Molecular Neurobiology

, Volume 31, Issue 1–3, pp 3–16 | Cite as

Kainic acid-mediated excitotoxicity as a model for neurodegeneration

  • Qun Wang
  • Sue Yu
  • Agnes Simonyi
  • Grace Y. Sun
  • Albert Y. SunEmail author


Neuronal excitation involving the excitatory glutamate receptors is recognized as an important underlying mechanism in neurodegenerative disorders. Excitation resulting from stimulation of the ionotropic glutamate receptors is known to cause the increase in intracellular calcium and trigger calcium-dependent pathways that lead to neuronal apoptosis. Kainic acid (KA) is an agonist for a subtype of ionotropic glutamate receptor, and administration of KA has been shown to increase production of reactive oxygen species, mitochondrial dysfunction, and apoptosis in neurons in many regions of the brain, particularly in the hippocampal subregions of CA1 and CA3, and in the hilus of dentate gyrus (DG). Systemic injection of KA to rats also results in activation of glial cells and inflammatory responses typically found in neurodegenerative diseases. KA-induced selective vulnerability in the hippocampal neurons is related to the distribution and selective susceptibility of the AMPA/kainate receptors in the brain. Recent studies have demonstrated ability of KA to alter a number of intracellular activities, including accumulation of lipofuscin-like substances, induction of complement proteins, processing of amyloid precursor protein, and alteration of tau protein expression. These studies suggest that KA-induced excitotoxicity can be used as a model for elucidating mechanisms underlying oxidative stress and inflammation in neurodegenerative diseases. The focus of this review is to summarize studies demonstrating KA-induced excitotoxicity in the central nervous system and possible intervention by anti-oxidants.

Index Entries

Kainic acid excitotoxicity oxidative stress neuronal death astrocyte microglia selective vulnerability hippocampal neurodegeneration resveratrol antioxidant 


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  1. 1.
    Jellinger K.A. and Stadelmann C. (2000) Mechanisms of cell death in neurodegenerative disorders. J. Neural. Transm. 59(Suppl.), 95–114.Google Scholar
  2. 2.
    Doble A. (1999) The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol. Ther. 81, 163–221.PubMedCrossRefGoogle Scholar
  3. 3.
    Meldrum B.S. (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J. Nutr. 130, 1007S-1015S.PubMedGoogle Scholar
  4. 4.
    Sun A.Y. and Chen Y.M. (1998) Oxidative stress and neurodegenerative disorders. J. Biomed. Sci. 5, 401–414.PubMedCrossRefGoogle Scholar
  5. 5.
    Coyle J.T. (1987) Kainic acid: insights into excitatory mechanisms causing selective neuronal degeneration. Ciba Found. Symp. 126, 186–203.PubMedGoogle Scholar
  6. 6.
    Bleakman D. and Lodge D. (1998) Neuropharmacology of AMPA and kainate receptors. Neuropharmacology 37, 1187–1204.PubMedCrossRefGoogle Scholar
  7. 7.
    Sun A.Y., Cheng Y., and Sun G.Y. (1992) Kainic acid-induced excitotoxicity in neurons and glial cells. Prog. Brain Res. 94, 271–280.PubMedGoogle Scholar
  8. 8.
    Cheng Y. and Sun A.Y. (1994) Oxidative mechanisms involved in kainate-induced cytotoxicity in cortical neurons. Neurochem. Res. 19, 1557–1564.PubMedCrossRefGoogle Scholar
  9. 9.
    Gluck M.R., Jayatilleke E., Shaw S., et al. (2000) CNS oxidative stress associated with the kainic acid rodent model of experimental epilepsy. Epilepsy Res. 39, 63–71.PubMedCrossRefGoogle Scholar
  10. 10.
    Milatovic D., Gupta R.C., and Dettbarn W.D. (2002) Involvement of nitric oxide in kainic acid-induced excitotoxicity in rat brain. Brain Res. 957, 330–337.PubMedCrossRefGoogle Scholar
  11. 11.
    Candelario-Jalil E., Al-Dalain S.M., Castillo R., et al. (2001) Selective vulnerability to kainate-induced oxidative damage in different rat brain regions. J. Appl. Toxicol. 21, 403–407.PubMedCrossRefGoogle Scholar
  12. 12.
    Dawson R., Jr., Beal M.F., Bondy S.C., et al. (1995) Excitotoxins, aging, and environmental neurotoxins: implications for understanding human neurodegenerative diseases. Toxicol. Appl. Pharmacol. 134, 1–17.PubMedCrossRefGoogle Scholar
  13. 13.
