1121. Increased Survival Following Treatment with Dimethyl Fumarate in an Elastase Mouse Model of Intracranial Aneurysm Formation and Rupture

Authors: Christopher Carr; Crissey Pascale; Alejandra Martinez; Mimi Chen; Devon O'Donnell; Aaron Dumont (New Orleans, LA)

Introduction:

Subarachnoid hemorrhage (SAH) from intracranial aneurysm (IA) rupture is associated with significant morbidity and mortality. There is a need for non-invasive pharmacological therapy. Work conducted by our laboratory suggests dimethyl fumarate (DMF) has effects on IAs that may be mediated by activating the Keap1-Nrf2-ARE system related to inflammatory pathways.

Methods:

To induce aneurysm formation in mice we used a well-established model including nephrectomy, implantation of a DOCA pellet, replacement of drinking water with saline, and stereotactically injecting elastase into the basal cistern. Mice were treated with DMF or vehicle from time of aneurysm induction until sacrifice two weeks later, when aneurysm formation and rupture was examined at necropsy. Statistical analyses were performed using SAS 9.4; these included analysis of 2-by-2 contingency tables, survival analysis, and validation of clinical signs.

Results:

Seventy percent (42/60) of control mice formed aneurysms versus 51% (31/61) of DMF-treated mice (p=0.04, RR=0.73, 95%CI=0.54-0.98, NNT=6). Sixty-four percent (38/60) of control mice experienced SAH versus 43% (26/61) of DMF-treated mice (p=0.03, RR=0.67, 95%CI=0.47-0.95, NNT=5). Cox proportional hazards regression showed reduced risk of instantaneous death in DMF-treated mice compared to controls (p=0.04, HR=0.52, 95%CI=0.28-0.96). Aneurysm formation was predicted by weight drop (p=0.01, sensitivity=96%, specificity=13%) and hunch (<0.0001, 81%, 63%). Rupture (p <0.0001, 86%, 61%) and death (p=0.0007, 84%, 47%) were predicted by hunch.

Conclusion:

DMF treatment significantly reduced aneurysms formed, aneurysms ruptured, and risk of death in an elastase mouse model. High sensitivity validates clinical signs of IA formation and rupture including weight drop and hunch in this model.