Targeting the Nrf2-Keap1 Antioxidant Defence Pathway for Neurovascular Protection in Stroke

Overview

Journal J Physiol

Specialty Physiology

Date 2011 Jun 8

PMID 21646410

Citations 84

Authors

Alessio Alfieri

Salil Srivastava

Richard C M Siow

Michel Modo

Paul A Fraser

Giovanni E Mann

Affiliations

Soon will be listed here.

Abstract

Endogenous defence mechanisms by which the brain protects itself against noxious stimuli and recovers from ischaemic damage are a key target of stroke research. The loss of viable brain tissue in the ischaemic core region after stroke is associated with damage to the surrounding area known as the penumbra. Activation of the redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the cellular defence against oxidative stress via transcriptional upregulation of phase II defence enzymes and antioxidant stress proteins. Although recent evidence implicates Nrf2 in neuroprotection, it is not known whether activation of this pathway within the neurovascular unit protects the brain against blood-brain barrier breakdown and cerebrovascular inflammation. Targeting the neurovascular unit should provide novel insights for effective treatment strategies and facilitate translation of experimental findings into clinical therapy. This review focuses on the cytoprotective role of Nrf2 in stroke and examines the evidence that the Nrf2-Keap1 defence pathway may serve as a therapeutic target for neurovascular protection.

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References

Carmichael S . Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx. 2006; 2(3):396-409. PMC: 1144484. DOI: 10.1602/neurorx.2.3.396. View

Baron J . Perfusion thresholds in human cerebral ischemia: historical perspective and therapeutic implications. Cerebrovasc Dis. 2001; 11 Suppl 1:2-8. DOI: 10.1159/000049119. View

Schroeter M, Mertsch K, Giese H, Muller S, Sporbert A, Hickel B . Astrocytes enhance radical defence in capillary endothelial cells constituting the blood-brain barrier. FEBS Lett. 1999; 449(2-3):241-4. DOI: 10.1016/s0014-5793(99)00451-2. View

Innamorato N, Rojo A, Garcia-Yague A, Yamamoto M, de Ceballos M, Cuadrado A . The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol. 2008; 181(1):680-9. DOI: 10.4049/jimmunol.181.1.680. View

Jain A, Jaiswal A . GSK-3beta acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2. J Biol Chem. 2007; 282(22):16502-10. DOI: 10.1074/jbc.M611336200. View

Halliwell B . Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging. 2001; 18(9):685-716. DOI: 10.2165/00002512-200118090-00004. View

Lakhan S, Kirchgessner A, Hofer M . Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med. 2009; 7:97. PMC: 2780998. DOI: 10.1186/1479-5876-7-97. View

Faraci F . Oxidative stress: the curse that underlies cerebral vascular dysfunction?. Stroke. 2005; 36(2):186-8. DOI: 10.1161/01.STR.0000153067.27288.8b. View

Kensler T, Wakabayashi N, Biswal S . Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2006; 47:89-116. DOI: 10.1146/annurev.pharmtox.46.120604.141046. View

10.

Abbott N, Patabendige A, Dolman D, Yusof S, Begley D . Structure and function of the blood-brain barrier. Neurobiol Dis. 2009; 37(1):13-25. DOI: 10.1016/j.nbd.2009.07.030. View

11.

Stack C, Ho D, Wille E, Calingasan N, Williams C, Liby K . Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington's disease. Free Radic Biol Med. 2010; 49(2):147-58. PMC: 2916021. DOI: 10.1016/j.freeradbiomed.2010.03.017. View

12.

Chen R, Balami J, Esiri M, Chen L, Buchan A . Ischemic stroke in the elderly: an overview of evidence. Nat Rev Neurol. 2010; 6(5):256-65. DOI: 10.1038/nrneurol.2010.36. View

13.

Negi G, Kumar A, Sharma S . Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: effects on NF-κB and Nrf2 cascades. J Pineal Res. 2010; 50(2):124-31. DOI: 10.1111/j.1600-079X.2010.00821.x. View

14.

Surh Y, Kundu J, Na H . Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med. 2008; 74(13):1526-39. DOI: 10.1055/s-0028-1088302. View

15.

Cheng X, Siow R, Mann G . Impaired redox signaling and antioxidant gene expression in endothelial cells in diabetes: a role for mitochondria and the nuclear factor-E2-related factor 2-Kelch-like ECH-associated protein 1 defense pathway. Antioxid Redox Signal. 2010; 14(3):469-87. DOI: 10.1089/ars.2010.3283. View

16.

Simpson J, Ince P, HAYNES L, Theaker R, Gelsthorpe C, Baxter L . Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain. Neuropathol Appl Neurobiol. 2009; 36(1):25-40. DOI: 10.1111/j.1365-2990.2009.01030.x. View

17.

Liverman C, Cui L, Yong C, Choudhuri R, Klein R, Welch K . Response of the brain to oligemia: gene expression, c-Fos, and Nrf2 localization. Brain Res Mol Brain Res. 2004; 126(1):57-66. DOI: 10.1016/j.molbrainres.2004.02.028. View

18.

Allen C, Bayraktutan U . Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke. 2009; 4(6):461-70. DOI: 10.1111/j.1747-4949.2009.00387.x. View

19.

Jung J, Kim G, Chen H, Maier C, Narasimhan P, Song Y . Reperfusion and neurovascular dysfunction in stroke: from basic mechanisms to potential strategies for neuroprotection. Mol Neurobiol. 2010; 41(2-3):172-9. PMC: 2877155. DOI: 10.1007/s12035-010-8102-z. View

20.

Halliwell B . Free radicals and antioxidants - quo vadis?. Trends Pharmacol Sci. 2011; 32(3):125-30. DOI: 10.1016/j.tips.2010.12.002. View