An adenosineï¿½A1R-A2aR imbalance regulates low glucose/hypoxia-induced microglial activation, thereby contributing to oligodendrocyte damage through NF-κB and CREB phosphorylation

Huang, Wen; Bai, Shunjie; Zuo, Xuzheng; Tang, Weiju; Chen, Pengfei; Chen, Xiuying; Gong, Wei; Wang, Haoxiang; Xie, Peng

doi:10.3892/ijmm.2018.3546

Cited by 6 publications

(5 citation statements)

References 36 publications

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“…58,59 The regulation of NF-κB is crucial for the expression of iNOS and MCT1 in pro-inflammatory microglia. [60][61][62][63] However, the relationship between MCT1 and iNOS in stroke models has not been explored before. Here, knocking down MCT1 significantly reduces the expression of iNOS.…”

Section: Discussionmentioning

confidence: 99%

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Pyruvate maintains and enhances the pro‐inflammatory response of microglia caused by glucose deficiency in early stroke

Zhou,

Yu,

Cao

et al. 2024

J of Cellular Biochemistry

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Pro‐inflammatory microglia mainly rely on glycolysis to maintain cytokine production during ischemia, accompanied by an increase in inducible nitric oxide synthase (iNOS) and monocarboxylate transporter 1 (MCT1). The role of energy metabolism in the pro‐inflammatory response of microglia is currently unclear. In this study, we tested the response of microglia in mice after cerebral ischemia and simulated an energy environment in vitro using low glucose culture medium. The research results indicate that the expression levels of iNOS and arginase 1 (ARG1) increase in the ischemic mouse brain, but the upregulation of MCT1 expression is mainly present in iNOS positive microglia. In microglia exposed to low glucose conditions, iNOS and MCT1 levels increased, while ARG1 levels decreased. Under the same conditions, knocking down MCT1 in microglia leads to a decrease in iNOS levels, while overexpression of MCT1 leads to the opposite result. The use of NF‐κB inhibitors reduced the expression levels of iNOS and MCT1 in microglia. In summary, our data indicate that pyruvate maintains and enhances the NF‐κB regulated pro‐inflammatory response of microglia induced by low glucose.

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Section: Discussionmentioning

confidence: 99%

“…The regulation of NF‐κB is crucial for the expression of iNOS and MCT1 in pro‐inflammatory microglia 60–63 . However, the relationship between MCT1 and iNOS in stroke models has not been explored before.…”

Section: Discussionmentioning

confidence: 99%

Pyruvate maintains and enhances the pro‐inflammatory response of microglia caused by glucose deficiency in early stroke

Zhou,

Yu,

Cao

et al. 2024

J of Cellular Biochemistry

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“…We used a group of rats treated with CGS 21680 (an A2AR agonist) to investigate the effects of XYS on A2AR signaling in the striatum. Previous studies have suggested that A2AR serves an important role in the onset of microglial activation and inflammation after exposure to a low glucose/hypoxia in a NF-κB-dependent manner ( Huang et al, 2018 ). We found that intraperitoneal injection of CGS 21680 can also activate the A2AR-ERK-NF-κB pathway in the striatum and induce a depression-like phenotype, which was reversed by treatment with XYS.…”

Section: Discussionmentioning

confidence: 99%

“…After 1 week of adaptation, the rats in the MS group and MSX group were treated with the A2AR antagonist SCH 58261, and the rats in the CC group and CCX group were treated with the A2AR agonist CGS 21680. The dosages were 0.05 mg/kg·d and 0.1 mg/kg·d, respectively ( Pan and Chen, 2007 ; Costenla et al, 2011 ; Kaster et al, 2015 ; Huang et al, 2018 ). The rats in the other groups were given the same amount of 0.9% NS.…”

Section: Methodsmentioning

confidence: 99%

Xiaoyaosan Ameliorates Chronic Restraint Stress-Induced Depression-Like Phenotype by Suppressing A2AR Signaling in the Rat Striatum

Zhu

Yang

et al. 2022

Front. Pharmacol.