    1Berger R. and Garnier Y. (1999) Pathophysiology of perinatal brain damage. Brain Res. Brain Res. Rev. 30, 107–134.CrossRefGoogle Scholar
  14. 14.
    Arundine M. and Tymianski M. (2003) Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium 34, 325–337.PubMedCrossRefGoogle Scholar
  15. 15.
    Arundine M. and Tymianski M. (2004) Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell. Mol. Life Sci. 61, 657–668.PubMedCrossRefGoogle Scholar
  16. 16.
    Shen W., Zhang C., and Zhang G. (2002) Nuclear factor kappaB activation is mediated by NMDA and non-NMDA receptor and L-type voltage-gated Ca(2+) channel following severe global ischemia in rat hippocampus. Brain Res. 933, 23–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Yin H.Z., Sensi S.L., Carriedo S.G., et al. (1999) Dendritic localization of Ca(2+)-permeable AMPA/kainate channels in hippocampal pyramidal neurons. J. Comp. Neurol. 409, 250–260.PubMedCrossRefGoogle Scholar
  18. 18.
    Ogoshi F. and Weiss J.H. (2003) Heterogeneity of Ca2+-permeable AMPA/kainate channel expression in hippocampal pyramidal neurons: fluorescence imaging and immunocytochemical assessment. J. Neurosci. 23, 10,521–10,530.Google Scholar
  19. 19.
    Grooms S.Y., Opitz T., Bennett M.V., et al. (2000) Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death. Proc. Natl. Acad. Sci. USA 97, 3631–3636.PubMedCrossRefGoogle Scholar
  20. 20.
    Li S.Y., Ni J.H., Xu D.S., et al. (2003) Down-regulation of GluR2 is associated with Ca2+-dependent protease activities in kainate-induced apoptotic cell death in cultured rat hippocampal neurons. Neurosci. Lett. 352, 105–108.PubMedCrossRefGoogle Scholar
  21. 21.
    Pellegrini-Giampietro D.E., Gorter J.A., Bennett M.V., et al. (1997) The GluR2 (GluR-B) hypothesis: Ca(2+)-permeable AMPA receptors in neurological disorders. Trends Neurosci. 20, 464–470.PubMedCrossRefGoogle Scholar
  22. 22.
    Friedman L.K. (1998) Selective reduction of GluR2 protein in adult hippocampal CA3 neurons following status epilepticus but prior to cell loss. Hippocampus 8, 511–525.PubMedCrossRefGoogle Scholar
  23. 23.
    Weiss J.H. and Sensi S.L. (2000) Ca2+-Zn2+ permeable AMPA or kainate receptors: possible key factors in selective neurodegeneration. Trends Neurosci. 23, 365–371.PubMedCrossRefGoogle Scholar
  24. 24.
    Sun A.Y., Cheng Y., Bu Q., et al. (1992) The biochemical mechanisms of the excitotoxicity of kainic acid. Free radical formation. Mol. Chem. Neuropathol. 17, 51–63.PubMedCrossRefGoogle Scholar
  25. 25.
    Candelario-Jalil E. and Sonia Leon O. (2003) Effects of nimesulide on kainate-induced in vitro oxidative damage in rat brain homogenates. BMC Pharmacol. 3, 7.PubMedCrossRefGoogle Scholar
  26. 26.
    Wang Q., Yu S., Simonyi A., Rottinghaus G., Sun G.Y., and Sun A.Y. (2004) Resveratrol protects against neurotoxicity induced by kainic acid. Neurochem. Res., 29, 2105–2112.PubMedCrossRefGoogle Scholar
  27. 27.
    Patel M. and Li Q.Y. (2003) Age dependence of seizure-induced oxidative stress. Neuroscience 118, 431–437.PubMedCrossRefGoogle Scholar
  28. 28.
    Lei D.L., Yang D.L., and Liu H.M. (1996) Local injection of kainic acid causes widespread degeneration of NADPH-d neurons and induction of NADPH-d in neurons, endothelial cells and reactive astrocytes. Brain Res. 730, 199–206.PubMedGoogle Scholar
  29. 29.
    Yasuda H., Fujii M., Fujisawa H., et al. (2001) Changes in nitric oxide synthesis and epileptic activity in the contralateral hippocampus of rats following intrahippocampal kainate injection. Epilepsia 42, 13–20.PubMedCrossRefGoogle Scholar
  30. 30.
