rahmani B (2012) Gemfibrozil pretreatment affecting antioxidant defense system and inflammatory, but not Nrf-2 signaling pathways resulted in female neuroprotection and male neurotoxicity in the rat models of global cerebral ischemia–reperfusion. Neurotox Res (Epub ahead of print)Google Scholar
  30. Mukherjee PK, Ahamed KF, Kumar V, Mukherjee K, Houghton PJ (2007) Protective effect of biflavones from Araucaria bidwillii Hook in rat cerebral ischemia/reperfusion induced oxidative stress. Behav Brain Res 178:221–228CrossRefPubMedGoogle Scholar
  31. Mullane KM, Bruce Smith ND (1985) Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into lschemic myocardium. J Pharmacol Methods 14:157–167CrossRefPubMedGoogle Scholar
  32. Nassar NN, Abdelsalam RM, Abdel-Rahman AA, Abdallah DM (2012) Possible involvement of oxidative stress and inflammatory mediators in the protective effects of the early preconditioning window against transient global ischemia in rats. Neurochem Res 37(3):614–621CrossRefPubMedGoogle Scholar
  33. Okhawa H, Ohishi N, Yagi K (1979) Assay of lipid peroxides in animal tissue by thiobarbituric acid reaction. Anal Biochem 95:351–358CrossRefGoogle Scholar
  34. Park JS, Kim KM, Kim MH, Chang HJ, Baek MK (2009) Resveratrol inhibits tumor cell adhesion to endothelial cells by blocking ICAM-1 expression. Anticancer Res 29(1):355–362PubMedGoogle Scholar
  35. Rahman A, Bando M, Kefer J, Anwar KN, Malik AB (1999) Protein kinase C-activated oxidant generation in endothelial cells signals intercellular adhesion molecule-1 gene transcription. Mol Pharmacol 55(3):575–583PubMedGoogle Scholar
  36. Saito K, Suyama K, Nishida K, Sei Y, Basile AS (1996) Early increases in TNF-alpha, IL-6 and IL-1 beta following transient cerebral ischemia in gerbil brain. Neurosci Lett 206:149–152CrossRefPubMedGoogle Scholar
  37. Sinha K, chaudhary G, Gupta YK (2002) Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats. Life Sci 71:655–665CrossRefPubMedGoogle Scholar
  38. Slemmer JE, Shacka JJ, Sweeney MI, Weber JT (2008) Antioxidants and free radical scavengers for the treatment of stroke, traumatic brain injury and aging. Curr Med Chem 15(4):404–414CrossRefPubMedGoogle Scholar
  39. Solaroglu I, Solaroglu A, Kaptanoglu E, Dede S, Haberal A, Beskonakli E, Kilinc K (2003) Erythropoietin prevents ischemia-reperfusion from inducing oxidative damage in fetal rat brain. Childs Nerv Syst 19:19–22PubMedGoogle Scholar
  40. Thirunavukkarasu M, Penumathsa SV, Koneru S et al (2007) Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of nitric oxide, thioredoxin, and heme oxygenase. Free Radic Biol Med 43(5):720–729CrossRefPubMedGoogle Scholar
  41. Tosaki A, Koltai M, Joo F, Adam G et al (1985) Actinomycin D suppresses the protective effect of dexamethasone in rats affected by global cerebral ischemia. Stroke 16(3):501–505CrossRefPubMedGoogle Scholar
  42. Tosaki A, Szerdahelyi P, Joo F (1994) Treatment with ranitidine of ischemic brain edema. Eur J Pharmacol 264(3):455–458CrossRefPubMedGoogle Scholar
  43. Vidavalur R, Otani H, Singal PK, Singal MN (2006) Significance of wine and resveratrol in cardiovascular disease: French paradox revisited. Exp Clin Cardiol 11(3):217–225PubMedGoogle Scholar
  44. Virgili M, Contestabile A (2000) Partial neuroprotection of in vivo excitotoxic brain damage by chronic administration of the red wine antioxidant agent, trans resveratrol in rats. Neurosci Lett 281(2–3):123–126CrossRefPubMedGoogle Scholar
  45. Wang Q, Xu J, Rottinghaus GE, Simonyi A, Lubahn D, Sun GY, Sun AY (2002) Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res 958(2):439–447CrossRefPubMedGoogle Scholar
  46. Wong CH, Crack PJ (2008) Modulation of neuro-inflammation and vascular response by oxidative stress following cerebral ischemia–reperfusion injury. Curr Med Chem 15(1):1–14CrossRefPubMedGoogle Scholar
  47. Yousuf S, Atif F, Ahmad M, Hoda MN, Khan MB, Ishrat T, Islam F (2007) Selenium plays a modulatory role against cerebral ischemia-induced neuronal damage in rat hippocampus. Brain Res 1147:218–225CrossRefPubMedGoogle Scholar
  48. Yousuf S, Atif F, Ahmad M, Hoda N, Ishrat T, Khan B, Islam F (2009) Resveratrol exerts its neuroprotective effect by modulating mitochondrial dysfunctions and associated cell death during cerebral ischemia. Brain Res 1250:242–253CrossRefPubMedGoogle Scholar
  49. Zhang F, Liu J, Shi JS (2010) Anti-inflammatory activities of resveratrol in the brain: role of resveratrol in microglial activation. Eur J Pharmacol 636:1–7CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  • Prabhakar Orsu
    • 1
    Email author
  • B. V. S. N. Murthy
    • 2
  • Annapurna Akula
    • 3
  1. 1.Srinivasarao College of PharmacyVisakhapatnamIndia
  2. 2.Govt. Polytechnic College for WomenSrikakulamIndia
  3. 3.A.U. College of Pharmaceutical Sciences, Andhra UniversityVisakhapatnamIndia

Personalised recommendations