Background and purpose
The 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.
Conclusions
IL-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.
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-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.
Purpose
The 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.
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-1beta induction, only high-dose treatment group significantly inhibited the phosphorylation of JNK, MMP-9 induction, and ZO-1 degradation. Conclusions: IL-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.