title: Tumor necrosis factor-α-mediated threonine 435 phosphorylation of p65 nuclear factor-κB subunit in endothelial cells induces vasogenic edema and neutrophil infiltration in the rat piriform cortex following status epilepticus.
abstract: BACKGROUND
  Status epilepticus (SE) induces severe vasogenic edema in the piriform cortex (PC) accompanied by neuronal and astroglial damages. To elucidate the mechanism of SE-induced vasogenic edema, we investigated the roles of tumor necrosis factor (TNF)-α in blood-brain barrier (BBB) disruption during vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced SE.
  
  
  METHODS
  SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline-, and soluble TNF p55 receptor (sTNFp55R) prior to SE induction. Thereafter, we performed Fluoro-Jade B staining and immunohistochemical studies for TNF-α and NF-κB subunits.
  
  
  RESULTS
  Following SE, most activated microglia showed strong TNF-α immunoreactivity. In addition, TNF p75 receptor expression was detected in endothelial cells as well as astrocytes. In addition, only p65-Thr435 phosphorylation was increased in endothelial cells accompanied by SMI-71 expression (an endothelial barrier antigen). Neutralization of TNF-α by soluble TNF p55 receptor (sTNFp55R) infusion attenuated SE-induced vasogenic edema and neuronal damages via inhibition of p65-Thr435 phosphorylation in endothelial cells. Furthermore, sTNFp55R infusion reduced SE-induced neutrophil infiltration in the PC.
  
  
  CONCLUSIONS
  These findings suggest that impairments of endothelial cell functions via TNF-α-mediated p65-Thr 485 NF-κB phosphorylation may be involved in SE-induced vasogenic edema. Subsequently, vasogenic edema results in extensive neutrophil infiltration and neuronal-astroglial loss.
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon, Kangwon-Do, South Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Hea Jin
authors.initials: HJ
authors.lastname: Ryu
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Tae-Cheon
authors.initials: TC
authors.lastname: Kang
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001929:Brain Edema / Q000209:etiology*; D002452:Cell Count / Q000379:methods; D054426:Chemokine CXCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009930:Organic Chemicals; D010766:Phosphorylation / Q000187:drug effects; D010862:Pilocarpine; D017397:Prefrontal Cortex / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D013912:Threonine / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000954:Antigens, Surface; D054426:Chemokine CXCL2; D005452:Fluoresceins; D016328:NF-kappa B; D009930:Organic Chemicals; D014409:Tumor Necrosis Factor-alpha; C114781:endothelial barrier antigen, rat; C435731:fluoro jade; D010862:Pilocarpine; D013912:Threonine