Critical role of TNF-α in cerebral aneurysm formation and progression to rupture

Robert M. Starke, Nohra Chalouhi, Pascal M. Jabbour, Stavropoula I. Tjoumakaris, L. F. Gonzalez, Robert H. Rosenwasser, Kosuke Wada, Kenji Shimada, David M. Hasan, Nigel H. Greig, Gary K. Owens, Aaron S. Dumont

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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.

Original languageEnglish (US)
Article number77
JournalJournal of Neuroinflammation
Volume11
DOIs
StatePublished - Apr 16 2014
Externally publishedYes

Keywords

  • Aneurysm
  • Cerebral
  • Rupture
  • Subarachnoid hemorrhage
  • TNF-alpha
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

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