AMPK activation: Role in the signaling pathways of neuroinflammation and neurodegeneration

Peixoto, Christina Alves; Oliveira, W.; Araújo, Shyrlene Meiry da Racho; Nunes, Ana Karolina Santana

doi:10.1016/j.expneurol.2017.08.013

Cited by 126 publications

(110 citation statements)

References 108 publications

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“…S4), but interestingly, there is a prominent representation of pathways involved in immunoregulatory functions (e.g. AMPK, PTEN, B Cell Receptor signaling) 12 in diffuse injuries (Fig. S4B).…”

Section: Resultsmentioning

confidence: 99%

MicroRNA sequencing of rat hippocampus and human biofluids identifies acute, chronic, focal and diffuse traumatic brain injuries

Weisz

Kennedy

Widen

et al. 2020

Sci Rep

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age-matched control serum. In these exploratory studies with rat and human tissues, we tested three hypotheses, 1) miRNA-seq profiles would identify TBI at all acute and chronic post-injury intervals, 2) miRNA-seq profiles would discriminate between focal and diffuse TBI and 3) serum miRNA-seq would reveal potential miRNA markers of neuropsychiatric and neurodegenerative sequelae. Methods Study design. The miRNA-seq and data analyses workflow is shown in Fig. 1A (rat studies) and Fig. 2A (human studies). Detailed methods, including rat surgical procedures, are described in Supplementary Materials and are summarized below. All procedures were done under a protocol (No. 1312056A) approved by the University of Texas Medical Branch at Galveston's Institutional Animal Care and Use Committee. All procedures performed as part of this study were performed in accordance with institutional, state, and U.S. federal guidelines and regulations. In the rat studies, for each post-injury interval, we sequenced four TBI and four sham-control hippocampi, thus 56 rats were used for miRNA-seq analysis. In the human studies, we sequenced 51 serum samples (six acute and six aged controls, 33 acute TBI representing 24, 48, 96 h post-injury, six chronic TBI [2-32 years post-injury]). Demographic characteristics are shown in Table 1. Rat hippocampus and serum isolation and PCR array analysis. Total RNA from rat hippocampal tissue was extracted and purified using Ribopure (Ambion) as in Boone and Weisz et al. 9. Serum from rats subjected to FPI and CCI was used for miRNA isolation and PCR array analysis as described in Supplementary Methods.

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Section: Resultsmentioning

confidence: 99%

MicroRNA sequencing of rat hippocampus and human biofluids identifies acute, chronic, focal and diffuse traumatic brain injuries

Weisz

Kennedy

Widen

et al. 2020

Sci Rep

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“…In this study, we used an in ammatory pain model to determine the signaling mechanism involved in the analgesic effect produced by local AMPK activation. AMPK is a member of the family of metabolically sensitive protein kinases, which contains α-catalytic subunits and β-and γ-regulatory subunits [24,25]. AMPK activation can inhibit a variety of pro-in ammatory signal cascades, including c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF kappa B) and JAK-STAT (Janus kinase signal transducer and activator of transcription) [26][27][28][29].…”

Section: Discussionmentioning

confidence: 99%

AICAR activates AMPK to regulate STAT3 nuclear translocation and phosphorylation and iNOS expression in inflammatory pain

