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A likely protective effect of dimethyl itaconate on cerebral ischemia/reperfusion injury

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Abstract

As a membrane-permeable derivative of itaconate, dimethyl itaconate (DMI) was recently showed to limit inflammatory response of activated macrophages, and to decrease the generation of reactive oxygen species and reduce cardiac ischemia/reperfusion injury. However, the effect of DMI in the context of cerebral ischemia/reperfusion injury remains unclear. Here, we treated the transient middle cerebral artery occlusion (tMCAO) mice with DMI or saline at the beginning of occlusion, and allowed them to recover for 3 days. We found that DMI obviously decreased the neurologic deficit score. Further, DMI significantly inhibited the toxic conversion of the peri-infarct microglia, and decreased the protein level of interleukin 1β. The present findings suggest that DMI might be recognized as a promising candidate for the treatment of ischemic stroke.

Introduction

Although preclinical studies on neuroprotective agents have been moving on, timely restoration of the interrupted cerebral blood flew after brain ischemia is still the most widely accepted and effective strategy. Following the made progress of thrombolytic therapy and endovascular treatment, ischemia/reperfusion brain injury has attracted close attention. Reperfusion induces the excessive reactive oxygen species (ROS) and subsequent oxidative stress which aggravates ischemic brain injury [1]. ROS also exacerbates neurotoxic inflammatory response [2]. Recent study highlighted the causal role of ischemic succinate accumulation in multiple ischemia/reperfusion injuries, and showed that dimethyl malonate, a competitive inhibitor of succinate dehydrogenase (Sdh), could reduce ischemic succinate accumulation and reperfusion damage [3], uncovering a possible target of treating ischemia/reperfusion diseases.

Nuclear factor erythroid 2-related factor (Nrf2) is well known for the endogenous defense against oxidative stress and inflammation. Nrf2 maintains physiological low expression through being associated with Kelch-like ECH-associated protein 1 (KEAP 1) [4]. The expression of Nrf2 and its target proteins like heme oxygenase (HO)-1 in brain are elevated after ischemic stroke, indicating an adaptively defensive mechanism [5]. It’s also showed that the downstream metabolites of heme produced by HO-1 catalysis, such as carbon monoxide and bilirubin, could offer potent anti-inflammatory and antioxidant effects on ischemic brain injury [6], [7]. Nrf2 pathway has been generally considered as a protective target of ischemic stroke.

Lately, dimethyl itaconate (DMI), which is a cell-permeable derivative of itaconate, was identified to suppress inflammatory response of activated bone marrow-derived macrophages (BMDMs) via inhibiting Sdh [8]. In a myocardial ischemia/reperfusion mouse model, DMI reduced infarct size through limiting Sdh and decreasing ROS levels [8], suggesting that DMI could alleviate Sdh-mediated oxidative stress. In addition, DMI could increase LPS-stimulated Nrf2 expression and decrease protein levels of inflammatory cytokines, for example interleukin 1β (IL1β), in vitro assay [9], indicating that DMI may function as the Nrf2 activator. However, whether DMI affects the outcomes of cerebral ischemia/reperfusion injury remains unknown. In this study, we investigated the role of DMI in the mouse model of transient middle cerebral artery occlusion (tMCAO) to test our hypothesis that DMI might protect against ischemia/reperfusion-induced brain injury.

Section snippets

Animals

Adult male C57BL/6 mice (26–29 g) were obtained from the Animal Experimental Center of Zhengzhou University. Animal use and procedures were in accordance with the regulations for the management of experimental animals issued by the Ministry of Science and Technology of the People’s Republic of China, and approved by the Animal Care and Use Committee of the Fifth Affiliated Hospital of Zhengzhou University. Every effort was made to minimize the number of mice used and their suffering.

tMCAO model

We carried

DMI alleviates neurologic deficits after tMCAO

We assessed the neurologic deficit score on day 3 post stroke, and found that the DMI-treated mice had significantly lower score than did those treated with saline (Fig. 1).

DMI attenuates the toxic conversion of the microglia 3 days after tMCAO

Immunofluorescence staining showed that the number of the peri-infarct toxic M1 microglia labeled by Iba-1 and CD16/CD32, was notably fewer in the DMI-treated group than that in the saline-treated group (Fig. 2A, B). Further, DMI significantly limited the tMCAO-induced elevation of IL1β protein level (Fig. 2C, D).

Discussion

We studied whether the itaconate derivative DMI could be beneficial for the cerebral ischemia/reperfusion injury. Using tMCAO mouse model, we showed that DMI decreased neurologic deficits, indicating a potentially protective effect of DMI on ischemic stroke. Further, DMI inhibited the toxic M1 microglia polarization and decreased the expression of IL1β. These findings preliminarily suggest that DMI may likely be an option for the treatment of the ischemia/reperfusion-induced brain injury.

Conclusion

In conclusion, we partly identified that DMI could promote functional recovery, and suppress the toxic polarization of the microglia in tMCAO mice. These findings might suggest DMI as a potential applicable agent for the treatment of cerebral ischemia/reperfusion injury.

Funding

This work was supported by grants from the National Natural Science Foundation of China (81571137 and 81771247).

Declaration of Competing Interest

The authors declare that they have no conflict of interest.

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