3 H -1,2-Dithiole-3-thione as a novel therapeutic agent for the treatment of ischemic stroke through Nrf2 defense pathway

Kuo, Ping‐Chang; Yu, I‐Chen; Scofield, Barbara A.; Brown, Dennis A.; Curfman, Eric; Paraiso, Hallel C.; Chang, Fen‐Lei; Yen, Jui‐Hung

doi:10.1016/j.bbi.2017.01.018

Cited by 51 publications

(40 citation statements)

References 62 publications

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“…De ciency in IRG1 results in decreased cerebral HO-1 expression following ischemic stroke IRG1 induces the production of itaconate, and two itaconate derivatives, DMI and 4-octyl-itaconate, have been shown to induce Nrf2 activation and subsequent HO-1 upregulation (5,8,9). In addition, previous studies have demonstrated that the induction of HO-1 exerts a protective effect against ischemic brain injury (16,18,19). We therefore evaluated whether ischemic stroke induces HO-1 expression in the ischemic brain.…”

Section: Irg1 De Ciency Enhances Neuroin Ammation In Ischemic Strokementioning

confidence: 99%

“…Adult male (3-4 months old) C57BL/6 and IRG1 −/− mice were used for cerebral ischemia experiments as previously described (16). The transient ischemic stroke was induced by an intraluminal suture occlusion model.…”

Section: Middle Cerebral Artery Occlusion (Mcao) Modelmentioning

confidence: 99%

“…Brie y, the ischemic brain harvested from MCAO mice was subjected to 2-mm coronal slicing with a rodent brain matrix followed by 1% TTC staining. After staining, the brain sections were scanned and the infarct volume was calculated by ImageJ as previously described (16).…”

Section: Infarct Volume Measurementsmentioning

confidence: 99%

“…5A and C). To further evaluate whether IRG1 de ciencyinduced BDNF repression can be rescued by the induction of HO-1 expression, IRG1 −/− MCAO mice were administered with either vehicle or D3T, an Nrf2/HO-1 pathway inducer (16,(22)(23)(24), and the ischemic brains were then harvested to assess BDNF expression. D3T strongly upregulated BDNF expression in the ischemic brain of IRG1 −/− MCAO mice at both mRNA and protein levels ( Fig.…”

Section: Irg1 De Ciency Represses Bdnf Expression In the Ischemic Bramentioning

confidence: 99%

“…Neuroin ammation plays a pivotal role in brain injury following ischemic stroke. MG activation and peripheral immune cell in ltration have been shown to contribute to the induction and aggravation of neuroin ammation in ischemic stroke (14,16). Since we observed exacerbated ischemic brain injury in IRG1 −/− stroke animals, we speculate that IRG1 de ciency may promote neuroin ammation in ischemic stroke.…”

Section: Irg1 De Ciency Represses Bdnf Expression In the Ischemic Bramentioning

confidence: 99%

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Induction of IRG1 following ischemic stroke promotes HO-1 and BDNF expression to alleviate neuroinflammation and restrain ischemic brain injury

Kuo¹,

Weng²,

Scofield³

et al. 2020

Preprint

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Background Inflammatory stimuli induce immunoresponsive gene 1 (IRG1) expression that in turn catalyzes the production of itaconate through diverting cis-aconitate away from the tricarboxylic acid cycle. The immunoregulatory effect of IRG1/itaconate axis has recently documented in LPS-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 IRG1/itaconate axis exerts an immunomodulatory effect in ischemic stroke is unknown. Thus, we investigated whether IRG1 plays a role in modulating brain injury in ischemic stroke. In addition, the molecular mechanisms underlying the protective effects of IRG1 in ischemic stroke were elucidated. Methods Wild type (WT) C57BL/6 and IRG1−/− mice were subjected to 40 minutes middle cerebral artery occlusion (MCAO). Ischemic brain injury, microglia (MG) activation and peripheral immune cell infiltration of the ischemic brain were assessed. Furthermore, the expression of HO-1 and BDNF in the ischemic brain was measured. Finally, IRG1−/− MCAO mice were administered with D3T, an Nrf2/HO-1 pathway inducer, to determine its effects on cerebral BDNF expression and ischemic brain injury. Results We observed IRG1 was highly induced in the ischemic brain of WT but not IRG1−/− MCAO mice. Strikingly, IRG1−/− MCAO mice exhibited exacerbated brain injury with enlarged cerebral infarct, enhanced MG activation, and elevated immune cell infiltrates compared to WT MCAO controls. Further analysis of molecular mechanisms underlying the protective effects of IRG1 in ischemic stroke revealed that IRG1 promoted HO-1 and BDNF expression to restrain ischemic brain injury, as IRG1−/− MCAO mice exhibited reduced HO-1 and BDNF expression in the ischemic brain compared to WT MCAO controls. Notably, D3T, an Nrf2/HO-1 pathway inducer, promoted BDNF expression and lessened ischemic brain injury in IRG1−/− MCAO mice. Conclusions We demonstrate that the induction of IRG1 following ischemic stroke may serve as an endogenous protective mechanism to restrain ischemic brain injury, and that may be mediated through the protective effect of IRG1 on the induction of HO-1 and BDNF expression in the ischemic brain. Thus, our study suggests that targeting IRG1 may represent a novel approach for the treatment of ischemic stroke.