    Brown G.C. and Borutaite V. (2001) Nitric oxide, mitochondria, and cell death. IUBMB Life 52, 189–195.PubMedCrossRefGoogle Scholar
  31. 31.
    Michaelis E.K. (1998) Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog. Neurobiol. 54, 369–415.PubMedCrossRefGoogle Scholar
  32. 32.
    Malva J.O., Carvalho A.P., and Carvalho C.M. (1998) Kainate receptors in hippocampal CA3 subregion: evidence for a role in regulating neurotransmitter release. Neurochem. Int. 32, 1–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Araki T., Simon R.P., Taki W., et al. (2002) Characterization of neuronal death induced by focally evoked limbic seizures in the C57BL/6 mouse. J. Neurosci. Res. 69, 614–621.PubMedCrossRefGoogle Scholar
  34. 34.
    Tomioka M., Shirotani K., Iwata N., et al. (2002) In vivo role of caspases in excitotoxic neuronal death: generation and analysis of transgenic mice expressing baculoviral caspase inhibitor, p35, in postnatal neurons. Brain Res. Mol. Brain Res. 108, 18–32.PubMedCrossRefGoogle Scholar
  35. 35.
    Chen Z., Ljunggren H.G., Zhu S.W., et al. (2004) Reduced susceptibility to kainic acid-induced excitoxicity in T-cell deficient CD4/CD8(−/−) and middle-aged C57BL/6 mice. J. Neuroimmunol. 146, 33–38.PubMedCrossRefGoogle Scholar
  36. 36.
    Schauwecker P.E. (2002) Modulation of cell death by mouse genotype: differential vulnerability to excitatory amino acid-induced lesions. Exp. Neurol. 178, 219–235.PubMedCrossRefGoogle Scholar
  37. 37.
    Nishiyama K., Kwak S., Takekoshi S., et al. (1996) In situ nick end-labeling detects necrosis of hippocampal pyramidal cells induced by kainic acid. Neurosci. Lett. 212, 139–142.PubMedCrossRefGoogle Scholar
  38. 38.
    Osaka H., McGinty A., Hoepken U.E., et al. (1999) Expression of C5a receptor in mouse brain: role in signal transduction and neurodegeneration. Neuroscience 88, 1073–1082.PubMedCrossRefGoogle Scholar
  39. 39.
    Liu W., Kato M., Itoigawa M., et al. (2001) Distinct involvement of NF-kappaB and p38 mitogen-activated protein kinase pathways in serum deprivation-mediated stimulation of inducible nitric oxide synthase and its inhibition by 4-hydroxynonenal. J. Cell. Biochem. 83, 271–280.PubMedCrossRefGoogle Scholar
  40. 40.
    Faherty C.J., Xanthoudakis S., and Smeyne R.J. (1999) Caspase-3-dependent neuronal death in the hippocampus following kainic acid treatment. Brain Res. Mol. Brain Res. 70, 159–163.PubMedCrossRefGoogle Scholar
  41. 41.
    Aschner M. (1998) Astrocytes as mediators of immune and inflammatory responses in the CNS. Neurotoxicology 19, 269–281.PubMedGoogle Scholar
  42. 42.
    Zhang W., Smith C., Howlett C., et al. (2000) Inflammatory activation of human brain endothelial cells by hypoxic astrocytes in vitro is mediated by IL-1beta. J. Cereb. Blood Flow Metab. 20, 967–978.PubMedCrossRefGoogle Scholar
  43. 43.
    Li W., Xia J., and Sun G.Y. (1999) Cytokine induction of iNOS and sPLA2 in immortalized astrocytes (DITNC): response to genistein and pyrrolidine dithiocarbamate. J. Interferon Cytokine Res. 19, 121–127.PubMedCrossRefGoogle Scholar
  44. 44.
    Calabrese V., Copani A., Testa D., et al. (2000) Nitric oxide synthase induction in astroglial cell cultures: effect on heat shock protein 70 synthesis and oxidant/antioxidant balance. J. Neurosci. Res. 60, 613–622.PubMedCrossRefGoogle Scholar
  45. 45.
    Akama K.T. and Van Eldik L.J. (2000) Beta-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1beta- and tumor necrosis factor-alpha (TNFalpha)-dependent, and involves a TNFalpha receptor-associated factor- and NFkappaB-inducing kinase-dependent signaling mechanism. J. Biol. Chem. 275, 7918–7924.PubMedCrossRefGoogle Scholar
  46. 46.