Xiang¹,

Cai²,

Hu³

et al. 2020

Preprint

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Background: AMP-activated protein kinase (AMPK) activators can improve inflammatory pain and neuropathic pain. Inflammation translocate signal transducers and activators of transcription 3 (STAT3) to the nuclei of activated macrophages, and STAT3 phosphorylation promotes the expression of inducible nitric oxide synthetase (iNOS). In this study, we determined whether AMPK activation alleviate inflammatory pain via STAT3 nuclear translocation and phosphorylation. Methods: Immunoblotting was used to measure the expression of p-AMPK, and iNOS. Immunoblotting and immunofluorescence were used to detect the nuclear translocation of p-STAT3(Ser727) and STAT3 in macrophages of local inflammatory tissues. Flow cytometry was used to measure reactive oxygen species (ROS) accumulation and mitochondrial damage.Results: AMPK activation with AICAR significantly alleviated pain hypersensitivity and inhibited the expression of iNOS in complete Freund's adjust (CFA)-induced inflamed skin tissues. CFA caused nuclear translocation of STAT3 and p-STAT3(Ser727) in macrophages of inflamed skin tissues. AICAR inhibited nuclear translocation of STAT3 and p-STAT3(Ser727) and promoted the phosphorylation of STAT3(Ser727) in the cytoplasm of macrophages. AICAR also inhibited the expression of iNOS and nuclear translocation of STAT3 and p-STAT3(Ser727), and promoted the phosphorylation of STAT3(Ser727) in NR8383 macrophages treated with CFA. AMPK activation also inhibited the ROS generation and the mitochondrial damage of NR8383 macrophages caused by CFA. In addition, transfection of STAT3 S727D decreased ROS and alleviated mitochondrial damage.Conclusions: Activation of AMPK attenuates inflammatory pain and suppresses STAT3 nuclear translocation and phosphorylation of STAT3(Ser727) in macrophages, resulting in reduced iNOS. Activation of AMPK also promotes phosphorylation of STAT3(Ser727) in the cytoplasm of macrophages to alleviate ROS accumulation and mitochondrial damage associated with inflammation.

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“…Second, binding of AMP or ADP extends the functional “half-life” of AMPK by protecting pThr172 from dephosphorylation [13]. In the absence of such protection, pThr172 is rapidly dephosphorylated by phosphatases, including protein phosphatase 2A (PP2A) and 2C (PP2C) [28]. And third, in addition to promoting and protecting the phosphorylation of Thr172, AMP allosterically increases the catalytic activity of AMPK by as much as 10-fold [26].…”

Section: Regulation Of Ampkmentioning

confidence: 99%

“…AMPK exerts powerful anti-inflammatory effects, including inhibition of NOX-mediated ROS production [139,140], iNOS-mediated NO production [141], and NF-κB-mediated production of proinflammatory cytokines such as IL-1 and TNFα [28,142]. Furthermore, the transition from M2 to M1, involves a critical metabolic switch from OXPHOS to glycolysis.…”

Section: Functions Of Ampk and Their Relevance To Pdmentioning

confidence: 99%

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson’s Disease

Curry

Stutz

Andrews

et al. 2018

JPD

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterized by the accumulation of intracellular α-synuclein aggregates and the degeneration of nigrostriatal dopaminergic neurons. While no treatment strategy has been proven to slow or halt the progression of the disease, there is mounting evidence from preclinical PD models that activation of 5’-AMP-activated protein kinase (AMPK) may have broad neuroprotective effects. Numerous dietary supplements and pharmaceuticals (e.g. metformin) that increase AMPK activity are available for use in humans, but clinical studies of their effects in PD patients are limited. AMPK is an evolutionarily conserved serine/threonine kinase that is activated by falling energy levels and functions to restore cellular energy balance. However, in response to certain cellular stressors, AMPK activation may exacerbate neuronal atrophy and cell death. This review describes the regulation and functions of AMPK, evaluates the controversies in the field, and assesses the potential of targeting AMPK signaling as a neuroprotective treatment for PD.

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AMPK activation: Role in the signaling pathways of neuroinflammation and neurodegeneration

Cited by 126 publications

References 108 publications

MicroRNA sequencing of rat hippocampus and human biofluids identifies acute, chronic, focal and diffuse traumatic brain injuries

MicroRNA sequencing of rat hippocampus and human biofluids identifies acute, chronic, focal and diffuse traumatic brain injuries

AICAR activates AMPK to regulate STAT3 nuclear translocation and phosphorylation and iNOS expression in inflammatory pain

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson’s Disease

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