Molecular and Cellular Biochemistry

, Volume 294, Issue 1–2, pp 137–144 | Cite as

Neuroprotection by resveratrol against traumatic brain injury in rats

  • Ozkan AtesEmail author
  • Suleyman Cayli
  • Eyup Altinoz
  • Iclal Gurses
  • Neslihan Yucel
  • Metin Sener
  • Ayhan Kocak
  • Saim Yologlu


Oxidative stress after traumatic brain injury may contribute to many of the pathophysiologic changes. Resveratrol, naturally present at high concentration in grape skin, seeds, and red wine, has significant antioxidant properties in a variety of in vitro and in vivo models. In this study, we investigate the effect of resveratrol on oxidative stress after traumatic brain injury in rat model.

A total of 54 adult Wistar albino male rats weighing 250–300 g were used. The rats were allocated into three groups. The first group was control (sham-operated) group in which only a craniotomy was performed, the others were trauma and resveratrol groups. A 100 mg/kg single dose of resveratrol, freshly prepared by dissolving in 50% ethanol and diluted in physiological saline (2%), for resveratrol group, and 1 ml ethanol (2%) for trauma group, was administered intraperitoneally immediately after trauma. Weight-drop method was used for achieving head trauma. Then, all groups were separated into three subgroups for biochemical analysis, brain water content and histopathological assessment following trauma. Twenty-four hours after trauma brain water content and malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), xanthine oxidase (XO) levels of traumatic hemisphere were evaluated. Quantitative histopathological analysis was performed on 14th day postinjury. Trauma caused a significant increase in MDA, XO, NO levels and decrease in GSH level as compared to control group. Resveratrol administration significantly reduced MDA, XO and NO levels, increased GSH level, and also attenuated tissue lesion area. Our results indicate that treatment with resveratrol immediately after traumatic brain injury reduce oxidative stress and lesion volume. Future studies involving different doses and the dose–response relationship could promise better results.


