title: Sulforaphane induces neurovascular protection against a systemic inflammatory challenge via both Nrf2-dependent and independent pathways.
abstract: Sepsis is often characterized by an acute brain inflammation and dysfunction, which is associated with increased morbidity and mortality worldwide. Preventing cerebral leukocyte recruitment may provide the key to halt progression of systemic inflammation to the brain. Here we investigated the influence of the anti-inflammatory and anti-oxidant compound, sulforaphane (SFN) on lipopolysaccharide (LPS)-induced cellular interactions in the brain. The inflammatory response elicited by LPS was blunted by SFN administration (5 and 50mg/kg i.p.) 24h prior to LPS treatment in WT animals, as visualized and quantified using intravital microscopy. This protective effect of SFN was lost in Nrf2-KO mice at the lower dose tested, however 50mg/kg SFN revealed a partial effect, suggesting SFN works in part independently of Nrf2 activity. In vitro, SFN reduced neutrophil recruitment to human brain endothelial cells via a down regulation of E-selectin and vascular cell adhesion molecule 1 (VCAM-1). Our data confirm a fundamental dose-dependent role of SFN in limiting cerebral inflammation. Furthermore, our data demonstrate that not only is Nrf2 in part essential in mediating these neuroprotective effects, but they occur via down-regulation of E-selectin and VCAM-1. In conclusion, SFN may provide a useful therapeutic drug to reduce cerebral inflammation in sepsis.
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Holloway
authors.affiliation: Division of Brain Sciences, Imperial College London, London, United Kingdom.
authors.forename: Scarlett
authors.initials: S
authors.lastname: Gillespie
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA; Department for General and Visceral Surgery, University Hospital Muenster, Muenster, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Becker
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.
authors.forename: Shantel A
authors.initials: SA
authors.lastname: Vital
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.
authors.forename: J Steven
authors.initials: JS
authors.lastname: Alexander
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Evans
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA; Division of Brain Sciences, Imperial College London, London, United Kingdom. Electronic address: fgavin@lsuhsc.edu.
authors.forename: Felicity N E
authors.initials: FNE
authors.lastname: Gavins
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D017879:Isothiocyanates / Q000008:administration & dosage / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology; D020556:Neutrophil Infiltration / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy*; D013454:Sulfoxides; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D017879:Isothiocyanates; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D013454:Sulfoxides; C016766:sulforaphane
keywords: Cerebrovascular; Inflammation; Leukocyte; Nrf2; Sulforaphane