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(Stroke. 2009;40:2519.)
© 2009 American Heart Association, Inc.

Original Contributions

Role of Interleukin-1β in Early Brain Injury After Subarachnoid Hemorrhage in Mice

Takumi Sozen, MD; Reiko Tsuchiyama, MD; Yu Hasegawa, MD, PhD; Hidenori Suzuki, MD, PhD; Vikram Jadhav, MD, BS, PhD; Shigeru Nishizawa, MD, PhD John H. Zhang, MD, PhD

From the Departments of Physiology (T.S., R.T., Y.H., H.S., V.J., J.H.Z.) and Neurosurgery (J.H.Z.), Loma Linda University of Medicine, Calif; and the Department of Neurosurgery (T.S., S.N.), University of Occupational and Environmental Health, Japan.

Correspondence to John H. Zhang, MD, PhD, Department of Neurosurgery, Loma Linda University Medical Center, 11234 Anderson Street, Room 2562B, Loma Linda, CA 92354. E-mail johnzhang3910{at}yahoo.com

Background and Purpose— The role of interleukin (IL)-1β remains unknown in early brain injury (EBI) after subarachnoid hemorrhage (SAH), although IL-1β has been repeatedly reported to increase in the brain and cerebrospinal fluid. The aim of this study is to examine the effects of IL-1β inactivation on EBI after SAH in mice.

Methods— The endovascular perforation model of SAH was produced and 112 mice were assigned to sham, SAH+ vehicle, and SAH+ N-Ac-Tyr-Val-Ala-Asp-chloromethyl ketone (Ac-YVAD-CMK, 6 and 10 mg/kg) groups. Ac-YVAD-CMK, a selective inhibitor of IL-1β converting enzyme, or vehicle was administered intraperitoneally 1 hour post-SAH. EBI was assessed in terms of mortality within 24 hours, neurological scores, brain water content at 24 and 72 hours, Evans blue dye extravasation and Western blot for IL-1β, c-Jun N-Terminal kinase (JNK), matrix metalloproteinase (MMP)-9, and zonula occludens (ZO)-1 at 24 hours after SAH.

Results— High-dose (10 mg/kg) but not low-dose (6 mg/kg) treatment group significantly improved neurological scores, mortality, brain water content, and Evans blue dye extravasation compared with the vehicle group. Although both dosages of Ac-YVAD-CMK attenuated the mature IL-1β induction, only high-dose treatment group significantly inhibited the phosphorylation of JNK, MMP-9 induction, and ZO-1 degradation.

Conclusion— IL-1β activation may play an important role in the pathogenesis of EBI after SAH. The neurovascular protection of Ac-YVAD-CMK may be provided by the inhibition of JNK-mediated MMP-9 induction and the consequent preservation of tight junction protein ZO-1.

Key Words: subarachnoid hemorrhage • early brain injury • interleukin-1β • brain edema • neurovascular protection