title: Critical role of TNF-α in cerebral aneurysm formation and progression to rupture.
abstract: BACKGROUND
  Alterations in TNF-α expression have been associated with cerebral aneurysms, but a direct role in formation, progression, and rupture has not been established.
  
  
  METHODS
  Cerebral aneurysms were induced through hypertension and a single stereotactic injection of elastase into the basal cistern in mice. To test the role of TNF-α in aneurysm formation, aneurysms were induced in TNF-α knockout mice and mice pretreated with the synthesized TNF-α inhibitor 3,6'dithiothalidomide (DTH). To assess the role of TNF-α in aneurysm progression and rupture, DTH was started 6 days after aneurysm induction. TNF-α expression was assessed through real-time PCR and immunofluorescence staining.
  
  
  RESULTS
  TNF-α knockout mice and those pre-treated with DTH had significantly decreased incidence of aneurysm formation and rupture as compared to sham mice. As compared with sham mice, TNF-α protein and mRNA expression was not significantly different in TNF-α knockout mice or those pre-treated with DTH, but was elevated in unruptured and furthermore in ruptured aneurysms. Subarachnoid hemorrhage (SAH) occurred between 7 and 21 days following aneurysm induction. To ensure aneurysm formation preceded rupture, additional mice underwent induction and sacrifice after 7 days. Seventy-five percent had aneurysm formation without evidence of SAH. Initiation of DTH treatment 6 days after aneurysm induction did not alter the incidence of aneurysm formation, but resulted in aneurysmal stabilization and a significant decrease in rupture.
  
  
  CONCLUSIONS
  These data suggest a critical role of TNF-α in the formation and rupture of aneurysms in a model of cerebral aneurysm formation. Inhibitors of TNF-α could be beneficial in preventing aneurysmal progression and rupture.
authors.affiliation: Joseph and Marie Field Cerebrovascular Research Laboratory, Division of Neurovascular and Endovascular Surgery, Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, USA. bobby.starke@gmail.com.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Starke
authors.forename: Nohra
authors.initials: N
authors.lastname: Chalouhi
authors.forename: Pascal M
authors.initials: PM
authors.lastname: Jabbour
authors.forename: Stavropoula I
authors.initials: SI
authors.lastname: Tjoumakaris
authors.forename: L Fernando
authors.initials: LF
authors.lastname: Gonzalez
authors.forename: Robert H
authors.initials: RH
authors.lastname: Rosenwasser
authors.forename: Kosuke
authors.initials: K
authors.lastname: Wada
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimada
authors.forename: David M
authors.initials: DM
authors.lastname: Hasan
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Gary K
authors.initials: GK
authors.lastname: Owens
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Dumont
mesh_terms: D017542:Aneurysm, Ruptured / Q000188:drug therapy / Q000209:etiology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001808:Blood Vessels / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000235:genetics; D002532:Intracranial Aneurysm / Q000150:complications* / Q000188:drug therapy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger; D013792:Thalidomide / Q000031:analogs & derivatives / Q000627:therapeutic use; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C562075:3,6'-dithiothalidomide; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide
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