glutathione malondialdehyde nitric oxide oxidative stress resveratrol traumatic brain injury xanthine oxidase 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Yakovlev AG, Faden AI (2004) Mechanisms of neural cell death: implications for development of neuroprotective treatment strategies. NeuroRx 1:5–16PubMedCrossRefGoogle Scholar
  2. 2.
    Hall ED, Braughler JM (1989) Central nervous system trauma and stroke. Physiological and pharmacological evidence for the involvement of oxygen radicals and lipid peroxidation. Free Rad Biol Med 6:303–313PubMedCrossRefGoogle Scholar
  3. 3.
    Yukido I, Long DM (1990) The molecular basic of brain injury and brain edema. The role of oxygen free radicals. Neurosurgery 27:1–9Google Scholar
  4. 4.
    Awasthi D, Church DF, Torbati D, Carey ME, Pryor WA (1997) Oxidative stress following traumatic brain injury in rats. Surg Neurol 47:575–582PubMedCrossRefGoogle Scholar
  5. 5.
    Anderson DK, Means ED (1985) Iron-induced lipid peroxidation in spinal cord: protection with mannitol and methylprednisolone. J Free Rad Biol Med 1:59–64CrossRefGoogle Scholar
  6. 6.
    Demediuk P, Sanders RD, Clendenon NR, Means ED, Anderson DK, Horrocks LA (1985) Changes in lipid metabolism in traumatized spinal cord. Prog Brain Res 63:211–216PubMedCrossRefGoogle Scholar
  7. 7.
    Soleas GJ, Diamandis EP, Goldberg DM (1997) Wine as a biological fluid: history, production, and role in disease prevention. J Clin Lab Anal 11:287–313PubMedCrossRefGoogle Scholar
  8. 8.
    Daniel O, Meier MS, Schlatter J, Frischhnecht P (1999) Selected phenolic compounds in cultivated plants: ecologic functions, health implications, and modulation by pesticides. Environ Health Perspect 107:109–114PubMedGoogle Scholar
  9. 9.
    Sobolev VS, Cole RJ (1999) Trans-resveratrol content in commercial peanuts and peanut products. J Agric Food Chem 47:1435–1439PubMedCrossRefGoogle Scholar
  10. 10.
    Fremont L (2000) Biological effects of resveratrol. Life Sci 66:663–673PubMedCrossRefGoogle Scholar
  11. 11.
    Inoue H, Umesono K, Nishimori T, Hirata Y, Tanabe T (1999) Glucocorticoid-mediated suppression of the promoter activity of the cyclooxygenase-2 gene is modulated by expression of its receptor in vascular endothelial cells. Biochem Biophys Res Commun 254:292–298PubMedCrossRefGoogle Scholar
  12. 12.
    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 6:655–665CrossRefGoogle Scholar
  13. 13.
    Inoue H, Tanabe T, Umesono K (2000) Feedback control of cyclooygenase-2 gene expression through PPARgamma. J Biol Chem 275:28028–28032PubMedGoogle Scholar
  14. 14.
    Huang SS, Tsai MC, Chih CL, Hung LM, Tsai SK (2001) Resveratrol reduction of infarct size in Long_Evans rats subjected to focal cerebral ischemia. Life Sci 69:1057–1065PubMedCrossRefGoogle Scholar
  15. 15.
    Bloomfield Rubins H, Davenport J, Babikian V, Brass LM, Collins D, Wexler L, Wagner S, Papademetriou V, Rutan G, Robins SJ (2001) VA-HIT Study Group: reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation 103:2828–2833PubMedGoogle Scholar
  16. 16.
    Kimura Y, Okuda H, Arichi S (1985) Effects of stilbenes on arachidonate metabolism in leukocytes. Biochim Biophys Acta 834:275–278PubMedGoogle Scholar
  17. 17.
    Yang YB, Piao YJ (2003) Effects of resveratrol on secondary damages after acute spinal cord injury in rats. Acta Pharmacol Sin 24:703–710PubMedGoogle Scholar
  18. 18.
    Marklund N, Salci K, Lewen A, Hillered L (1997) Glycerol as a marker for post-traumatic membrane phospholipid degradation in rat brain. Neuroreport 717:109–117Google Scholar
  19. 19.
    Feeney DM, Boyeson MG, Linn RT, Murray HM, Dail WG (1981) Responses to cortical injury: I. Methodology and local effects of contusions in the rat. Brain Res 211:67–77PubMedCrossRefGoogle Scholar
  20. 20.
