Corticosterone induces neurotoxicity in PC12 cells via disrupting autophagy flux mediated by AMPK/mTOR signaling

Ma, Rundong; Zhou, Guijuan; Qu, Miao; Yi, Jihong; Tang, Yaling; Yang, Xiangyi; Nie, Yongzhan; Gu, Hong‐Feng

doi:10.1111/cns.13212

Cited by 21 publications

(15 citation statements)

References 36 publications

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“…As mentioned in previous studies, the AMPK-mTOR pathway is crucial in the modulation of autophagy ( Dai et al, 2017 ; Ma et al, 2020 ). Therefore, to evaluate whether the induction of autophagy resulting from Brd4 inhibition is mediated by the AMPK-mTOR axis, mice and neurons were co-treated JQ1 and Compound c. After treatment with JQ1, increased levels of p-AMPK and p-ULK1, and decreased levels of p-mTOR were observed in injured mice by western blot analysis, while treatment with Compound c blocked the JQ1-mediated regulation of AMPK and mTOR ( Figures 8A–D ).…”

Section: Resultsmentioning

confidence: 71%

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Xiang

Lin

et al. 2020

Front. Cell. Neurosci.

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Spinal cord injury (SCI) is a destructive neurological disorder that is characterized by impaired sensory and motor function. Inhibition of bromodomain protein 4 (Brd4) has been shown to promote the maintenance of cell homeostasis by activating autophagy. However, the role of Brd4 inhibition in SCI and the underlying mechanisms are poorly understood. Thus, the goal of the present study was to evaluate the effects of sustained Brd4 inhibition using the bromodomain and extraterminal domain (BET) inhibitor JQ1 on the regulation of apoptosis, oxidative stress and autophagy in a mouse model of SCI. First, we observed that Brd4 expression at the lesion sites of mouse spinal cords increased after SCI. Treatment with JQ1 significantly decreased the expression of Brd4 and improved functional recovery for up to 28 day after SCI. In addition, JQ1-mediated inhibition of Brd4 reduced oxidative stress and inhibited the expression of apoptotic proteins to promote neural survival. Our results also revealed that JQ1 treatment activated autophagy and restored autophagic flux, while the positive effects of JQ1 were abrogated by autophagy inhibitor 3-MA intervention, indicating that autophagy plays a crucial role in therapeutic effects Brd4 induced by inhibition of the functional recovery SCI. In the mechanistic analysis, we observed that modulation of the AMPK-mTOR-ULK1 pathway is involved in the activation of autophagy mediated by Brd4 inhibition. Taken together, the results of our investigation provides compelling evidence that Brd4 inhibition by JQ1 promotes functional recovery after SCI and that Brd4 may serve as a potential target for SCI treatment.

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Section: Resultsmentioning

confidence: 71%

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Xiang

Lin

et al. 2020

Front. Cell. Neurosci.

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“…The observed prominent role of astrocytes fits with transcriptomic studies where an astrocyte‐specific gene up‐regulation after glucocorticoid exposure was reported to occur prior to adaptations in other cell types (Carter et al., 2012). This may be necessary to prevent neuronal loss by ensuring metabolic support for example via shuttling lactate (Genc et al., 2011; Ma et al, 2020) to circumvent the glucose‐restricting effects of glucocorticoids (Homer et al., 1990; Virgin et al., 1991). Our data provide insights that astrocytes could fulfill this function by promptly up‐regulating Fkbp5 to inhibit glucocorticoid signaling and Sgk1 , a kinase favoring cellular glucose uptake from the circulation (Boini et al., 2006).…”

Section: Discussionmentioning

confidence: 99%

FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells – First insights from novel humanized mice