    Kyrkanides S., Moore A.H., Olschowka J.A., et al. (2002) Cyclooxygenase-2 modulates brain inflammation-related gene expression in central nervous system radiation injury. Brain Res. Mol. Brain Res. 104, 159–169.PubMedCrossRefGoogle Scholar
  47. 47.
    Dorandeu F., Pernot-Marino I., Veyret J., et al. (1998) Secreted phospholipase A2-induced neurotoxicity and epileptic seizures after intracerebral administration: an unexplained heterogeneity as emphasized with paradoxin and crotoxin. J. Neurosci. Res. 54, 848–862.PubMedCrossRefGoogle Scholar
  48. 48.
    Wang J.H. and Sun G.Y. (2000) Platelet activating factor (PAF) antagonists on cytokine induction of iNOS and sPLA2 in immortalized astrocytes (DITNC). Neurochem. Res. 25, 613–619.PubMedCrossRefGoogle Scholar
  49. 49.
    Xu J., Weng Y.I., Simonyi A., et al. (2002) Role of PKC and MAPK in cytosolic PLA2 phosphorylation and arachadonic acid release in primary murine astrocytes. J. Neurochem. 83, 259–270.PubMedCrossRefGoogle Scholar
  50. 50.
    Xu J., Yu S., Sun A.Y., et al. (2003) Oxidant-mediated AA release from astrocytes involves cPLA(2) and iPLA(2). Free Radical Biol. Med. 34, 1531–1543.CrossRefGoogle Scholar
  51. 51.
    Farooqui A.A., Yi Ong W., Lu X.R., et al. (2001) Neurochemical consequences of kainate-induced toxicity in brain: involvement of arachidonic acid release and prevention of toxicity by phospholipase A(2) inhibitors. Brain Res. Brain Res. Rev. 38, 61–78.PubMedCrossRefGoogle Scholar
  52. 52.
    Farooqui A.A., Yang H.C., Rosenberger T.A., et al. (1997) Phospholipase A2 and its role in brain tissue. J. Neurochem. 69, 889–901.PubMedCrossRefGoogle Scholar
  53. 53.
    Farooqui A.A., Ong W.Y., and Horrocks L.A. (2004) Neuroprotection abilities of cytosolic phospholipase A2 inhibitors in kainic acid-induced neurodegeneration. Curr. Drug Targets Cardiovasc. Haematol. Disord. 4, 85–96.PubMedCrossRefGoogle Scholar
  54. 54.
    Albers D.S. and Beal M.F. (2000) Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease. J. Neural. Transm. 59(Suppl.), 133–154.Google Scholar
  55. 55.
    Kim H.C., Bing G., Jhoo W.K., et al. (2002) Oxidative damage causes formation of lipofuscin-like substances in the hippocampus of the senescence-accelerated mouse after kainate treatment. Behav. Brain Res. 131, 211–220.PubMedCrossRefGoogle Scholar
  56. 56.
    Ivy G.O., Roopsingh R., Kanai S., et al. (1996) Leupeptin causes an accumulation of lipofuscin-like substances and other signs of aging in kidneys of young rats: further evidence for the protease inhibitor model of aging. Ann. NY Acad. Sci. 786, 12–23.PubMedCrossRefGoogle Scholar
  57. 57.
    Asha Devi S., Prathima S., and Subramanyam M.V. (2003) Dietary vitamin E and physical exercise: II. Antioxidant status and lipofuscinlike substances in aging rat heart. Exp. Gerontol. 38, 291–297.PubMedCrossRefGoogle Scholar
  58. 58.
    Maddalena A., Papassotiropoulos A., Muller-Tillmanns B., et al. (2003) Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42. Arch. Neurol. 60, 1202–1206.PubMedCrossRefGoogle Scholar
  59. 59.
    Rego A.C. and Oliveira C.R. (2003) Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases. Neurochem. Res. 28, 1563–1574.PubMedCrossRefGoogle Scholar
  60. 60.
    Panegyres P.K. (1998) The effects of excitotoxicity on the expression of the amyloid precursor protein gene in the brain and its modulation by neuroprotective agents. J. Neural. Transm. 105, 463–478.PubMedCrossRefGoogle Scholar
  61. 61.
    Shoham S. and Ebstein R.P. (1997) The distribution of beta-amyloid precursor protein in rat cortex after systemic kainate-induced seizures. Exp. Neurol. 147, 361–376.PubMedCrossRefGoogle Scholar
  62. 62.
