Pharmacological Stabilization of Intracranial Aneurysms in Mice

Abstract

Background and Purpose An increasing number of unruptured intracranial aneurysms are being detected, partly due to the increased use of brain imaging techniques. Pharmacological stabilization of aneurysms for the prevention of aneurysmal rupture could potentially be an attractive alternative approach to clipping or coiling in patients with unruptured intracranial aneurysms. We have developed a mouse model of intracranial aneurysm that recapitulates key features of intracranial aneurysms. In this model, subarachnoid hemorrhage from aneurysmal rupture causes neurological symptoms that can be easily detected by a simple neurological examination. Using this model, we tested whether anti-inflammatory agents such as tetracycline derivatives, or a selective inhibitor of matrix metalloproteinases-2 and -9 (SB-3CT) can prevent the rupture of intracranial aneurysms. Methods Aneurysms were induced by a combination of induced hypertension and a single injection of elastase into the cerebrospinal fluid in mice. Treatment with minocycline, doxycycline, or SB-3CT was started six days after aneurysm induction. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysm with subarachnoid hemorrhage. Results Minocycline and doxycycline significantly reduced rupture rates (vehicle vs. doxycycline = 80 vs. 35%, P < 0.05; vehicle vs. minocycline = 73 vs. 24%, P < 0.05) without affecting the overall incidence of aneurysms. However, SB-3CT did not affect the rupture rate (62 vs. 55%, P = 0.53). Conclusions Our data established the feasibility of using a mouse model of intracranial aneurysm to test pharmacological stabilization of aneurysms. Tetracycline derivatives could be potentially effective in preventing aneurysmal rupture.

Angiotensin-(1-7) Protects against the Development of Aneurysmal Subarachnoid Hemorrhage in Mice

“…Using the tail cuff method, systolic blood pressure was measured in the mice before aneurysm induction and every week after the elastase injection. 13,14 Real-Time PCR Analysis…”

“…We used a mouse model of intracranial aneurysms in which spontaneous aneurysmal rupture (i.e., aneurysmal subarachnoid hemorrhage) causes neurologic symptoms. 13,14 …”

Successful Serial Imaging of the Mouse Cerebral Arteries Using Conventional 3-T Magnetic Resonance Imaging

“…Therefore, the incidence of ruptured aneurysms was 50%, and the incidence of unruptured aneurysms was 10%, consistent with previous reports using this model. 2,[6][7][8] Intracranial Aneurysm Observation Using Magnetic Resonance Angiography We conducted a total of 54 MRA imaging sessions using the 10 mice. The MRA scanning time for each mouse was 3.7 ± 0.5 minutes.…”

“…7,9 The mice also received a single injection of elastase solution (35 milli-units Elastase: E7885, Sigma Aldrich dissolved in 2.5 μL of phosphate-buffered saline) into the cerebrospinal fluid in the right basal cistern on the same day as the DOCA pellet implantation. [6][7][8] The nephrectomy was performed under general anesthesia with 2% isoflurane. The elastase injection was performed under general anesthesia induced by an intraperitoneal injection of ketamine (100 mg/kg) and xylazine (10 mg/kg).…”

“…As a test case, we utilized a mouse model of an intracranial aneurysm that shows dynamic changes in the cerebral arteries. 2,6,7 In this model, intracranial aneurysms were induced by a combination of systemic hypertension and a single injection of elastase into the cerebrospinal fluid. 2 The aneurysms develop within 7 days after the elastase injection.…”