CORM-2 inhibits intracerebral hemorrhage-mediated inflammation

ABSTRACT

Background and purpose: Low-dose of carbon monoxide delivered by CO-releasing molecule-2 (CORM-2) had been confirmed having anti-inflammatory efficacy in some inflammatory diseases. Herein, we assessed the usefulness of CORM-2 in correcting intracerebral hemorrhage (ICH)-mediated inflammation.

Methods: Healthy male Sprague Dawley (SD) rats randomly entered into four groups: sham-ICH, ICH, ICH+CORM-2, and ICH+ inactive carbon monoxide releasing molecule 2 (iCORM-2). ICH was induced by 50 μl of autologous arterial blood injected in situ in the rat brain. Neuro-functions of the ICH rats were evaluated with Garcia 18 scores at the 6th, 24th , 48th hou, and the fifthh day post-ICH. And brain tissues surrounding the hematoma area were collected from all ICH rats and assayed with Western blot and immunofluoresence analysis.

Results: Neuro-dysfunctions in ICH rats were very severe than those in ICH +CORM-2 rats. Compared to sham group, the levels of HO-1, IKKβ, NF-κB, and TNF-α in ICH group began to elevate at the 6th hour, and reached to peak at the 48th hour post-ICH, all p < 0.05. While in ICH +CORM-2 group, the expressions of IKKβ, NF-κB, and TNF-α were very weaker than that in ICH group at every time points mentioned above; however, this phenomenon was not reproduced in ICH + iCORM-2 group. HO-1 in ICH+CORM-2 group highlighted in perihematomal area with many activated microglia (Iba-1-positive cells) and co-expressed with TNF-α, all of which were diminished at the fifth day post-ICH.

Conclusion: CORM-2 may attenuate ICH-mediated inflammation by inhibiting microglial activation, which may involve the IKK/NF-κB pathway.

AbbreviationsICH: intracerebral hemorrhage; CO: carbon monoxide; CORM-2: carbon monoxide releasing molecule-2; iCORM-2: inactive carbon monoxide releasing molecule-2; HO-1: heme oxygenase 1; IKKβ: inhibitor of IκB kinases β; NF-κB: nuclear factor-κB; TNF-α: tumor necrosis factor-α; Iba-1: ionized calcium binding adaptor molecule-1; IκB: inhibitor of NF-κB; iNOS: inducible nitric oxide synthase; Keap1: Kelch-like ECH-associated protein 1; Nrf2: NF-E2-related factor 2; DMSO: dimethylsulfoxide

KEYWORDS:

• Intracerebral hemorrhage
• carbon monoxide releasing molecule-2
• IKK/NF-κB signal pathway

Authors contributions

(I) Conception and design: Zhiying Chen, Xiaoping Yin and Ran Meng

(II) Administrative support: Zhiying Chen, Ran Meng

(III) Provision of study materials: Zhiying Chen, Huiyan Zhang, Xiaoping Yin and Ran Meng

(IV) Collection and assembly of data: Zhiying Chen, Huiyan Zhang

(V) Data analysis and interpretation: Zhiying Chen, Huiyan Zhang

(VI) Manuscript writing: All authors

(VII) Final approval of manuscript: All authors

(VIII) The final version has been revised by Ran Meng, Yuchuan Ding, and Christopher Stone.

Acknowledgments

We would like to thank all experimenters who participated in this study for their cooperation.

Disclosure Statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This study was sponsored by the National Key R&D Program of China [2017YFC1308401], the National Natural Science Foundation [81371289, 81660209, 81760221], National Science & Technology Foundational Resource Investigation Program of China [2018FY100900] and the Social Science and Technology Development Fund of Shanghai Fengxian District Science and Technology Commission [20191301].

Notes on contributors

Zhiying Chen

Zhiying Chen did his MD & PhD at the Xuanwu Hospital, Capital Medical University (China) and Beijing Institute for Brain Disorders (China). He participates in the National Key R&D Program of China (2017YFC1308400), the National Natural Science Foundation (81371289, 81660209), and the Project of Beijing Municipal Top Talent for Healthy Work of China (2014-2-015). He has published widely on cerebrovascular diseases.

Ran Meng

Ran Meng is a professor at the Xuanwu Hospital, Capital Medical University (China) and Beijing Institute for Brain Disorders (China). She is the principal receptor for the National Key R&D Program of China (2017YFC1308400), the National Natural Science Foundation (81371289), and the Project of Beijing Municipal Top Talent for Healthy Work of China (2014-2-015). He has published widely on cerebrovascular diseases, especially some valuable therapeutic approaches (such as remote ischemic preconditioning and normobaric oxygen).