    Ong W.Y., He Y., and Garey L.J. (1997) Distribution of amyloid beta-protein immunoreactivity in the hippocampus of rats injected with kainate. J. Hirnforsch. 38, 353–361.PubMedGoogle Scholar
  63. 63.
    Louzada P.R., Jr., Paula Lima A.C., de Mello F.G., et al. (2001) Dual role of glutamatergic neurotransmission on amyloid beta(1–42) aggregation and neurotoxicity in embryonic avian retina. Neurosci. Lett. 301, 59–63.PubMedCrossRefGoogle Scholar
  64. 64.
    Morimoto K. and Oda T. (2003) Kainate exacerbates beta-amyloid toxicity in rat hippocampus. Neurosci. Lett. 340, 242–244.PubMedCrossRefGoogle Scholar
  65. 65.
    Harris K.A., Oyler G.A., Doolittle G.M., et al. (1993) Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices. Ann. Neurol. 33, 77–87.PubMedCrossRefGoogle Scholar
  66. 66.
    Esclaire F., Lesort M., Blanchard C., et al. (1997) Glutamate toxicity enhances tau gene expression in neuronal cultures. J. Neurosci. Res. 49, 309–318.PubMedCrossRefGoogle Scholar
  67. 67.
    Hugon J., Terro F., Esclaire F., et al. (2000) Markers of apoptosis and models of programmed cell death in Alzheimer’s disease. J. Neural. Transm. 59(Suppl.), 125–131.Google Scholar
  68. 68.
    Esclaire F., Terro F., Yardin C., et al. (1998) Neuronal apoptosis is associated with a decrease in tau mRNA expression. Neuroreport 9, 1173–1177.PubMedCrossRefGoogle Scholar
  69. 69.
    Hugon J., Esclaire F., Lesort M., et al. (1999) Toxic neuronal apoptosis and modifications of tau and APP gene and protein expressions. Drug Metab. Rev. 31, 635–647.PubMedCrossRefGoogle Scholar
  70. 70.
    Verbeek M.M., Otte-Holler I., van den Born J., et al. (1999) Agrin is a major heparan sulfate proteoglycan accumulating in Alzheimer’s disease brain. Am. J. Pathol. 155, 2115–2125.PubMedGoogle Scholar
  71. 71.
    van Horssen J., Otte-Holler I., David G., et al. (2001) Heparan sulfate proteoglycan expression in cerebrovascular amyloid beta deposits in Alzheimer’s disease and hereditary cerebral hemorrhage with amyloidosis (Dutch) brains. Acta Neuropathol. (Berl). 102, 604–614.Google Scholar
  72. 72.
    van Horssen J., Kleinnijenhuis J., Maass C.N., et al. (2002) Accumulation of heparan sulfate proteoglycans in cerebellar senile plaques. Neurobiol. Aging 23, 537–545.PubMedCrossRefGoogle Scholar
  73. 73.
    Shee W.L., Ong W.Y., and Lim T.M. (1998) Distribution of perlecan in mouse hippocampus following intracerebroventricular kainate injections. Brain Res. 799, 292–300.PubMedCrossRefGoogle Scholar
  74. 74.
    Yasojima K., Schwab C., McGeer E.G., et al. (1999) Up-regulated production and activation of the complement system in Alzheimer’s disease brain. Am. J. Pathol. 154, 927–936.PubMedGoogle Scholar
  75. 75.
    Lynch N.J., Willis C.L., Nolan C.C., et al. (2004) Microglial activation and increased synthesis of complement component C1q precedes blood-brain barrier dysfunction in rats. Mol. Immunol. 40, 709–716.PubMedCrossRefGoogle Scholar
  76. 76.
    Fonseca M.I., Kawas C.H., Troncoso J.C., et al. (2004) Neuronal localization of C1q in preclinical Alzheimer’s disease. Neurobiol. Dis. 15, 40–46.PubMedCrossRefGoogle Scholar
  77. 77.
    Fan R. and Tenner A.J. (2004) Complement C1q expression induced by Abeta in rat hippocampal organotypic slice cultures. Exp. Neurol. 185, 241–253.PubMedCrossRefGoogle Scholar
  78. 78.
    Sarvari M., Vago I., Weber C.S., et al. (2003) Inhibition of C1q-beta-amyloid binding protects hippocampal cells against complement mediated toxicity. J. Neuroimmunol. 137, 12–18.PubMedCrossRefGoogle Scholar
  79. 79.
