Role of interleukin-1beta in early brain injury after subarachnoid hemorrhage in mice.
OBJECTIVE
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.


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.


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.
Sozen
Takumi
T
Department of Physiology, Loma Linda University of Medicine, Loma Linda, CA 92354, USA.
Tsuchiyama
Reiko
R
Hasegawa
Yu
Y
Suzuki
Hidenori
H
Jadhav
Vikram
V
Nishizawa
Shigeru
S
Zhang
John H
JH
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001929:Brain Edema / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D001930:Brain Injuries / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D053583:Interleukin-1beta / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D010750:Phosphoproteins / Q000378:metabolism; D015843:Serpins / Q000494:pharmacology / Q000627:therapeutic use; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D014764:Viral Proteins / Q000494:pharmacology / Q000627:therapeutic use; D062826:Zonula Occludens-1 Protein
D000590:Amino Acid Chloromethyl Ketones; D053583:Interleukin-1beta; D008565:Membrane Proteins; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D010750:Phosphoproteins; D015843:Serpins; C569043:Tjp1 protein, mouse; D014764:Viral Proteins; D062826:Zonula Occludens-1 Protein; C074641:interleukin-1beta-converting enzyme inhibitor; D048670:MAP Kinase Kinase 4; D020780:Matrix Metalloproteinase 9