Dynamic cell type‐specific expression of Nrf2 after traumatic brain injury in mice

Dong, Wenwen; Sun, Yuansong; Cheng, Hao; Yang, Bei; Wang, Linlin; Jiang, Zhenfei; Li, Bingxuan; Wen, Shuheng; Guo, Xiangshen; Guan, Dawei; Zhao, Rui

doi:10.1111/ejn.14399

Cited by 12 publications

(12 citation statements)

References 60 publications

(90 reference statements)

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“…has been recently emerged as a master regulator of endogenous defense against OS, thus draws the researcher's focus to utilize it as a therapeutic target in a variety of diseases. Previous studies have demonstrated that Nrf2 is activated in the brain in various animal models of neurological diseases such as TBI [43,44], neurodegenerative diseases such as Alzheimer and…”

Section: Discussionmentioning

confidence: 99%

Spatio-Temporal and Cell Type-Specific Expression of Nrf2 Following an Acute Epileptic Seizure in Rats

Sandouka¹,

Saadi²,

Olowe³

et al. 2022

Preprint

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The modulation of Nrf2 activity has been reported to be implicated in the pathology of various neurological disorders, including epilepsy. Previous studies have demonstrated that Nrf2 is activated in the post-status epilepticus rat model, however, the spatio-temporal, as well as cell type-specific expression of Nrf2 following brief epileptic seizures remains unclear. Here, we evaluated how an acute epileptic seizure affected the expression of Nrf2 and its downstream genes in the cortex and the hippocampus up to 1-week following the induced seizure. We found that after a pentylenetetrazol-induced seizure, Nrf2 significantly increased at 24 h at the mRNA level and 3 to 6 h at the protein level in the cortex. In the hippocampus, the Nrf2 mRNA level peaked at 3 h after the seizure, and no significant changes were observed in the protein level. Interestingly, the mRNA level of Nrf2 downstream genes peaked at 3-6 h after seizure in both the cortex and the hippocampus. A significant increase in the expression of Nrf2 was observed in the neuronal population of CA1 and CA3 regions of the hippocampus, as well as in the cortex. Moreover, we observed no change in the co-localization of Nrf2 with astrocytes neither in the cortex nor in CA1 and CA3. Our results revealed that following a brief acute epileptic seizure, the expression of Nrf2 and its downstream genes is transiently increased and peaked at early timepoints after seizure predominantly in the hippocampus, and this expression is restricted to the neuronal population.

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Section: Discussionmentioning

confidence: 99%

Spatio-Temporal and Cell Type-Specific Expression of Nrf2 Following an Acute Epileptic Seizure in Rats

Sandouka¹,

Saadi²,

Olowe³

et al. 2022

Preprint

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“…Astrocytes and microglia, which can secret and response to various cytokines and chemokines, are crucial in inflammatory cascades post TBI [7]. After TBI, astrocytes are activated, showing a hypertrophic morphology involving swelling of cell bodies and extension of processes, and the number of astrocytes increases significantly and peaks at 7 dpi [41]. Recent investigations have shown that astrocytes can produce numerous inflammatory mediators, including IL-1β, IL-6, IL-10, IL-17, TNF-α, CCL2, CCL5, CCL7, CCL8, CCL12, CXCL1, CXCL10, CXCL12 and CXCL16 [47].…”

Section: Discussionmentioning

confidence: 99%

“…After TBI, microglia become activated, and the cells number peaks at 7 dpi [41]. Microglia release proinflammatory cytokines, including IL-1β, IL-6, IL-12, and TNF-α, and chemokines, including CCL2, CCL3, CCL5, CXCL10, and CXCL12 [50].…”

Section: Discussionmentioning

confidence: 99%

Deficiency in interleukin-18 ameliorated glial activation and neuroinflammation after traumatic brain injury in mice

