Ac-YVAD-cmk improves neurological function by inhibiting caspase-1-mediated inflammatory response in the intracerebral hemorrhage of rats.

Abstract

OBJECTIVE:

Intracerebral hemorrhage (ICH) is acknowledged as a serious clinical problem lacking effective treatments. And caspase-1-mediated inflammatory response happened during the progression of ICH. Therefore, we aimed to investigate the effects of caspase-1 inhibitor Ac-YVAD-cmk on ICH.

MATERIALS AND METHODS:

Microglia cells were isolated and activated by thrombin for 24 h. Then the transcript and protein expressions of NLRP3 and inflammatory factors were assessed by RT-PCR and western blotting. Moreover, Ac-YVAD-cmk was injected into the ICH model. The mNSS and brain water content were tested at 24 h post-ICH. Finally, the pathological changes of microglia activation following ICH were discovered by the immunohistochemical and HE staining ways.

RESULTS:

Ac-YVAD-cmk inhibited the activation of pro-caspase-1 and decreased brain edema, in association with decreasing activated microglia and the expression of inflammation-related factors at 24 h post-ICH. Consequently, Ac-YVAD-cmk reduced the release of mature IL-1β/IL-18 in perihematoma, improved the behavioral performance, and alleviated microglia in perihematoma region in ICH rats.

CONCLUSIONS:

These results indicate that caspase-1 could amplify the plural inflammatory responses in the ICH. Administration of Ac-YVAD-cmk has the potential to be a novel therapeutic strategy for ICH.

• Authors: Hongsheng Liang, Yong Sun, Aili Gao, Nannan Zhang, Ying Jia, Shanshan Yang, Meng Na, Huailei Liu, Xingbo Cheng, Xiaofeng Fang, Wei Ma, Xiangtong Zhang, Fan Wang
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 75 Pg. 105771 (Oct 2019) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 31352322 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Amino Acid Chloromethyl Ketones
• Anti-Inflammatory Agents
• Caspase Inhibitors
• IL1B protein, rat
• Interleukin-18
• Interleukin-1beta
• N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
• NLR Family, Pyrin Domain-Containing 3 Protein
• Neuroprotective Agents
• Nlrp3 protein, rat
• Caspase 1

Topics

• Amino Acid Chloromethyl Ketones (pharmacology, therapeutic use)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Behavior, Animal (drug effects)
• Brain (drug effects, pathology)
• Caspase 1 (immunology)
• Caspase Inhibitors (pharmacology, therapeutic use)
• Cells, Cultured
• Cerebral Hemorrhage (drug therapy, immunology, pathology)
• Interleukin-18 (genetics, immunology)
• Interleukin-1beta (genetics, immunology)
• Male
• Microglia
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, immunology)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Rats, Sprague-Dawley