IMM-H004 Protects against Cerebral Ischemia Injury and Cardiopulmonary Complications via CKLF1 Mediated Inflammation Pathway in Adult and Aged Rats.

Naihong Chen,Chen Chen,Qidi Ai,Yun Luo,Shifeng Chu,Zhao Zhang,Yan Gao,Shuai Zhang,Xiaoling Zhang,Pengfei Yang

doi:10.3390/ijms20071661

Abstract

(1) Background: Chemokine-like factor 1 (CKLF1) is a chemokine with potential to be a target for stroke therapy. Compound IMM-H004 is a novel coumarin derivative screened from a CKLF1/C-C chemokine receptor type 4 (CCR4) system and has been reported to improve cerebral ischemia/reperfusion injury. This study aims to investigate the protective effects of IMM-H004 on cerebral ischemia injury and its infectious cardiopulmonary complications in adult and aged rats from the CKLF1 perspective. (2) Methods: The effects of IMM-H004 on the protection was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining, behavior tests, magnetic resonance imaging (MRI) scans, enzyme-linked immunosorbent assay (ELISA), Nissl staining, histo-pathological examination, and cardiopulmonary function detection. Immunohistological staining, immunofluorescence staining, quantitative real-time PCR (qPCR), and western blotting were used to elucidate the underlying mechanisms. (3) Results: IMM-H004 protects against cerebral ischemia induced brain injury and its cardiopulmonary complications, inhibiting injury, and inflammation through CKLF1-dependent anti-inflammation pathway in adult and aged rats. IMM-H004 downregulates the amount of CKLF1, suppressing the followed inflammatory response, and further protects the damaged organs from ischemic injury. (4) Conclusions: The present study suggested that the protective mechanism of IMM-H004 is dependent on CKLF1, which will lead to excessive inflammatory response in cerebral ischemia. IMM-H004 could also be a therapeutic agent in therapy for ischemic stroke and cardiopulmonary complications in the aged population.

Highlights

Acute ischemic stroke is a devastating and debilitating disease, leading to high morbidity and mortality worldwide [1]
(4) Conclusions: The present study suggested that the protective mechanism of IMM-H004 is dependent on Chemokine-like factor 1 (CKLF1), which will lead to excessive inflammatory response in cerebral ischemia
The mRNA and protein expression levels of chemokine receptor type 4 (CCR4) showed no differences among all of the groups (Figure 14A,B). These results demonstrated that the protective effects of IMM-H004 against ischemic stroke-induced brain injury and inflammation is through the CKLF1 pathway involved with NF-κB

Summary

Introduction

Acute ischemic stroke is a devastating and debilitating disease, leading to high morbidity and mortality worldwide [1]. Aging is the biggest risk factor of stroke [2], with incidence doubled every decade after 55 years old [3]. The average age of first stroke onset was at about 70 years old in very large reports, highlighting the large aged population of stroke patients [5,6]. Thrombolytic therapy is commonly used in patients with acute ischemic stroke, and recombinant tissue plasminogen activator (tPA) is the only Food and Drug Administration (FDA)-approved drug in clinical application. It is widely known that thrombolytic therapy only beneficial within 4.5 h after ischemic onset [7], and with high incidences of side effects—such as causing hemorrhagic transformation or augmenting the inflammatory response [8,9]. It is necessary and urgent to develop safer and more effective therapeutic agents for ischemic stroke in the aged population

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