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

Curry, Daniel W.; Stutz, Bernardo; Andrews, Zane B.; Elsworth, John D.

doi:10.3233/jpd-171296

Cited by 91 publications

(64 citation statements)

References 218 publications

(270 reference statements)

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“…chain, leading to a decline in cellular ATP and a rise in both AMP/ATP and ADP/ATP ratios. Low energy level activates AMPK, a key energy sensor, which is implicated in various activities within the cells to reestablish energy homeostasis (23)(24)(25).…”

Section: Resultsmentioning

confidence: 99%

Administration of metformin to increase the efficacy of chemotherapy regimen in cancers; a new look to an old drug

Hooshyar¹,

Tolouian²,

Ghasemi³

et al. 2019

Immunopathol Persa

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Chemotherapeutic agents are still the major and most common therapy to prevent tumor growth. These drugs have various adverse effects in different organs in addition to systemic effects. Finding more specific and effective drugs or new adjuvant therapeutic substance is needed to improve the success rate. Several studies have proposed the possible mechanisms of anti-neoplastic of metformin, however, its exact mechanism is still obscure. The suggested mechanisms are; alteration in the host metabolic environment after administration of metformin, such as decreases in insulin-dependent stimulation of tumor growth or direct effect on cancer cells, such as the impact on adenosine monophosphate (AMP)-activated protein kinase signaling pathway. Metformin, as an adjuvant therapy, synergistically exerts growth inhibitory effects against cell growth and can induce cell apoptosis in an animal model. Adding metformin to the chemotherapy regimen may reduce resistance and enhance therapeutic efficacy.

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Section: Resultsmentioning

confidence: 99%

Administration of metformin to increase the efficacy of chemotherapy regimen in cancers; a new look to an old drug

Hooshyar¹,

Tolouian²,

Ghasemi³

et al. 2019

Immunopathol Persa

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show abstract

“…The current evidence suggests that the neuroprotective effects of metformin occur via activation of AMPK/mTOR pathway and inhibition of tau phosphorylation [164,165]. In addition, it is known that metformin enhances angiogenesis and neurogenesis, induces autophagy, reduces oxidative stress, and improves neurological deficits [166][167][168][169][170].…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

New Insight into Metformin Mechanism of Action and Clinical Application

Yan¹,

Kover²,

Moore³

2020

Metformin [Working Title]

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Metformin is the first-line medication for Type 2 diabetes (T2D) treatment, and it is the only US FDA approved oral antidiabetic medication for pediatric patients with T2D 10 years and older. Metformin is also used to treat polycystic ovary syndrome (PCOS), another condition with underlying insulin resistance. The clinical applications of metformin are continuing to expand into other fields including cancer, aging, cardiovascular diseases, and neurodegenerative diseases. Metformin modulates multiple biological pathways. Its novel properties and effects continue to evolve; however, its molecular mechanism of action remains incompletely understood. In this chapter, we focus on the recent translational research and clinical data on the molecular action of metformin and the evidence linking the effects of metformin on insulin resistance, prediabetes, diabetes, aging, cancer, PCOS, cardiovascular diseases, and neurodegenerative diseases. Metformin 2 Mechanisms of actionThe potential mechanisms of metformin action involve several pathways. The AMPK-pathway plays an important role in metformin actions [2, 3]. Metformin inhibits the mitochondrial respiratory chain (complex I), which increases the AMP to ATP ratio, leading to the phosphorylation of AMP-activated protein kinase (AMPK) at Thr-172. We have demonstrated that metformin treatment increases protein level of phosphorylated AMPK in high-glucose-treated endothelial cells [4]. The phosphorylated AMPK subsequently phosphorylates multiple downstream effectors to regulate cellular metabolism and energy homeostasis [5]. These downstream effectors include thioredoxin interacting protein (TXNIP) and TBC1D1, a RAB-GTPase activating protein and a member of the tre-2/BUB2/cdc1 domain family. Phosphorylated TXNIP and TBC1D1 increase the plasma membrane localization of glucose transporter 1 (GLUT1) and GLUT4, respectively [6, 7], and regulate glycogen synthases (GYS1 and GYS2) to prevent the storage of glycogen [8]. Some actions of metformin have been found to be AMPK-independent [9].In diabetic mice, metformin has an effect on gut microbiota by inducing a profound shift in the gut microbial community profile, resulting in an increase in the Akkermansia spp. population [10] and cAMP-induced agmatine production [11], which may decrease absorption of glucose from the gastrointestinal tract and increase lipid metabolism respectively. In addition, metformin decreases insulin-induced suppression of fatty acid oxidation and lowers lipid content of hepatic cells [12].New Insight into Metformin Mechanism of Action and Clinical Application DOI: http://dx.doi.org/10.5772/intechopen.91148 association with insulin resistance. Metformin decreases the level of circulating branched-chain amino acids and reduces insulin resistance in a high-fat diet mouse model [22]. Metformin treatment lowers plasma ADMA which is associated with improved glycemic control in patients with T2D [23].Recent studies indicate that phosphatidylinositol-3-kinase/protein kinase B protein (PI3K/PKB, also known as ...

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“…Intriguingly, the metabolic pathway is the most enriched pathway with many DEGs involved and the pathway of highest significance. Additional pathways highly relevant to PD include the apoptosis-related PI3K/AKT signaling pathway, the AMPK signaling pathway activated by falling energy levels yet exacerbating cell death (Curry et al, 2018), and the TNF signaling pathway associated with mediating neurotoxicity. Collectively, the enrichment further highlights our hypothesized axis of "exposure/mutations-mitochondrial dysfunction-metabolite-H3K27ac-transcriptome' for PD pathogenesis.…”

Section: Transcriptomic Similarity Of Neurotoxicant-exposed and Tfam-mentioning

confidence: 99%

Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

Huang¹,

Lou

Charli

et al. 2019

Preprint

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Genetic mutations explain only 10-15% of cases of Parkinson's disease (PD), while an overriding environmental component has been implicated in the etiopathogenesis of PD. But regardless of where the underlying triggers for the onset of familial and sporadic PD fall on the gene-environment axis, mitochondrial dysfunction emerges as a common mediator of dopaminergic neuronal degeneration. Herein, we employ a multidisciplinary approach to convincingly demonstrate that neurotoxicant exposure-and genetic mutation-driven mitochondrial dysfunction share a common mechanism of epigenetic dysregulation. Under both scenarios, lysine 27 acetylation of likely variant H3.2 (H3.2K27ac) increased in dopaminergic neuronal models of PD, thereby opening that region to active enhancer activity via H3K27 hyperacetylation. These vulnerable epigenomic loci represent potential transcription factor motifs for PD pathogenesis. We further confirmed the mitochondrial dysfunction induced H3K27ac during neurodegeneration in ex vivo models of PD. Our results reveal an exciting axis of 'exposure/mutation-mitochondrial dysfunction-metabolism-H3K27ac-transcriptome' for PD pathogenesis. Collectively, the novel mechanistic insights presented here interlinks mitochondrial dysfunction to epigenetic transcriptional regulation in dopaminergic degeneration as well as offer potential new epigenetic intervention strategies for PD.

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

Cited by 91 publications

References 218 publications

Administration of metformin to increase the efficacy of chemotherapy regimen in cancers; a new look to an old drug

Administration of metformin to increase the efficacy of chemotherapy regimen in cancers; a new look to an old drug

New Insight into Metformin Mechanism of Action and Clinical Application

Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

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