    Uchiyama M, Mihara M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86:271–278PubMedCrossRefGoogle Scholar
  21. 21.
    Elman GL (1959) Tissue sulphydryl groups. Arch Biochem Biophys 82:70–77CrossRefGoogle Scholar
  22. 22.
    Jungersten L, Edlund A, Petersson AS, Wennmalm A (1996) Plasma nitrate as an index of nitric oxide formation in man: analyses of kinetics and confounding factors. Clin Physiol 16:369–379PubMedGoogle Scholar
  23. 23.
    Zeballos GA, Bernstein RD, Thompson CI, Forfia PR, Seyedi N, Shen W, Kaminski PM, Wolin MS, Hintze TH (1995) Pharmacodynamics of plasma nitrate/nitrite as an indication of nitric oxide formation in conscious dogs. Circulation 91:2982–2988PubMedGoogle Scholar
  24. 24.
    Ozbek E, Turkoz Y, Gokdeniz R, Davarci M, Ozugurlu F (2000) Increased nitric oxide production in the spermatic vein of patients with varicocele. Eur Urol 37:172–175PubMedCrossRefGoogle Scholar
  25. 25.
    Prajda N, Weber G (1975) Malignant transformation-linked imbalance: decreased xanthine oxidase activity in hepatomas. FEBS Lett 59:245–249PubMedCrossRefGoogle Scholar
  26. 26.
    Okiyama K, Smith DH, Gennarelli TA, Simon RP, Leach M, McIntosh TK (1995) The sodium channel blocker and glutamate release inhibitor BW1003C87 and magnesium attenuate regional cerebral edema following experimental brain injury in the rat. J Neurochem 64:802–809PubMedCrossRefGoogle Scholar
  27. 27.
    Huang L, Mehta MP, Nanda A, Zhang JH (2003) The role of multiple hyperbaric oxygenation in expanding therapeutic Windows after acute spinal cord injury in rats. J Neurosurg 99:198–205PubMedGoogle Scholar
  28. 28.
    Kontos HA, Povlishock JT (1986) Oxygen radicals in brain injury. Cent Nerv Syst Trauma 3:257–263PubMedGoogle Scholar
  29. 29.
    Kontos HA, Wei EP (1986) Superoxide production in experimental brain injury. J Neurosurg 64:803–807PubMedCrossRefGoogle Scholar
  30. 30.
    Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59:1609–1623PubMedCrossRefGoogle Scholar
  31. 31.
    Nishio S, Yunoki M, Noguchi Y, Kawauchi M, Asari S, Ohmoto T (1997) Detection of lipid peroxidation and hydroxyl radicals in brain contusion of rats. Acta Neurochir Suppl (Wien) 70:84–86Google Scholar
  32. 32.
    Inoue H, Jiang XF, Katayama T, Osada S, Umesono K, Namura S (2003) Brain protection by resveratrol and fenofibrate against stroke requires peroxisome proliferator-activated receptor α in mice. Neurosci Lett 352:203–206PubMedCrossRefGoogle Scholar
  33. 33.
    Huang SS, Tsai MC, Chih CL, Hung LM, Tsai SK (2001) Resveratrol reduction of infarct size in Long_Evans rats subjected to focal cerebral ischemia. Life Sci 69:1057–1065PubMedCrossRefGoogle Scholar
  34. 34.
    Ray PS, Maulik G, Cordis GA, Berteli AA, Berteli A, Das DK (1999) The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury. Free Radic Biol Med 27:160–169PubMedCrossRefGoogle Scholar
  35. 35.
    Olas B, Wachowicz B (2002) Resveratrol and vitamin C as antioxidants in blood platelets. Thrombosis Res 106:143–148CrossRefGoogle Scholar
  36. 36.
    Chander V, Tirkey N, Chopra K (2005) Resveratrol, a polyphenolic phytoalexin protects against cyclosporine-induced nephrotoxicity through nitric oxide dependent mechanism. Toxicology 210:55–64PubMedCrossRefGoogle Scholar
  37. 37.
    Tadolini B, Juliano C, Piu L, Franconi F, Cabrini L (2000) Resveratrol inhibition of lipid peroxidation. Free Radical Res 33:104–114Google Scholar
  38. 38.
    Chanvitayapongs S, Draczynska-Lusiak B, Sun AY (1997) Amelioration of oxidative stress by antioxidants and resveratrol in PC12 cells. Neuroreport 8:1499–1502PubMedCrossRefGoogle Scholar
  39. 39.
    Zini R, Morin C, Berteli A, Berteli AA, Tillement JP (1999) Effects of resveratrol on the rat brain respiratory chain. Drugs Exp Clin Res 25:87–97PubMedGoogle Scholar
  40. 40.
