• Takumi Sozen, Reiko Tsuchiyama, Yu Hasegawa, Hidenori Suzuki, Vikram Jadhav, Shigeru Nishizawa, and John H Zhang.
• Department of Physiology, Loma Linda University of Medicine, Loma Linda, CA 92354, USA.
• Stroke. 2009 Jul 1;40(7):2519-25.

Background And PurposeThe role of interleukin (IL)-1beta remains unknown in early brain injury (EBI) after subarachnoid hemorrhage (SAH), although IL-1beta has been repeatedly reported to increase in the brain and cerebrospinal fluid. The aim of this study is to examine the effects of IL-1beta inactivation on EBI after SAH in mice.MethodsThe 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-1beta 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-1beta, c-Jun N-Terminal kinase (JNK), matrix metalloproteinase (MMP)-9, and zonula occludens (ZO)-1 at 24 hours after SAH.ResultsHigh-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-1beta induction, only high-dose treatment group significantly inhibited the phosphorylation of JNK, MMP-9 induction, and ZO-1 degradation.ConclusionsIL-1beta 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.

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