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Section: Irg1 De Ciency Enhances Neuroin Ammation In Ischemic Strokementioning

confidence: 99%

Section: Middle Cerebral Artery Occlusion (Mcao) Modelmentioning

confidence: 99%

Section: Infarct Volume Measurementsmentioning

confidence: 99%

Section: Irg1 De Ciency Represses Bdnf Expression In the Ischemic Bramentioning

confidence: 99%

Section: Irg1 De Ciency Represses Bdnf Expression In the Ischemic Bramentioning

confidence: 99%

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Induction of IRG1 following ischemic stroke promotes HO-1 and BDNF expression to alleviate neuroinflammation and restrain ischemic brain injury

Kuo¹,

Weng²,

Scofield³

et al. 2020

Preprint

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SOD3 overexpression alleviates cerebral ischemia‐reperfusion injury in rats

Sun

Gao

et al. 2019

Molec Gen & Gen Med

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BackgroundIschemic stroke is a deadly disease that poses a serious threat to human life. Superoxide dismutase 3 (SOD3, ECSOD) is the main antioxidant enzyme that removes superoxide anions from cells. This study aimed to investigate the effect of SOD3 overexpression on cerebral ischemia‐reperfusion injury in rats.MethodsGV230‐EGFP‐ECSOD, the recombinant SOD3‐overexpressed vector, was constructed by genetic engineering technology, and mesenchymal stem cells (MSCs) were infected with lentiviral packaging. In animal experiment, cerebral ischemia‐reperfusion injury model rats were successfully established. ECSOD‐MSCs are the MSCs that successfully transfected with SOD3 overexpression vector. The animals were injected with ECSOD‐MSCs (ECSOD‐MSC group), normal MSCs (MSCs group), PBS (PBS group), and not do any processing (Model group) via the tail vein. Then MRI was used to detect the infarct volume of rats, modified Neurological Severity Scores (mNSS), and immunohistochemistry were used to evaluate the expression of neurological function and apoptosis‐related genes in rats.ResultsWestern blot analysis revealed that the SOD3 was highly expressed in MSCs. Animal experiments showed that the transplantation of ECSOD‐MSCs significantly reduced the infarct volume of ischemic stroke rats (p < 0.05), significantly improved neurological function in rats (p < 0.05), and found proapoptotic gene, Bax, expression was significantly decreased (p < 0.05), the expression of anti‐apoptotic gene, Bcl‐2, was significantly increased (p < 0.05). The highly expressed SOD3 has no correction with brain infarct volume, and the highly expressed SOD3 has a positive correlation with cell apoptosis. It is speculated that overexpression of SOD3 affects the expression of Bax and Bcl‐2, and improves apoptosis to alleviate ischemic stroke.ConclusionOur results indicated that MSCs transfected with SOD3 can effectively alleviate cerebral ischemia‐reperfusion injury in rats.

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Functional improvement and immune-inflammatory cytokines profile of ischaemic stroke patients after treatment with boswellic acids: a randomized, double-blind, placebo-controlled, pilot trial

et al. 2019

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3 H -1,2-Dithiole-3-thione as a novel therapeutic agent for the treatment of ischemic stroke through Nrf2 defense pathway

Cited by 51 publications

References 62 publications

Induction of IRG1 following ischemic stroke promotes HO-1 and BDNF expression to alleviate neuroinflammation and restrain ischemic brain injury

Induction of IRG1 following ischemic stroke promotes HO-1 and BDNF expression to alleviate neuroinflammation and restrain ischemic brain injury

SOD3 overexpression alleviates cerebral ischemia‐reperfusion injury in rats

Functional improvement and immune-inflammatory cytokines profile of ischaemic stroke patients after treatment with boswellic acids: a randomized, double-blind, placebo-controlled, pilot trial

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