Dong¹,

Wang²,

Chen³

et al. 2020

Preprint

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Background: Neuroinflammation is recognized as one of the main pathological mechanisms of secondary injury caused by traumatic brain injury (TBI). It has been reported that interleukin (IL)-18 is expressed in glial cells and involved in the regulation of neuroinflammation. Further studies have revealed that IL-18 expression is upregulated and may contribute to pathogenesis in the later phases of TBI; however, the mechanism underlying the effect of IL-18 on TBI remains unclear. Our present study assessed the roles of IL-18 in inflammatory and neurodegenerative pathology in mice subjected to TBI.Methods: A controlled cortical impact (CCI) injury model was conducted to mimic TBI, and brains were collected at 3 and 7 days post TBI (dpi). The levels of IL-18 were detected by qRT-PCR and immunofluorescence staining. In addition, neurological severity score (NSS) was used to assess neurological deficits after TBI. Furthermore, neuronal cell death, glial activation, and inflammatory cytokine and chemokine secretion were evaluated in wild-type ( WT ) and Il18-knockout ( Il18 -KO) mice to explore the role of IL-18 in TBI.Results: IL-18 levels were upregulated post TBI, accompanied by reactive glial activation. Il-18 deficiency significantly ameliorated glial activation and improved neuronal cell death and neurological deficits. In addition, Il-18 deficiency reduced the TBI-induced M1-like microglia frequency. Interestingly, the levels of all pro- and anti-inflammatory cytokines, including IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL17A, G-CSF, GM-CSF, IFN-γ, and TNF-α, were downregulated in Il18 -KO mice. The deletion of Il-18 attenuated the levels of most chemokines induced by TBI, including CCL2, CCL3, CCL4, CCL5, CCL7, CCL12, CCL20, CXCL1, CXCL2, CXCL10, CXCL12, CXCL13, and CXCL16.Conclusions: These data demonstrated that IL-18 is involved in TBI induced neuroinflammation, which suggests that IL-18 is important for the development of secondary injury induced by TBI.

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“…Approximately 4 mm of the tissue samples from the cortical area surrounding the ipsilateral-injured cortices ( Dong et al, 2019 ) were collected and homogenized in a RIPA buffer (P0013C; Beyotime Biotechnology, Shanghai, China) containing a protease inhibitor cocktail (P1006; Beyotime Biotechnology, Shanghai, China). A BCA assay kit (P0012; Beyotime Biotechnology, Shanghai, China) was used to quantify the protein concentration.…”

Section: Methodsmentioning

confidence: 99%

Spatial-temporal changes of iron deposition and iron metabolism after traumatic brain injury in mice

Cheng

Wang

et al. 2022

Front. Mol. Neurosci.

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Excessive iron released by hemoglobin and necrotic tissues is the predominant factor that aggravates the outcome of traumatic brain injury (TBI). Regulating the levels of iron and its metabolism is a feasible way to alleviate damage due to TBI. However, the spatial-temporal iron metabolism and iron deposition in neurons and glial cells after TBI remains unclear. In our study, male C57BL/6 mice (8–12 weeks old, weighing 20–26 g) were conducted using controlled cortical impact (CCI) models, combined with treatment of iron chelator deferoxamine (DFO), followed by systematical evaluation on iron deposition, cell-specific expression of iron metabolic proteins and ferroptosis in ipsilateral cortex. Herein, ferroptosis manifest by iron overload and lipid peroxidation was noticed in ipsilateral cortex. Furthermore, iron deposition and cell-specific expression of iron metabolic proteins were observed in the ipsilateral cortical neurons at 1–3 days post-injury. However, iron overload was absent in astrocytes, even though they had intense TBI-induced oxidative stress. In addition, iron accumulation in oligodendrocytes was only observed at 7–14 days post-injury, which was in accordance with the corresponding interval of cellular repair. Microglia play significant roles in iron engulfment and metabolism after TBI, and excessive affects the transformation of M1 and M2 subtypes and activation of microglial cells. Our study revealed that TBI led to ferroptosis in ipsilateral cortex, iron deposition and metabolism exhibited cell-type-specific spatial-temporal changes in neurons and glial cells after TBI. The different effects and dynamic changes in iron deposition and iron metabolism in neurons and glial cells are conducive to providing new insights into the iron-metabolic mechanism and strategies for improving the treatment of TBI.

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Dynamic cell type‐specific expression of Nrf2 after traumatic brain injury in mice

Cited by 12 publications

References 60 publications

Spatio-Temporal and Cell Type-Specific Expression of Nrf2 Following an Acute Epileptic Seizure in Rats

Spatio-Temporal and Cell Type-Specific Expression of Nrf2 Following an Acute Epileptic Seizure in Rats

Deficiency in interleukin-18 ameliorated glial activation and neuroinflammation after traumatic brain injury in mice

Spatial-temporal changes of iron deposition and iron metabolism after traumatic brain injury in mice

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