Role of Wnt/β-catenin in the tolerance to focal cerebral ischemia induced by electroacupuncture pretreatment

He, Xijing; Mo, Yunchang; Geng, Wujun; Shi, Yiyi; Zhuang, Xiuxiu; Han, Kunyuan; Dai, Qinxue; Jin, Shenhui; Wang, Junlu

doi:10.1016/j.neuint.2016.03.011

Cited by 20 publications

(15 citation statements)

References 34 publications

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“…22 Bcl2 is known to play a critical role in cerebral ischemic stroke, and our previous results also demonstrate that Bcl2 protein expression is significantly reduced in MCAO-treated rats. 23 We thought that this reduction was most likely due to an increase in Bcl2 methylation levels, causing a decrease in Fto, leading to an increase in Bcl2 degradation. Therefore, we overexpressed Fto in neurons, which significantly increased Bcl2 mRNA.…”

Section: Discussionmentioning

confidence: 99%

N⁶-methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury

et al. 2020

Therapeutic Advances in Chronic Disease

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Background: Although N6-methyladenosine (m6A) plays a very important role in different biological processes, its function in the brain has not been fully explored. Thus, we investigated the roles of the RNA demethylases Alkbh5/Fto in cerebral ischemia-reperfusion injury. Methods: We used a rat model and primary neuronal cell culture to study the role of m6A and Alkbh5/Fto in the cerebral cortex ischemic penumbra after cerebral ischemia-reperfusion injury. We used Alkbh5-shRNA and Lv-Fto ( in vitro) to regulate the expression of Alkbh5/Fto to study their regulation of m6A in the cerebral cortex and to study brain function after ischemia-reperfusion injury. Results: We found that RNA m6A levels increased consecutive to the increase of Alkbh5 expression in both the cerebral cortex of rats after middle cerebral artery occlusion, and in primary neurons after oxygen deprivation/reoxygenation. In contrast, Fto expression decreased after these perturbations. Our results suggest that knocking down Alkbh5 can aggravate neuronal damage. This is due to the demethylation of Alkbh5 and Fto, which selectively demethylate the Bcl2 transcript, preventing Bcl2 transcript degradation and enhancing Bcl2 protein expression. Conclusion: Collectively, our results demonstrate that the demethylases Alkbh5/Fto co-regulate m6A demethylation, which plays a crucial role in cerebral ischemia-reperfusion injury. The results provide novel insights into potential therapeutic mechanisms for stroke.

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Section: Discussionmentioning

confidence: 99%

N⁶-methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury

et al. 2020

Therapeutic Advances in Chronic Disease

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“…Also, the inactivation of b-catenin by small interfering RNA increased the ischemia-induced infarct volume in rats (39). Additionally, the Wnt/b-catenin pathway also plays a critical role in the protective effects of preconditioning against lethal ischemic injury in the heart (40), kidneys (41), liver (42), and brain (43). Likewise, in the present study, we found that HPC markedly elevated nuclear b-catenin levels post cerebral ischemia, with a relative decrease in p-b-catenin in CA1 after 50 h of reperfusion.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic postconditioning activates the Wnt/β‐catenin pathway and protects against transient global cerebral ischemia through Dkk1 Inhibition and GSK‐3β inactivation

et al. 2019

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The Wingless/Int (Wnt)/β‐catenin pathway plays an essential role in cell survival. Although post‐conditioning with 8% oxygen can alleviate transient global cerebral ischemia (tGCI)‐induced neuronal damage in hippocampal CA1 subregion in adult rats as demonstrated by our previous studies, little is understood about the role of Wnt/β‐catenin pathway in hypoxic postconditioning (HPC)‐induced neuroprotection. This study tried to investigate the involvement of Wnt/β‐catenin pathway in HPC‐induced neuroprotection against tGCI and explore the underlying molecular mechanism thereof. We observed that HPC elevated nuclear β‐catenin level as well as increased Wnt3a and decreased Dickkopf‐1 (Dkk1) expression in CA1 after tGCI. Accordingly, HPC enhanced the expression of survivin and reduced the ratio of B‐cell lymphoma/lewkmia‐2 (Bcl‐2)–associated X protein (Bax) to Bcl‐2 following reperfusion. Moreover, our study has shown that these effects of HPC were abolished by lentivirus‐mediated overexpression of Dkk1, and that the overexpression of Dkk1 completely reversed HPC‐induced neuroprotection. Furthermore, HPC suppressed the activity of glycogen synthase kinase‐3β (GSK‐3β) in CA1 after tGCI, and the inhibition of GSK‐3β activity with SB216763 increased the nuclear accumulation of β‐catenin, up‐regulated the expression of survivin, and reduced the ratio of Bax to Bcl‐2, thus preventing the delayed neuronal death after tGCI. Finally, the administration of LY294002, an inhibitor of PI3K, increased GSK‐3β activity and blocked nuclear β‐catenin accumulation, thereby decreasing survivin expression and elevating the Bax‐to‐Bcl‐2 ratio after HPC. These results suggest that activation of the Wnt/β‐catenin pathway through Dkk1 inhibition and PI3K/protein kinase B pathway–mediated GSK‐3β inactivation contributes to the neuroprotection of HPC against tGCI.—Zhan, L., Liu, D., Wen, H., Hu, J., Pang, T., Sun, W., Xu, E. Hypoxic postconditioning activates the Wnt/β‐catenin pathway and protects against transient global cerebral ischemia through Dkk1 inhibition and GSK‐3β inactivation. FASEB J. 33, 9291–9307 (2019). http://www.fasebj.org

