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

Authors

Robert M Starke, Department of Neurological Surgery, Thomas Jefferson University, Department of Neurological Surgery and University of VirginiaFollow
Nohra Chalouhi, MD, Department of Neurological Surgery, Thomas Jefferson UniversityFollow
Pascal Jabbour MD, Department of Neurological Surgery, Thomas Jefferson UniversityFollow
Stavropoula Tjoumakaris, Department of Neurological Surgery, Thomas Jefferson UniversityFollow
L. Fernando Gonzalez, Department of Neurological Surgery, Thomas Jefferson UniversityFollow
Robert H. Rosenwasswer MD, Department of Neurological Surgery, Thomas Jefferson UniversityFollow
Kosuke Wada, Center for Cerebrovascular Research, University of California San Francisco
Kenji Shimada, Center for Cerebrovascular Research, University of California San Francisco
David M Hasan, Department of Neurosurgery, University of IowaFollow
Nigel H Greig, National Institute on Aging, National Institutes of Health Translational Gerontology Branch, Intramural Research Program, District of Columbia
Gary K Owens, Department of Molecular Physiology and Biophysics, Robert M. Berne Cardiovascular Research Center, University of VirginiaFollow
Aaron Dumont, Department of Neurological Surgery, Thomas Jefferson University and Department of Neurological Surgery, Tulane UniversityFollow

Document Type

Article

Publication Date

4-16-2014

Comments

This article is the final published version in Journal of Neuroinflammation Volume 11, April 2014, Article number 77.

The published version is available at DOI: 10.1186/1742-2094-11-77. Copyright © BioMed Central

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.

Recommended Citation

Starke, Robert M; Chalouhi, MD, Nohra; Jabbour, Pascal MD; Tjoumakaris, Stavropoula; Gonzalez, L. Fernando; Rosenwasswer MD, Robert H.; Wada, Kosuke; Shimada, Kenji; Hasan, David M; Greig, Nigel H; Owens, Gary K; and Dumont, Aaron, "Critical role of TNF-α in cerebral aneurysm formation and progression to rupture." (2014). Department of Neurosurgery Faculty Papers. Paper 58.
https://jdc.jefferson.edu/neurosurgeryfp/58

PubMed ID

24739142