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

Zhang, Di; Lu, Zhaoming; Zhang, Zhen; Jiang, Man; Guo, Ruiming; Liu, Chang; Wang, Jianping

doi:10.1016/j.intimp.2019.105924

Cited by 20 publications

(12 citation statements)

References 19 publications

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“…Cordes et al found that exogenous itaconate also suppressed SDH and dramatically affected the expression levels of Hmox1, Nqo1, and Gpx1 genes, initiating the transcription of multiple antioxidant and anti-inflammatory protein in cerebral I/R injury model (Cordes et al, 2020 ). Zhang et al further showed that intraperitoneal administration DI significantly alleviated neurologic deficits and promoted neural functional recovery on day 3 after surgery (Zhang et al, 2019 ). In addition, DI was also showed to inhibit the conversion of M1 microglia which was a critical determinant of pro-inflammatory effects.…”

Section: The Candidate Mechanisms Of Itaconatementioning

confidence: 99%

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

et al. 2021

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Metabolites have recently been found to be involved in significant biological regulation and changes. Itaconate, an important intermediate metabolite isolated from the tricarboxylic acid cycle, is derived from cis-aconitate decarboxylation mediated by immune response gene 1 in mitochondrial matrix. Itaconate has emerged as a key autocrine regulatory component involved in the development and progression of inflammation and immunity. It could directly modify cysteine sites on functional substrate proteins which related to inflammasome, signal transduction, transcription, and cell death. Itaconate can be a connector among immunity, metabolism, and inflammation, which is of great significance for further understanding the mechanism of cellular immune metabolism. And it could be the potential choice for the treatment of inflammation and immune-related diseases. This study is a systematic review of the potential mechanisms of metabolite associated with different pathology conditions. We briefly summarize the structural characteristics and classical pathways of itaconate and its derivatives, with special emphasis on its promising role in future clinical application, in order to provide theoretical basis for future research and treatment intervention.

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Section: The Candidate Mechanisms Of Itaconatementioning

confidence: 99%

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

et al. 2021

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“… 9 Moreover, DMI was shown to offer protection against myocardial and cerebral ischaemic/reperfusion injury in animal models. 10 , 11 Recently, DMI was reported to attenuate neuroinflammation and ameliorate disease severity in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, by our group. 12 …”

Section: Introductionmentioning

confidence: 99%

Immunoresponsive gene 1 modulates the severity of brain injury in cerebral ischaemia

Kuo

Weng

Scofield

et al. 2021

Brain Communications

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Inflammatory stimuli induce immunoresponsive gene 1 expression that in turn catalyses the production of itaconate through diverting cis-aconitate away from the tricarboxylic acid cycle. The immunoregulatory effect of the immunoresponsive gene 1/itaconate axis has been recently documented in lipopolysaccharide-activated mouse and human macrophages. In addition, dimethyl itaconate, an itaconate derivative, was reported to ameliorate disease severity in the animal models of psoriasis and multiple sclerosis. Currently, whether immunoresponsive gene 1/itaconate axis exerts a modulatory effect in ischaemic stroke remains unexplored. In this study, we investigated whether immunoresponsive gene 1 plays a role in modulating ischaemic brain injury. In addition, the molecular mechanism underlying the protective effects of immunoresponsive gene 1 in ischaemic stroke was elucidated. Our results showed that immunoresponsive gene 1 was highly induced in the ischaemic brain following ischaemic injury. Interestingly, we found that IRG1−/− stroke animals exhibited exacerbated brain injury, displayed with enlarged cerebral infarct, compared to wild-type stroke controls. Furthermore, IRG1−/− stroke animals presented aggravated blood–brain barrier disruption, associated with augmented Evans blue leakage and increased immune cell infiltrates in the ischaemic brain. Moreover, IRG1−/− stroke animals displayed elevated microglia activation, demonstrated with increased CD68, CD86 and Iba1 expression. Further analysis revealed that immunoresponsive gene 1 was induced in microglia after ischaemic stroke, and deficiency in immunoresponsive gene 1 resulted in repressed microglial heme oxygenase-1 expression and exacerbated ischaemic brain injury. Notably, the administration of dimethyl itaconate to compensate for the deficiency of immunoresponsive gene 1/itaconate axis led to enhanced microglial heme oxygenase-1 expression, alleviated ischaemic brain injury, improved motor function and decreased mortality in IRG1−/− stroke animals. In summary, we demonstrate for the first time that the induction of immunoresponsive gene 1 in microglia following ischaemic stroke serves as an endogenous protective mechanism to restrain brain injury through heme oxygenase-1 up-regulation. Thus, our findings suggest that targeting immunoresponsive gene 1 may represent a novel therapeutic approach for the treatment of ischaemic stroke.

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“…A variety of immunomodulatory and cytoprotective properties have been identified in addition to its previously postulated antibacterial effects [ 3 , 4 , 5 ]. Consequently, therapeutic efficacy of exogenously applied itaconate, or its methylated or octylated variants, has been demonstrated in preclinical models of infections [ 6 , 7 ], sterile inflammation [ 8 ], and ischemic reperfusion injury [ 9 , 10 , 11 ]. In addition, altered concentrations of itaconate in biological fluids, cells, or tissue have been found in animal diseases [ 12 , 13 ], a mouse model of arthritis [ 14 ], and in a variety of human diseases [ 13 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Establishment, Validation, and Initial Application of a Sensitive LC-MS/MS Assay for Quantification of the Naturally Occurring Isomers Itaconate, Mesaconate, and Citraconate

et al. 2021

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Itaconate is derived from the tricarboxylic acid (TCA) cycle intermediate cis-aconitate and links innate immunity and metabolism. Its synthesis is altered in inflammation-related disorders and it therefore has potential as clinical biomarker. Mesaconate and citraconate are naturally occurring isomers of itaconate that have been linked to metabolic disorders, but their functional relationships with itaconate are unknown. We aimed to establish a sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay for the quantification of itaconate, mesaconate, citraconate, the pro-drug 4-octyl-itaconate, and selected TCA intermediates. The assay was validated for itaconate, mesaconate, and citraconate for intra- and interday precision and accuracy, extended stability, recovery, freeze/thaw cycles, and carry-over. The lower limit of quantification was 0.098 µM for itaconate and mesaconate and 0.049 µM for citraconate in 50 µL samples. In spike-in experiments, itaconate remained stable in human plasma and whole blood for 24 and 8 h, respectively, whereas spiked-in citraconate and mesaconate concentrations changed during incubation. The type of anticoagulant in blood collection tubes affected measured levels of selected TCA intermediates. Human plasma may contain citraconate (0.4–0.6 µM, depending on the donor), but not itaconate or mesaconate, and lipopolysaccharide stimulation of whole blood induced only itaconate. Concentrations of the three isomers differed greatly among mouse organs: Itaconate and citraconate were most abundant in lymph nodes, mesaconate in kidneys, and only citraconate occurred in brain. This assay should prove useful to quantify itaconate isomers in biomarker and pharmacokinetic studies, while providing internal controls for their effects on metabolism by allowing quantification of TCA intermediates.

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

Cited by 20 publications

References 19 publications

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

Immunoresponsive gene 1 modulates the severity of brain injury in cerebral ischaemia

Establishment, Validation, and Initial Application of a Sensitive LC-MS/MS Assay for Quantification of the Naturally Occurring Isomers Itaconate, Mesaconate, and Citraconate

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