Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurological deficits in stroke.
Free Radic Biol Med
; 65: 1012-1022, 2013 Dec.
Article
en En
| MEDLINE
| ID: mdl-24017972
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 peri-infarct regions after 4-72 h, with HO-1 preferentially associated with perivascular astrocytes rather than the cerebrovascular endothelium. In naïve rats, treatment with sulforaphane increased Nrf2 expression in cerebral microvessels after 24h. Upregulation of Nrf2 by sulforaphane treatment prior to transient MCAo (1h) was associated with increased HO-1 expression in perivascular astrocytes in peri-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.
Palabras clave
3,3'-diaminobenzidine; 4,6-diamidino-2-phenylindole; ARE; BBB; Bloodbrain barrier; DAB; DAPI; GFAP; Gliovascular complex; HO; Heme oxygenase; Iba1; Keap1; Kelch-like ECH associated protein 1; MCAo; Nrf2; Preconditioning; Prx1; RECA-1; RNS; ROS; Stroke; Sulforaphane; antioxidant response element; bloodbrain barrier; glial fibrillary acidic protein; heme oxygenase; ionized calcium binding adaptor molecule 1; middle cerebral artery occlusion; nuclear factor erythroid 2-related factor 2; peroxiredoxin 1; rat endothelial cell antigen-1; reactive nitrogen species; reactive oxygen species
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Trastornos Psicomotores
/
Barrera Hematoencefálica
/
Isotiocianatos
/
Fármacos Neuroprotectores
/
Infarto de la Arteria Cerebral Media
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Hemo-Oxigenasa 1
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Factor 2 Relacionado con NF-E2
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Proteínas de la Membrana
Límite:
Animals
Idioma:
En
Revista:
Free Radic Biol Med
Asunto de la revista:
BIOQUIMICA
/
MEDICINA
Año:
2013
Tipo del documento:
Article
País de afiliación:
Reino Unido