Inhibition of GSK3β and RIP1K Attenuates Glial Scar Formation Induced by Ischemic Stroke via Reduction of Inflammatory Cytokine Production

Liu, Jin; Zhu, Yong‐Ming; Guo, Yi; Lin, Liang; Wang, Zhanxiang; Gu, Feng; Dong, Xin-Yi; Zhou, Ming; Wang, Yifan; Zhang, Huiling

doi:10.3389/fphar.2020.00812

Cited by 20 publications

(20 citation statements)

References 58 publications

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“…Activated microglia are associated with some nervous system diseases, such as Alzheimer's disease and chronic pain 55 . Previous reports have shown that inhibiting necroptosis can reduce not only the inflammatory response but also the expression of the astrocytic marker GFAP and the microglial marker Iba‐1 22,56 . Moreover, there is evidence that necroptosis causes neuronal damage by affecting microglia or astrocytes 57,58 .…”

Section: Discussionmentioning

confidence: 99%

“… 55 Previous reports have shown that inhibiting necroptosis can reduce not only the inflammatory response but also the expression of the astrocytic marker GFAP and the microglial marker Iba‐1. 22 , 56 Moreover, there is evidence that necroptosis causes neuronal damage by affecting microglia or astrocytes. 57 , 58 In this study, we found that microglia and astrocytes were activated in the hippocampus and cortex of mice after hydrocephalus, and this response was alleviated by Nec‐1 and GSK872.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of neuronal necroptosis mediated by RIP1/RIP3/MLKL provides neuroprotective effects on kaolin‐induced hydrocephalus in mice

et al. 2021

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Objectives Necroptosis is widespread in neurodegenerative diseases. Here, we examined necroptosis in the hippocampus and cortex after hydrocephalus and found that a necroptosis pathway inhibitor alleviates necroptosis and provides neuroprotective effects. Materials and methods Hydrocephalus was induced in C57BL/6 mice by kaolin. Haematoxylin and eosin (HE), Nissl, PI and Fluoro‐Jade B (FJB) staining were used for general observations. Phosphorylated receptor‐interacting protein kinase 3 (p‐RIP3) and phosphorylated mixed lineage kinase domain‐like (p‐MLKL) were measured by Western blotting and immunohistochemistry. Scanning electron microscopy (SEM) was used to observe ependymal cilia. Magnetic resonance imaging (MRI) and the Morris water maze (MWM) test were used to assess neurobehavioral changes. Immunofluorescence was used to detect microglial and astrocyte activation. Inflammatory cytokines were measured by Western blotting and RT‐PCR. Results Obvious pathological changes appeared in the hippocampus and cortex after hydrocephalus, and expression of the necroptosis markers p‐RIP3, p‐MLKL and inflammatory cytokines increased. Necrostatin‐1 (Nec‐1) and GSK872 reduced necrotic cell death, attenuated p‐RIP3 and p‐MLKL levels, slightly improved neurobehaviours and inhibited microglial and astrocyte activation and inflammation. Conclusions RIP1/RIP3/MLKL mediates necroptosis in the cortex and hippocampus in a hydrocephalus mouse model, and Nec‐1 and GSK872 have some neuroprotective effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of neuronal necroptosis mediated by RIP1/RIP3/MLKL provides neuroprotective effects on kaolin‐induced hydrocephalus in mice

et al. 2021

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“…The RIP1 inhibitor Nec-1 reduces the cell death ratios of neurons after CIRI by inhibiting RIP1-RIP3 interaction and RIP3 activation [ 200 ]. Besides, the combination of Nec-1 and a glycogen synthase kinase-3 beta inhibitor can downregulate the levels of necroptosis-related proteins (RIP1, RIP3, and MLKL), decrease glial scar markers, and ameliorate chronic inflammatory responses, which suppress astrocyte necroptosis after CIRI [ 201 ]. β -Caryophyllene (8-methylene-4,11,11-trimethylbicyclo [7.2.0] undec-4-ene), an odoriferous bicyclic sesquiterpene, alleviates cerebral ischemic injury or CIRI by inhibiting necroptotic neuronal death and inflammatory response [ 202 ].…”

