Introduction: Alterations in TNF-a expression have been associated with cerebral aneurysms, but a direct role in aneurysm formation and rupture has not been established.
Methods: Aneurysms were induced in mice by a combination of induced hypertension and a single stereotactic injection of elastase into the right basal cistern. To test the role of TNF-a in aneurysm formation, aneurysms were induced in TNF-a knock-out mice and mice pretreated with the synthesized TNF-a inhibitor 3,6’dithiothalidomide (DTH). Aneurysmal rupture was detected by alteration of neurological symptoms and confirmed by the presence of intracranial aneurysms with subarachnoid hemorrhage. TNF-a expression was assessed through real-time PCR and with immunofluorence staining.
Results: Cerebral aneurysm formation occurred in 18 of 22 (81.8%) animals receiving only vehicle as compared to 3 of 12 TNF-a knock-out mice receiving vehicle (25%, p=0.002) and 4 of 12 mice (33%, p=0.008) treated with DTH. TNF-a knock-out mice were 12.4 times (95% CI 1.6-94.2, p=0.015) and those treated with DTH were 4.1 times (95% CI 1.2-14.1, p=0.028) less likely to have aneurysm rupture as compared to those receiving vehicle only. As compared with untreated mice, TNF-a expression was not significantly different in TNF-a knock-out mice or those pre-treated with DTH, but was significantly elevated in unruptured and furthermore ruptured aneurysms.
Conclusions: These data suggests a critical role of TNF-a in the formation and rupture of aneurysms in a model of cerebral aneurysm formation. Inhibitors of TNF-a could be beneficial in preventing aneurysm rupture.
Patient Care: Cerebral aneurysm rupture is associated with significant morbidity and mortality. A significant number of patients may be treated with microsurgery or endovascular coiling, but intervention is not without the risk of neurological injury. A large number of patients are followed clinical as they are deemed either lower risk of hemorrhage or high risk for treatment. Even in these patients, a significant number of patients will go on to experience aneurysmal rupture or receive treatment for aneurysm progression despite originally being considered high risk for intervention or low risk of rupture. Medical therapy that stabilizes aneurysmal progression or rupture could be a beneficial therapy, but currently there are no pharmacological alternatives.
Learning Objectives: 1) Assess animal models of cerebral aneurysm formation and rupture.
2) Determine key proteins involved in cerebral aneurysm pathogenesis
3) Discuss potential future developments in medical therapy for cerebral aneurysms