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Depression is a common mental disorder characterized by pessimism and world-weariness. In our previous study, we found that Xiaoyaosan (XYS) could have antidepressive effects, however the underlying mechanisms remain unclear. Several studies have shown that adenosine A (2 A) receptor (A2AR) in the brain is a key point in the treatment of depression. Our present study aimed to investigate the effects of XYS on A2AR signaling in the striatum of rats exposed to chronic restraint stress (CRS). Ninety-six male Sprague–Dawley rats were randomly divided into 8 groups (control, model, negative control, XYS, A2AR antagonist, A2AR antagonist + XYS, A2AR agonist, A2AR agonist + XYS). The rats in the model group, XYS group, A2AR antagonist group and A2AR antagonist + XYS group were subjected to CRS for 3 h a day. The XYS decoction [2.224 g/(kg·d)] was intragastrical administered by oral gavage to the rats in the negative control group, XYS group, A2AR antagonist + XYS group, and A2AR agonist + XYS group. The rats in the A2AR antagonist group and A2AR antagonist + XYS group were treated with SCH 58261 [0.05 mg/(kg·d)], and the rats in the A2AR agonist and A2AR agonist + XYS group were treated with CGS 21680 [0.1 mg/(kg·d)]. These procedures were performed for 21 consecutive days. Behavioral studies including the open field test, elevated plus maze test, sucrose preference test and forced swimming test, were performed to examine depression-like phenotypes. Then, the effects of XYS on CRS- or A2AR agonist-induced striatal subcellular damage, microglial activation and A2AR signaling changes in the striatum were examined. Here, we report that XYS ameliorates depression-like phenotypes (such as body weight loss as well as depression- and anxiety-like behaviors) and improves synaptic survival and growth in the stratum of the CRS rats. Moreover, XYS reduces A2AR activity and suppresses hyper-activation of striatal microglia. The tissue and cellular effects of XYS were similar to those of the known A2AR antagonists. In conclusion, XYS alleviates depression in the CRS rats via inhibiting A2AR in the striatum.

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“…Therefore, under ischemia, it is possible that lactate, another monocarboxylate, is taken up by the highly expressed MCT1 and converted to pyruvate for use in the mitochondria. NF-κB is vital in low glucose-induced microglial activation [51] and for iNOS [52,53] and MCT1 [54] expressions. But, the relationship between MCT1 and iNOS has not been explored.…”

Section: Discussionmentioning

confidence: 99%

Pyruvate enhances M1 microglial polarization via NF-κB/MCT1/iNOS signaling axis under low glucose condition

Zhou

et al. 2020

Preprint

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Background Proinflammatory microglia rely predominantly on glycolysis to maintain cytokine production during an inflammatory response. However, during ischemia, where glucose supply is low, inducible nitric oxide synthase (iNOS) production remains high accompanied by an increase in monocarboxylate transporter 1 (MCT1) expression. In this study, we explored whether there is a link between iNOS and MCT1 expressions, and whether pyruvate can act as an energy source to sustain the M1 phenotype. Methods Using a mouse model with laser-induced brain ischemia and cell culture with low-glucose treatment, we examined responses from microglia. Results The expressions of iNOS and MCT1, as well as arginase-1 (ARG1), were increased in the brain of the ischemic mouse model. In the BV2 microglial cell line and primary microglia treated under low glucose condition, iNOS and MCT1 also increased, while ARG1 decreased. The addition of pyruvate under low-glucose or lipopolysaccharide (LPS) treatment enhanced iNOS and MCT1 expressions compared with groups without pyruvate. MCT1 knockdown resulted in decreased iNOS while MCT1 overexpression increased iNOS. Furthermore, inhibitor of nuclear factor-kappaB (NF-κB) reduced both iNOS and MCT1. Conclusion Our data suggested that after proinflammatory microglial polarization, MCT1 is upregulated through the NF-κB signaling pathway, which leads to iNOS production. We speculate that microglia may continuously pick up monocarboxylates such as pyruvate through MCT1 to sustain the M1 phenotype.

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An adenosineï¿½A1R-A2aR imbalance regulates low glucose/hypoxia-induced microglial activation, thereby contributing to oligodendrocyte damage through NF-κB and CREB phosphorylation

Cited by 6 publications

References 36 publications

Pyruvate maintains and enhances the pro‐inflammatory response of microglia caused by glucose deficiency in early stroke

Pyruvate maintains and enhances the pro‐inflammatory response of microglia caused by glucose deficiency in early stroke

Xiaoyaosan Ameliorates Chronic Restraint Stress-Induced Depression-Like Phenotype by Suppressing A2AR Signaling in the Rat Striatum

Pyruvate enhances M1 microglial polarization via NF-κB/MCT1/iNOS signaling axis under low glucose condition

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