Metformin ameliorates brain damage caused by cardiopulmonary resuscitation via targeting endoplasmic reticulum stress-related proteins GRP78 and XBP1

Chuan, Libo; Huang, Xin; Fan, Chuming; Wen, Shiyuan; Yang, Xiaohua; Wang, Jingrong; Ren, Jingyu; Jin, Ran; Ding, Li

doi:10.1016/j.ejphar.2020.173716

Cited by 12 publications

(8 citation statements)

References 42 publications

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“…The IRE1/XBP1 UPR branch is activated in the brain as well as other organs after CA/CPR (6,29). In the current study, we provide the first evidence that activation of the XBP1 UPR branch in the post-CA brain is neuroprotective, as knockout mice with neuron-specific deletion of Xbp1 in the brain exhibited worse CA outcome, while transgenic mice with neuronspecific expression of Xbp1s in the brain showed improved CA outcome.…”

Section: Discussionmentioning

confidence: 51%

Activation of the XBP1s/O-GlcNAcylation Pathway Improves Functional Outcome After Cardiac Arrest and Resuscitation in Young and Aged Mice

Shen

et al. 2021

Shock

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After cardiac arrest (CA) and resuscitation, the unfolded protein response (UPR) is activated in various organs including the brain. However, the role of the UPR in CA outcome remains largely unknown. One UPR branch involves spliced X-box-binding protein-1 (XBP1s). Notably, XBP1s, a transcriptional factor, can upregulate expression of specific enzymes related to glucose metabolism, and subsequently boost O-linked b-N-acetylglucosamine modification (O-GlcNAcylation). The current study is focused on effects of the XBP1 UPR branch and its downstream O-GlcNAcylation on CA outcome. Using both loss-of-function and gain-of-function mouse genetic tools, we provide the first evidence that activation of the XBP1 UPR branch in the post-CA brain is neuroprotective. Specifically, neuron-specific Xbp1 knockout mice had worse CA outcome, while mice with neuron-specific expression of Xbp1s in the brain had better CA outcome. Since it has been shown that the protective role of the XBP1s signaling pathway under ischemic conditions is mediated by increasing O-GlcNAcylation, we then treated young mice with glucosamine, and found that functional deficits were mitigated on day 3 post CA. Finally, after confirming that glucosamine can boost O-GlcNAcylation in the aged brain, we subjected aged mice to 8 min CA, and then treated them with glucosamine. We found that glucosamine-treated aged mice performed significantly better in behavioral tests. Together, our data indicate that the XBP1s/O-GlcNAc pathway is a promising target for CA therapy.

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Section: Discussionmentioning

confidence: 51%

Activation of the XBP1s/O-GlcNAcylation Pathway Improves Functional Outcome After Cardiac Arrest and Resuscitation in Young and Aged Mice

Shen

et al. 2021

Shock

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“…In the nervous system, MET regulated the UPR in a galactose-ageing model of neurodegeneration [237] . In cerebral ischaemia-reperfusion, MET reduced levels of ERS-related proteins and increased neurological scores and survival [238] .…”

Section: Cellular and Molecular Mechanisms Of Met As Applied To The P...mentioning

confidence: 94%

Protection by metformin against severe Covid-19: An in-depth mechanistic analysis

Wiernsperger

Al‐Salameh

Cariou

et al. 2022

Diabetes & Metabolism

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“…Finally, metformin can ameliorate endoplasmic reticulum stress and the unfolded protein response in SCI through modulation of CCAAT/enhancer-binding protein homologous protein or X-box binding protein 1 signaling (Guo et al, 2019). Suppression of the pathways involved in endoplasmic reticulum stress was suggested to promote neuronal survival in CNS diseases (Zhong et al, 2020;Chuan et al, 2021). Therefore, .…”

Section: Alleviating Endoplasmic Reticulum Stressmentioning

confidence: 99%

The effect of metformin on ameliorating neurological function deficits and tissue damage in rats following spinal cord injury: A systematic review and network meta-analysis

Zhou

Chen

et al. 2022

Front. Neurosci.

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Spinal cord injury (SCI) is a devastating condition with few treatment options. Metformin, a classical antidiabetic and antioxidant, has extended its application to experimental SCI treatment. Here, we performed a systematic review to evaluate the neurobiological roles of metformin for treating SCI in rats, and to assess the potential for clinical translation. PubMed, Embase, China National Knowledge Infrastructure, WanFang data, SinoMed, and Vip Journal Integration Platform databases were searched from their inception dates to October 2021. Two reviewers independently selected controlled studies evaluating the neurobiological roles of metformin in rats following SCI, extracted data, and assessed the quality of methodology and evidence. Pairwise meta-analyses, subgroup analyses and network analysis were performed to assess the roles of metformin in neurological function and tissue damage in SCI rats. Twelve articles were included in this systematic review. Most of them were of moderate-to-high methodological quality, while the quality of evidence from those studies was not high. Generally, Basso, Beattie, and Bresnahan scores were increased in rats treated with metformin compared with controls, and the weighted mean differences (WMDs) between metformin and control groups exhibited a gradual upward trend from the 3rd (nine studies, n = 164, WMD = 0.42, 95% CI = −0.01 to 0.85, P = 0.06) to the 28th day after treatment (nine studies, n = 136, WMD = 3.48, 95% CI = 2.04 to 4.92, P < 0.00001). Metformin intervention was associated with improved inclined plane scores, tissue preservation ratio and number of anterior horn motor neurons. Subgroup analyses indicated an association between neuroprotection and metformin dose. Network meta-analysis showed that 50 mg/kg metformin exhibited greater protection than 10 and 100 mg/kg metformin. The action mechanisms behind metformin were associated with activating adenosine monophosphate-activated protein kinase signaling, regulating mitochondrial function and relieving endoplasmic reticulum stress. Collectively, this review indicates that metformin has a protective effect on SCI with satisfactory safety and we demonstrate a rational mechanism of action; therefore, metformin is a promising candidate for future clinical trials. However, given the limitations of animal experimental methodological and evidence quality, the findings of this pre-clinical review should be interpreted with caution.

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Metformin ameliorates brain damage caused by cardiopulmonary resuscitation via targeting endoplasmic reticulum stress-related proteins GRP78 and XBP1

Cited by 12 publications

References 42 publications

Activation of the XBP1s/O-GlcNAcylation Pathway Improves Functional Outcome After Cardiac Arrest and Resuscitation in Young and Aged Mice

Activation of the XBP1s/O-GlcNAcylation Pathway Improves Functional Outcome After Cardiac Arrest and Resuscitation in Young and Aged Mice

Protection by metformin against severe Covid-19: An in-depth mechanistic analysis

The effect of metformin on ameliorating neurological function deficits and tissue damage in rats following spinal cord injury: A systematic review and network meta-analysis

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