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

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. © 2014 starke et al.; licensee biomed central ltd.