Pharmacological stabilization of intracranial aneurysms in mice: a feasibility study.
OBJECTIVE
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 6 days after aneurysm induction. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysms with subarachnoid hemorrhage.


RESULTS
Minocycline and doxycycline significantly reduced rupture rates (vehicle versus doxycycline=80% versus 35%, P<0.05; vehicle versus minocycline=73% versus 24%, P<0.05) without affecting the overall incidence of aneurysms. However, SB-3CT did not affect the rupture rate (62% versus 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.
Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue, No. 3C-38, San Francisco, CA 94110, USA.
Hiroshi
H
Makino
Yoshiteru
Y
Tada
Kosuke
K
Wada
Elena I
EI
Liang
Mayland
M
Chang
Shahriar
S
Mobashery
Yasuhisa
Y
Kanematsu
Chie
C
Kurihara
Emma
E
Palova
Miyuki
M
Kanematsu
Keiko
K
Kitazato
Tomoki
T
Hashimoto
D017542:Aneurysm, Ruptured / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004318:Doxycycline / Q000627:therapeutic use; D005240:Feasibility Studies; D018093:Gelatinases / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000627:therapeutic use; D002532:Intracranial Aneurysm / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000627:therapeutic use; D009460:Neurologic Examination; D011480:Protease Inhibitors / Q000627:therapeutic use; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy / Q000473:pathology; D013450:Sulfones / Q000627:therapeutic use; D016019:Survival Analysis; D013754:Tetracyclines / Q000627:therapeutic use
D006573:Heterocyclic Compounds, 1-Ring; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; C429533:SB 3CT compound; D013450:Sulfones; D013754:Tetracyclines; D018093:Gelatinases; D008911:Minocycline; D004318:Doxycycline