Nold

Richter

Hengerer

et al. 2020

Eur J of Neuroscience

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The brain is a central hub for integration of internal and external conditions and, thus, a regulator of the stress response. Glucocorticoids are the essential communicators of this response. Aberrations in glucocorticoid signaling are a common symptom in patients with psychiatric disorders. The gene FKBP5 encodes a chaperone protein that functionally inhibits glucocorticoid signaling and, thus, contributes to the regulation of stress. In the context of childhood trauma, differential expression of FKBP5 has been found in psychiatric patients compared to controls. These variations in expression levels of FKBP5 were reported to be associated with differences in stress responsiveness in human carriers of the single nucleotide polymorphism (SNP) rs1360780. Understanding the mechanisms underlying FKBP5 polymorphism‐associated glucocorticoid responsiveness in the CNS will lead to a better understanding of stress regulation or associated pathology. To study these mechanisms, two novel humanized mouse lines were generated. The lines carried either the risk (A/T) allele or the resilient (C/G) allele of rs1360780. Primary cells from CNS (astrocytes, microglia, and neurons) were analyzed for their basal expression levels of FKBP5 and their responsiveness to glucocorticoids. Differential expression of FKBP5 was found for these cell types and negatively correlated with the cellular glucocorticoid responsiveness. Astrocytes revealed the strongest transcriptional response, followed by microglia and neurons. Furthermore, the risk allele (A/T) was associated with greater induction of FKBP5 than the resilience allele. Novel FKBP5‐humanized mice display differential glucocorticoid responsiveness due to a single intronic SNP. The vulnerability to stress signaling in the shape of glucocorticoids in the brain correlated with FKBP5 expression levels. The strong responsiveness of astrocytes to glucocorticoids implies astrocytes play a prominent role in the stress response, and in FKBP5‐related differences in glucocorticoid signaling. The novel humanized mouse lines will allow for further study of the role that FKBP5 SNPs have in risk and resilience to stress pathology.

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“…Similarly, water extract of Vaccinium bracteatum leaf showed neuroprotective effects by increasing phosphorylation of CREB in CORT-induced cell damage mediated by the mTOR signaling pathway [ 87 ]. Cortisol induces PC12 cell injury by blocking autophagy mediated by the AMPK-mTOR pathway [ 88 , 89 ]. Autophagy activated AMPK activator metformin and mTOR inhibitor rapamycin, and chlorogenic acid significantly reduced CORT-induced PC12 cytotoxicity by activating autophagy [ 88 , 89 ].…”

Section: Role Of Bdnf-mtor1 Signaling Pathway In Depressionmentioning

confidence: 99%

“…Cortisol induces PC12 cell injury by blocking autophagy mediated by the AMPK-mTOR pathway [ 88 , 89 ]. Autophagy activated AMPK activator metformin and mTOR inhibitor rapamycin, and chlorogenic acid significantly reduced CORT-induced PC12 cytotoxicity by activating autophagy [ 88 , 89 ]. The potential regulatory role of the estrogen-BDNF-mTORC1 signaling pathway in depression is shown in Figure 1 .…”

Section: Role Of Bdnf-mtor1 Signaling Pathway In Depressionmentioning

confidence: 99%

Role of BDNF-mTORC1 Signaling Pathway in Female Depression

Yao

et al. 2021

Neural Plasticity

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Depression is a common psychological and mental disorder, characterized by low mood, slow thinking and low will, and even suicidal tendencies in severe cases. It imposes a huge mental and economic burden on patients and their families, and its prevention and treatment have become an urgent public health problem. It is worth noting that there is a significant gender difference in the incidence of depression. Studies have shown that females are far more likely to suffer from depression than males, confirming a close relationship between estrogen and the onset of depression. Moreover, recent studies suggest that the brain-derived neurotrophic factor- (BDNF-) mammalian target of rapamycin complex-1 (mTORC1) signaling pathway is a crucial target pathway for improving depression and mediates the rapid antidepressant-like effects of various antidepressants. However, it is not clear whether the BDNF-mTORC1 signaling pathway mediates the regulation of female depression and how to regulate female depression. Hence, we focused on the modulation of estrogen-BDNF-mTORC1 signaling in depression and its possible mechanisms in recent years.

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Corticosterone induces neurotoxicity in PC12 cells via disrupting autophagy flux mediated by AMPK/mTOR signaling

Cited by 21 publications

References 36 publications

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells – First insights from novel humanized mice

Role of BDNF-mTORC1 Signaling Pathway in Female Depression

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