    Goldsmith S.K., Wals P., Rozovsky I., et al. (1997) Kainic acid and decorticating lesions stimulate the synthesis of C1q protein in adult rat brain. J. Neurochem. 68, 2046–2052.PubMedCrossRefGoogle Scholar
  80. 80.
    Miller N.J. and Rice-Evans C.A. (1995) Antioxidant activity of resveratrol in red wine. Clin. Chem. 41, 1789.PubMedGoogle Scholar
  81. 81.
    Fremont L. (2000) Biological effects of resveratrol. Life Sci. 66, 663–673.PubMedCrossRefGoogle Scholar
  82. 82.
    Sun A.Y., Simonyi A., and Sun G.Y. (2002) The “French Paradox” and beyond: neuroprotective effects of polyphenols. Free Radical Biol. Med. 32, 314–318.CrossRefGoogle Scholar
  83. 83.
    Chanvitayapongs S., Draczynska-Lusiak B., and Sun A.Y. (1997) Amelioration of oxidative stress by antioxidants and resveratrol in PC12 cells. Neuroreport 8, 1499–1502.PubMedCrossRefGoogle Scholar
  84. 84.
    Draczynska-Lusiak B., Doung A., and Sun A.Y. (1998) Oxidized lipoproteins may play a role in neuronal cell death in Alzheimer disease. Mol. Chem. Neuropathol. 33, 139–148.PubMedGoogle Scholar
  85. 85.
    Draczynska-Lusiak B., Chen Y.M., and Sun A.Y. (1998) Oxidized lipoproteins activate NF-kap-paB binding activity and apoptosis in PC12 cells. Neuroreport 9, 527–532.PubMedCrossRefGoogle Scholar
  86. 86.
    Sun A.Y., Chen Y.M., James-Kracke M., et al. (1997) Ethanol-induced cell death by lipid peroxidation in PC12 cells. Neurochem. Res. 22, 1187–1192.PubMedCrossRefGoogle Scholar
  87. 87.
    Sun A.Y. and Sun G.Y. (2001) Ethanol and oxidative mechanisms in the brain. J. Biomed. Sci. 8, 37–43.PubMedCrossRefGoogle Scholar
  88. 88.
    Sun A.Y., Ingelman-Sundberg M., Neve E., et al. (2001) Ethanol and oxidative stress. Alcohol Clin. Exp. Res. 25, 237S-243S.PubMedGoogle Scholar
  89. 89.
    Bastianetto S., Zheng W.H., and Quirion R. (2000) Neuroprotective abilities of resveratrol and other red wine constituents against nitric oxide-related toxicity in cultured hippocampal neurons. Br. J. Pharmacol. 131, 711–720.PubMedCrossRefGoogle Scholar
  90. 90.
    Jang J.H. and Surh Y.J. (2001) Protective effects of resveratrol on hydrogen peroxide-induced apoptosis in rat pheochromocytoma (PC12) cells. Mutat. Res. 496, 181–190.PubMedGoogle Scholar
  91. 91.
    Zini R., Morin C., Bertelli A., et al. (1999) Effects of resveratrol on the rat brain respiratory chain. Drugs Exp. Clin. Res. 25, 87–97.PubMedGoogle Scholar
  92. 92.
    Tadolini B., Juliano C., Piu L., et al. (2000) Resveratrol inhibition of lipid peroxidation. Free Radical Res. 33, 105–114.CrossRefGoogle Scholar
  93. 93.
    Mizutani K., Ikeda K., Kawai Y., et al. (2001) Protective effect of resveratrol on oxidative damage in male and female stroke-prone spontaneously hypertensive rats. Clin. Exp. Pharmacol. Physiol. 28, 55–59.PubMedCrossRefGoogle Scholar
  94. 94.
    Win W., Cao Z., Peng X., et al. (2002) Different effects of genistein and resveratrol on oxidative DNA damage in vitro. Mutat. Res. 513, 113–120.PubMedGoogle Scholar
  95. 95.
    Wang Q., Xu J., Rottinghaus G.E., et al. (2002) Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res. 958, 439–447.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Qun Wang
    • 1
  • Sue Yu
    • 2
  • Agnes Simonyi
    • 2
  • Grace Y. Sun
    • 2
  • Albert Y. Sun
    • 1
    Email author
  1. 1.Department of Medical Pharmacology and PhysiologyUniversity of Missouri School of MedicineColumbia
  2. 2.Department of BiochemistryUniversity of Missouri School of MedicineColumbia

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