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“…Activation of the Wnt pathway is known to support neuronal survival, and induction of the Wnt inhibitor, Dkk-1, contributes to neuronal death in experimental animal models of cerebrovascular disorders (Cappuccio et al, 2005 ; Zhang et al, 2008 ; Mastroiacovo et al, 2009 ; He et al, 2016 ; Li et al, 2017 ), AD (Caricasole et al, 2004 ; Wang et al, 2016 ), temporal lobe epilepsy (Busceti et al, 2007 ), and stress-related disorders (Matrisciano et al, 2011 ). Dkk3 differs from all other Dkk family members because its modulatory action on Wnt signaling is complex and context-dependent.…”

Section: Discussionmentioning

confidence: 99%

Dickkopf-3 Causes Neuroprotection by Inducing Vascular Endothelial Growth Factor

Busceti

Menna

Bianchi

et al. 2018

Front. Cell. Neurosci.

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Dickkopf-3 (Dkk3) is an atypical member of the Dkk family of Wnt inhibitors, which has been implicated in the pathophysiology of neurodegenerative disorders. However, the role of Dkk3 in mechanisms of cell degeneration and protection is unknown. We used Dkk3 knockout mice to examine how endogenous Dkk3 influences ischemic brain damage. In addition, we used primary cultures of astrocytes or mixed cultures of astrocytes and neurons to investigate the action of Dkk3 on cell damage and dissect the underlying molecular mechanisms. In a model of focal brain ischemia induced by permanent middle cerebral artery (MCA) occlusion (MCAO) Dkk3−/− mice showed a significantly greater infarct size with respect to their wild-type counterparts at all time points investigated (1, 3 and 7 days after MCAO). Immunohistochemical analysis showed that Dkk3 expression was enhanced at the borders of the ischemic focus, and was predominantly detected in astrocytes. This raised the possibility that Dkk3 produced by astrocytes acted as a protective molecule. We tested this hypothesis using either primary cultures of cortical astrocytes or mixed cortical cultures containing both neurons and astrocytes. Genetic deletion of Dkk3 was permissive to astrocyte damage induced by either oxidative stress or glucose deprivation. In addition, application of human recombinant Dkk3 (hrDkk3) was highly protective against oxidative stress in cultured astrocytes. We tested the hypothesis that the protective activity of Dkk3 was mediated byvascular endothelial growth factor (VEGF). Interestingly, glucose deprivation up-regulated both Dkk3 and VEGF in cultured astrocytes prepared from wild-type mice. VEGF induction was not observed in astrocytes lacking Dkk3 (i.e., in cultures prepared from Dkk3−/− mice). In mixed cultures of cortical cells, excitotoxic neuronal death induced by a brief pulse with N-methyl-D-aspartate (NMDA) was significantly enhanced when Dkk3 was lacking in astrocytes, whereas post-NMDA addition of hrDkk3 was neuroprotective. Neuroprotection by hrDkk3 was significantly reduced by pharmacological blockade of type-2 VEGF receptors and was mimicked by hrVEGF. These data offer the first evidence that Dkk3 protects both neurons and astrocytes against a variety of toxic insults, and at least in culture, protection involves VEGF induction.

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Role of Wnt/β-catenin in the tolerance to focal cerebral ischemia induced by electroacupuncture pretreatment

Cited by 20 publications

References 34 publications

N⁶-methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury

N⁶-methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury

Hypoxic postconditioning activates the Wnt/β‐catenin pathway and protects against transient global cerebral ischemia through Dkk1 Inhibition and GSK‐3β inactivation

Dickkopf-3 Causes Neuroprotection by Inducing Vascular Endothelial Growth Factor

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Role of Wnt/β-catenin in the tolerance to focal cerebral ischemia induced by electroacupuncture pretreatment

Cited by 20 publications

References 34 publications

N6-methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury

N6-methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury

Hypoxic postconditioning activates the Wnt/β‐catenin pathway and protects against transient global cerebral ischemia through Dkk1 Inhibition and GSK‐3β inactivation

Dickkopf-3 Causes Neuroprotection by Inducing Vascular Endothelial Growth Factor

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N⁶-methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury

N⁶-methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury