Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurological deficits in stroke

Alessio Alfieri, Salil Srivastava, Richard C. M. Siow, Diana Cash, Michel Modo, Michael R. Duchen, Paul A. Fraser, Steven C. R. Williams, Giovanni E. Mann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

189 Citations (Scopus)

Abstract

Disruption of the blood-brain barrier (BBB) and cerebral edema are the major pathogenic mechanisms leading to neurological dysfunction and death after ischemic stroke. The brain protects itself against infarction via activation of endogenous antioxidant defense mechanisms, and we here report the first evidence that sulforaphane-mediated preactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1) in the cerebral vasculature protects the brain against stroke. To induce ischemic stroke, Sprague-Dawley rats were subjected to 70 min middle cerebral artery occlusion (MCAo) followed by 4, 24, or 72 h reperfusion. Nrf2 and HO-1 protein expression was upregulated in cerebral microvessels of pen-infarct regions after 4-72 h, with HO-1 preferentially associated with perivascular astrocytes rather than the cerebrovascular endothelium. In naive rats, treatment with sulforaphane increased Nrf2 expression in cerebral microvessels after 24 h. Upregulation of Nrf2 by sulforaphane treatment prior to transient MCAo (1 h) was associated with increased HO-1 expression in perivascular astrocytes in pen-infarct regions and cerebral endothelium in the infarct core. BBB disruption, lesion progression, as analyzed by MRI, and neurological deficits were reduced by sulforaphane pretreatment. As sulforaphane pretreatment led to a moderate increase in peroxynitrite generation, we suggest that hormetic preconditioning underlies sulforaphane-mediated protection against stroke. In conclusion, we propose that pharmacological or dietary interventions aimed to precondition the brain via activation of the Nrf2 defense pathway in the cerebral microvasculature provide a novel therapeutic approach for preventing BBB breakdown and neurological dysfunction in stroke.

Original languageEnglish
Pages (from-to)1012-1022
Number of pages11
JournalFree Radical Biology and Medicine
Volume65
DOIs
Publication statusPublished - Dec 2013

Keywords

  • Stroke
  • Nrf2
  • Hems oxygenase
  • Gliovascular complex
  • Blood-brain barrier
  • Sulforaphane
  • Preconditioning
  • TRANSCRIPTION FACTOR NRF2
  • HEME OXYGENASE-1 GENE
  • OXIDATIVE STRESS
  • NEUROVASCULAR PROTECTION
  • ARTERY OCCLUSION
  • ISCHEMIC BRAIN
  • RAT-BRAIN
  • PERMEABILITY TRANSITION
  • BEHAVIORAL-ASSESSMENT
  • MOLECULAR-MECHANISMS

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