    Mizutani K, Ikeda K, Kawai Y, Yamori Y (2001) Protective effective of resveratrol on oxidative damage in male and female stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 28:55–59PubMedCrossRefGoogle Scholar
  41. 41.
    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 958:439–447PubMedCrossRefGoogle Scholar
  42. 42.
    Hile R, Nishino T (1995) Flavoprotein structure and mechanism. 4. Xanthine oxidase and xanthine dehydrogenase. FASEB J 9:995–1003Google Scholar
  43. 43.
    Corte ED, Stirpe F (1972) The regulation of rat liver xanthine oxidase. Involvement of thiol groups in the conversion of the enzyme activity from dehydrogenase (type D) into oxidase (type O) and purification of the enzyme. Biochem J 126:739–745PubMedGoogle Scholar
  44. 44.
    McCord JM, Fridovich I (1968) The reduction of cytochrome C by milk xanthine oxidase. J Biol Chem 243:5753–5760PubMedGoogle Scholar
  45. 45.
    Lynch DR, Dawson TM (1994) Secondary mechanisms in neuronal trauma. Curr Opin Neurol 7:510–516PubMedCrossRefGoogle Scholar
  46. 46.
    McIntosh TK (1994) Neurochemical sequelae of traumatic brain injury: therapeutic implications. Cerebrovasc Brain Metab Rev 6:109–162PubMedGoogle Scholar
  47. 47.
    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
  48. 48.
    Kanemitsu H, Tamura A, Kirino T, Oka H, Sano K, Iwamoto T (1989) Allopurinol inhibits uric acid accumulation in the rat brain following focal cerebral ischemia. Brain Res 499:367–370PubMedCrossRefGoogle Scholar
  49. 49.
    Itoh T, Kawakami M, Yamauchi Y, Shimizu S, Nakamura M (1986) Effect of allopurinol on ischemia and reperfusion-induced cerebral injury in spontaneously hypertensive rats. Stroke 17:1284–1287PubMedGoogle Scholar
  50. 50.
    Solaroglu I, Okutan O, Kaptanoglu E, Beskonakli E, Kilinc K (2005) Increased xanthine oxidase activity after traumatic brain injury in rats. J Clin Neurosci 12:273–275PubMedCrossRefGoogle Scholar
  51. 51.
    Moncada S, Higgs A (1993) The l-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012PubMedCrossRefGoogle Scholar
  52. 52.
    Peunova N, Enikolopov G (1993) Amplification of calcium-induced gene transcription by nitric oxide in neuronal cells. Nature 364:450–453PubMedCrossRefGoogle Scholar
  53. 53.
    Ikeda Y, Long DM (1990) The molecular basis of brain injury and brain edema: the role of oxygen free radicals. Neurosurgery 27:1–11PubMedCrossRefGoogle Scholar
  54. 54.
    Eriskat J, Schurer L, Kempski O, Baetmann A (1994) Growth kinetics of primary brain tissue necrosis from a focal lesion. Acta Neurochir Suppl(Wien) 60:425–427Google Scholar
  55. 55.
    Plesnila N, Friedrich D, Eriskat J, Baethmann A, Stoffel M (2003) Relative cerebral blood flow during the secondary expansion of a cortical lesion rats. Neurosci Lett 345:85–88PubMedCrossRefGoogle Scholar
  56. 56.
    Stoffel M, Blau C, Reinl H, Breidt J, Gersonde K, Baethmann A, Plesnila N (2004) Identification of brain tissue necrosis by MRI: validation by histomorphometry. J Neurotrauma 21:733–740PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Ozkan Ates
    • 1
    • 6
    Email author
  • Suleyman Cayli
    • 1
  • Eyup Altinoz
    • 2
  • Iclal Gurses
    • 3
  • Neslihan Yucel
    • 4
  • Metin Sener
    • 1
  • Ayhan Kocak
    • 1
  • Saim Yologlu
    • 5
  1. 1.School of Medicine, Department of NeurosurgeryInonu UniversityMalatyaTurkey
  2. 2.School of Medicine, Department of BiochemistryInonu UniversityMalatyaTurkey
  3. 3.School of Medicine, Department of PathologyInonu UniversityMalatyaTurkey
  4. 4.School of Medicine, Department of Emergency MedicineInonu UniversityMalatyaTurkey
  5. 5.School of Medicine, Department of BiostatisticsInonu UniversityMalatyaTurkey
  6. 6.School of Medicine, Department of Neurosurgery, Turgut Ozal Medical Center Inonu UniversityMalatyaTurkey

Personalised recommendations