Section: Pharmacotherapies Against Ciri Targeting Ferroptosis and Necroptosismentioning

confidence: 99%

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Zhou

Liao

Mei

et al. 2021

Oxidative Medicine and Cellular Longevity

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Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. Necroptosis, an alternative form of programmed necrosis, is regulated by receptor-interacting protein (RIP) 1 activation and by RIP3 and mixed-lineage kinase domain-like (MLKL) phosphorylation. Ferroptosis and necroptosis both play important roles in the pathological progress in ischemic stroke, which is a complex brain disease regulated by several cell death pathways. In the past few years, increasing evidence has suggested that the crosstalk occurs between necroptosis and ferroptosis in ischemic stroke. However, the potential links between ferroptosis and necroptosis in ischemic stroke have not been elucidated yet. Hence, in this review, we overview and analyze the mechanism underlying the crosstalk between necroptosis and ferroptosis in ischemic stroke. And we find that iron overload, one mechanism of ferroptosis, leads to mitochondrial permeability transition pore (MPTP) opening, which aggravates RIP1 phosphorylation and contributes to necroptosis. In addition, heat shock protein 90 (HSP90) induces necroptosis and ferroptosis by promoting RIP1 phosphorylation and suppressing glutathione peroxidase 4 (GPX4) activation. In this work, we try to deliver a new perspective in the exploration of novel therapeutic targets for the treatment of ischemic stroke.

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“…RIPK1-RIPK3 binding in the necroptotic complex depends on the phosphorylation of RHIM domain. The RIPK1-RIPK3 complex then binds to and phosphorylates MLKL, and triggers necroptosis [26,27]. We found that RIPK1 inhibition through gene silencing as well as pharmacological blockade also down-regulated RIPK3 and p-RIPK3, which can be attributed to the decreased expression levels of total RIPK1 and the subsequent decrease in binding to RIPK3 via the RHIM domain [26].…”

Section: Discussionmentioning

confidence: 81%

RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts

et al. 2022

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Receptor-interacting protein kinase 1 (RIPK1) and 3 (RIPK3) are critical regulators of programmed necrosis or necroptosis. However, the role of the RIPK1/RIPK3 signaling pathway in myocardial fibrosis and related diabetic cardiomyopathy is still unclear. We hypothesized that RIPK1/RIPK3 activation mediated myocardial fibrosis by impairing the autophagic flux. To this end, we established in vitro and in vivo models of type 2 diabetes mellitus with high glucose fat (HGF) medium and diet respectively. HGF induced myocardial fibrosis, and impaired cardiac diastolic and systolic function by activating the RIPK1/RIPK3 pathway, which increased the expression of autophagic related proteins such as LC3-II, P62 and active-cathepsin D. Inhibition of RIPK1 or RIPK3 alleviated HGF-induced death and fibrosis of cardiac fibroblasts by restoring the impaired autophagic flux. The autophagy blocker neutralized the effects of the RIPK1 inhibitor necrostatin-1 (Nec-1) and RIPK3 inhibitor GSK872 (GSK). RIPK1/RIPK3 inhibition respectively decreased the levels of RIPK3/p-RIPK3 and RIPK1/p-RIPK1. P62 forms a complex with RIPK1-RIPK3 and promotes the binding of RIPK1 and RIPK3, silencing of RIPK1 decreased the association of RIPK1 with P62 and the binding of P62 to LC3. Furthermore, inhibition of both kinases in combination with a low dose of Nec-1 and GSK in the HGF-treated fibroblasts significantly decreased cell death and fibrosis, and restored the autophagic flux. In the diabetic rat model, Nec-1 (1.65 mg/kg) treatment for 4 months markedly alleviated myocardial fibrosis, downregulated autophagic related proteins, and improved cardiac systolic and diastolic function. In conclusion, HGF induces myocardial fibrosis and cardiac dysfunction by activating the RIPK1-RIPK3 pathway and by impairing the autophagic flux, which is obviated by the pharmacological and genetic inhibition of RIPK1/RIPK3.

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Inhibition of GSK3β and RIP1K Attenuates Glial Scar Formation Induced by Ischemic Stroke via Reduction of Inflammatory Cytokine Production

Abstract: underlying mechanisms might be at least, partially related to reducing levels of inflammatory-related cytokines and to blocking an interaction between GSK3b-and RIP1K-mediated pathways.

Cited by 20 publications

References 58 publications

Inhibition of neuronal necroptosis mediated by RIP1/RIP3/MLKL provides neuroprotective effects on kaolin‐induced hydrocephalus in mice

Inhibition of neuronal necroptosis mediated by RIP1/RIP3/MLKL provides neuroprotective effects on kaolin‐induced hydrocephalus in mice

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts

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