Regression of Intracranial Aneurysms by Simultaneous Inhibition of Nuclear Factor-κB and Ets With Chimeric Decoy Oligodeoxynucleotide Treatment

Abstract

Abstract BACKGROUND: Despite a high mortality and morbidity of subarachnoid hemorrhage due to an intracranial aneurysm (IA), there is no effective medical treatment to prevent the rupture of IAs. Recent studies have revealed the involvement of the transactivation of proinflammatory genes by nuclear factor-κB (NF-κB) and Ets-1 in the pathogenesis of IA formation and enlargement. OBJECTIVE: To examine the regressive effect of chimeric decoy oligodeoxynucleotides (ODNs), which simultaneously inhibit NF-κB and Ets-1, on IA development in the rat model. METHODS: One month after IA induction, rats were treated with NF-κB decoy ODNs or chimeric decoy ODNs. Size, media thickness, macrophage infiltration, and collagen biosynthesis in IA walls were analyzed in both groups. RESULTS: The treatment with chimeric decoy ODNs decreased IA size and thickened IA walls of preexisting IAs induced in the rat model, although the treatment with NF-κB decoy ODNs failed to regress preexisting IAs. Chimeric decoy ODN-treated rats exhibited decreased expression of monocyte chemotactic protein-1 and macrophage infiltration in IA walls. In addition, decreased collagen biosynthesis in IA walls was ameliorated in the chimeric decoy ODN-treated group. CONCLUSION: The results suggest the possibility of a minimally invasive molecular therapy targeting the inhibition of NF-κB and ets-1 for IAs in humans.