A dual role for <scp>AMP</scp>‐activated protein kinase (AMPK) during neonatal hypoxic–ischaemic brain injury in mice

Rousset, Colette; Leiper, Fiona C.; Kichev, Anton; Gressèns, Pierre; Carling, David; Hagberg, Henrik; Thornton, Claire

doi:10.1111/jnc.13034

Cited by 48 publications

(31 citation statements)

References 69 publications

(70 reference statements)

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“…However, these reports failed to specifically examine AMPK phosphorylation by CaMKK2. A recent study on neonatal hypoxia-ischemic brain injury demonstrated the pathological activation of the CaMKK2-AMPK axis in neurons [32]. Interestingly, while inactivation of AMPK during the course of ischemic injury promotes neuronal survival, inhibiting AMPK prior to the insult sensitizes the neurons and exacerbates cell death [31].…”

Section: Tissue-specific Metabolic Regulation By the Ca2+/cam-dependementioning

confidence: 99%

The Ca 2+ /Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft

Marcelo

Means

York

2016

Trends in Endocrinology & Metabolism

170

119

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Calcium (Ca2+) is an essential ligand that binds its primary intracellular receptor Calmodulin (CaM) to trigger a variety of downstream processes and pathways. Central to the actions of Ca2+/CaM is the activation of a highly conserved Ca2+/CaM kinase (CaMK) cascade, which amplifies Ca2+ signals through a series of subsequent phosphorylation events. Proper regulation of Ca2+ flux is necessary for whole-body metabolism and disruption of Ca2+ homeostasis has been linked to a variety of metabolic diseases. Herein, we provide a synthesis of recent advances that highlight the roles of the Ca2+/CaM kinase axis in key metabolic tissues. An appreciation of this information is critical in order to understand the mechanisms by which Ca2+/CaM-dependent signaling contributes to metabolic homeostasis and disease.

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Section: Tissue-specific Metabolic Regulation By the Ca2+/cam-dependementioning

confidence: 99%

The Ca 2+ /Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft

Marcelo

Means

York

2016

Trends in Endocrinology & Metabolism

170

119

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“…2H). Since both the activation and inhibition of AMPK activity resulted in a similar inhibitory effect, we concluded that the effect was not specifically related to AMPK's function; rather, it might have been due to an intracellular metabolic disorder and stress (40,41). Due to the cytotoxicity of U0126 and JNK inhibitor II on HUVEC, they were used at relatively low concentrations, which did not cause any significant inhibition of ZIKV replication (Fig.…”

mentioning

confidence: 99%

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Cheng

Silva

Huang

et al. 2018

J Virol

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The recent outbreak of Zika virus (ZIKV), a reemerging flavivirus, and its associated neurological disorders, such as Guillain-Barré (GB) syndrome and microcephaly, have generated an urgent need to develop effective ZIKV vaccines and therapeutic agents. Here, we used human endothelial cells and astrocytes, both of which represent key cell types for ZIKV infection, to identify potential inhibitors of ZIKV replication. Because several pathways, including the AMP-activated protein kinase (AMPK), protein kinase A (PKA), and mitogen-activated protein kinase (MAPK) signaling pathways, have been reported to play important roles in flavivirus replication, we tested inhibitors and agonists of these pathways for their effects on ZIKV replication. We identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. PKI effectively suppressed the replication of ZIKV from both the African and Asian/American lineages with a high efficiency and minimal cytotoxicity. While ZIKV infection does not induce PKA activation, endogenous PKA activity is essential for supporting ZIKV replication. Interestingly, in addition to PKA, PKI also inhibited another unknown target(s) to block ZIKV replication. PKI inhibited ZIKV replication at the postentry stage by preferentially affecting negative-sense RNA synthesis as well as viral protein translation. Together, these results have identified a potential inhibitor of ZIKV replication which could be further explored for future therapeutic application.IMPORTANCE There is an urgent need to develop effective vaccines and therapeutic agents against Zika virus (ZIKV) infection, a reemerging flavivirus associated with neurological disorders, including Guillain-Barré (GB) syndrome and microcephaly. By screening for inhibitors of several cellular pathways, we have identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. We show that PKI effectively suppresses the replication of all ZIKV strains tested with minimal cytotoxicity to human endothelial cells and astrocytes, two key cell types for ZIKV infection. Furthermore, we show that PKI inhibits ZIKV negative-sense RNA synthesis and viral protein translation. This study has identified a potent inhibitor of ZIKV infection which could be further explored for future therapeutic application.

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“…AMPK senses stress in the cells (Rousset et al. ) and is also activated by some drugs or xenobiotics (Hawley et al. ).…”

Section: Discussionmentioning

confidence: 99%

The long‐term protective effects of neonatal administration of curcumin against nonalcoholic steatohepatitis in high‐fructose‐fed adolescent rats

et al. 2019

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There is an increased prevalence of nonalcoholic steatohepatitis ( NASH ) in adolescents. The suckling period is developmentally plastic, affecting later health outcomes. We investigated whether neonatal administration of curcumin would provide protection against the development of NASH later in adolescence in rats fed a high‐fructose diet. From postnatal day ( PN ) 6 to PN 21, the pups ( N = 128) were allocated to four groups and orally gavaged daily with either 0.5% dimethyl sulfoxide solution (vehicle control), curcumin (500 mg·kg −1 ), fructose (20%, w/v) or curcumin and fructose combined. All the pups were weaned and half the rats in each group had tap water, whereas the other received fructose (20%) as their drinking fluid ad libitum for 6 weeks. The rats’ liver NASH scores, lipid content, and RNA gene expression ratios of AMPK α and TNF α were determined. Hepatic lipid content was similar across the treatment groups in the males ( P > 0.05, ANOVA ). In the females, the hepatic lipid content in the treatment groups ranged from 2.7 to 4.3%. The livers of male and female rats that had fructose either as neonates and/or postweaning had significantly marked inflammation ( P = 0.0112, Kruskal–Wallis) and fibrosis ( P < 0.0001, ANOVA ) which were attenuated by curcumin. The hepatic gene expression ratios for AMPK α in both sexes were significantly downregulated ( P < 0.0001, ANOVA ), whereas the expression ratios of TNF α were significantly upregulated ( P < 0.0001) in rats fed a high‐fructose diet pre and/or postweaning compared to the other groups. Neonatal curcumin administration is a potential natural pharmacological candidate for the prevention of NASH .

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A dual role for AMP‐activated protein kinase (AMPK) during neonatal hypoxic–ischaemic brain injury in mice

Cited by 48 publications

References 69 publications

The Ca 2+ /Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft

The Ca 2+ /Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

The long‐term protective effects of neonatal administration of curcumin against nonalcoholic steatohepatitis in high‐fructose‐fed adolescent rats

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