Metformin treatment reduces motor and neuropsychiatric phenotypes in the zQ175 mouse model of Huntington disease

Sanchís, Ana; García-Gimeno, Maria Adelaida; Cañada-Martínez, Antonio José; Sequedo, María Dolores; Millán, José María; Sanz, Pascual; Vázquez‐Manrique, Rafael P.

doi:10.1038/s12276-019-0264-9

Cited by 60 publications

(93 citation statements)

References 58 publications

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“…Treatment with one of the main polyphenolic compounds of green tea, epigallocatechin-3-gallate (EGCG), which failed to improve polyQ-related phenotypes in C. elegans [ 115 ], inhibited the aggregation of Httex1p-93Q in a dose-dependent manner and improved photoreceptor degeneration and motor function [ 153 ]. These results were in agreement with previous results by Sanchis and co-workers showing that AMPK activation by metformin reduces polyQ aggregation in C. elegans [ 127 ].…”

Section: Oxidative Stress and Huntington Diseasesupporting

confidence: 94%

“…Aside from being a potent antioxidant, EGCG is also an activator of AMP-activated protein kinase (AMPK) [ 125 , 126 ], a master regulator of energy and metabolism. In contrast with the Machiela study, the activation of AMPK using metformin has been shown to improve aggregation of polyQs in worms expressing 40Q in muscle cells [ 127 ]. However, this is not always the case.…”

Section: Oxidative Stress and Huntington Diseasementioning

confidence: 98%

“…Moreover, in animal models and patients with HD, this process is inhibited by mHtt itself [ 257 ]. However, some authors have demonstrated that AMPK activators ( Figure 2 ) are able to reduce the amount of mHtt in different models of HD [ 127 , 258 , 259 ]. Moreover, metformin, a well-known activator of AMPK and a worldwide treatment against type 2 diabetes, is able to delay cognitive decline in patients with HD ( Figure 2 ) [ 260 ].…”

Section: Conclusion and Remarksmentioning

confidence: 99%

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Reactive Species in Huntington Disease: Are They Really the Radicals You Want to Catch?

et al. 2020

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Huntington disease (HD) is a neurodegenerative condition and one of the so-called rare or minority diseases, due to its low prevalence (affecting 1–10 of every 100,000 people in western countries). The causative gene, HTT, encodes huntingtin, a protein with a yet unknown function. Mutant huntingtin causes a range of phenotypes, including oxidative stress and the activation of microglia and astrocytes, which leads to chronic inflammation of the brain. Although substantial efforts have been made to find a cure for HD, there is currently no medical intervention able to stop or even delay progression of the disease. Among the many targets of therapeutic intervention, oxidative stress and inflammation have been extensively studied and some clinical trials have been promoted to target them. In the present work, we review the basic research on oxidative stress in HD and the strategies used to fight it. Many of the strategies to reduce the phenotypes associated with oxidative stress have produced positive results, yet no substantial functional recovery has been observed in animal models or patients with the disease. We discuss possible explanations for this and suggest potential ways to overcome it.

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Section: Oxidative Stress and Huntington Diseasesupporting

confidence: 94%

Section: Oxidative Stress and Huntington Diseasementioning

confidence: 98%

Section: Conclusion and Remarksmentioning

confidence: 99%

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Reactive Species in Huntington Disease: Are They Really the Radicals You Want to Catch?

et al. 2020

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“…Worms expressing polyQs in different tissues helped to uncover many genes modulating the rate of aggregation and/or the toxicity induced by these molecules [ 8 , 11 – 14 ]. Using neuronal and muscular models of polyQ toxicity in C. elegans , we described AMP-activated protein kinase (AMPK) as a good candidate to manipulate aggregation and toxicity induced by these molecules [ 15 , 16 ]. Moreover, AMPK activation is neuroprotective in in vivo mouse models of HD [ 15 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

Synergistic activation of AMPK prevents from polyglutamine-induced toxicity in Caenorhabditis elegans

Gómez-Escribano

Bono-Yagüe

García-Gimeno

et al. 2020

Pharmacological Research

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Expression of abnormally long polyglutamine (polyQ) tracks is the source of a range of dominant neurodegenerative diseases, such as Huntington disease. Currently, there is no treatment for this devastating disease, although some chemicals, e.g ., metformin, have been proposed as therapeutic solutions. In this work, we show that metformin, together with salicylate, can synergistically reduce the number of aggregates produced after polyQ expression in Caenorhabditis elegans . Moreover, we demonstrate that incubation polyQ-stressed worms with low doses of both chemicals restores neuronal functionality. Both substances are pleitotropic and may activate a range of different targets. However, we demonstrate in this report that the beneficial effect induced by the combination of these drugs depends entirely on the catalytic action of AMPK, since loss of function mutants of aak-2 /AMPKα2 do not respond to the treatment. To further investigate the mechanism of the synergetic activity of metformin/salicylate, we used CRISPR to generate mutant alleles of the scaffolding subunit of AMPK, aakb-1 /AMPKβ1. In addition, we used an RNAi strategy to silence the expression of the second AMPKβ subunit in worms, namely aakb-2 /AMPKβ2. In this work, we demonstrated that both regulatory subunits of AMPK are modulators of protein homeostasis. Interestingly, only aakb-2 /AMPKβ2 is required for the synergistic action of metformin/salicylate to reduce polyQ aggregation. Finally, we showed that autophagy acts downstream of metformin/salicylate-related AMPK activation to promote healthy protein homeostasis in worms.

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“…Moreover, metformin increases the sensitivity of insulin receptors and decreases glucagon release [9]. Recent reports suggest that metformin may have neuroprotective effects against many neurodegenerative disorders [10,11]. These effects may be attributed to the antioxidant and antiinflammatory properties of metformin together with its ability to restore mitochondrial functions and inhibit apoptosis [12].…”

Section: Introductionmentioning

confidence: 99%

Effect of metformin and indole-3-carbinol on a rat model of Parkinson’s disease induced by 6-hydroxydopamine

Borg

Kabel

Abdel-Kareem

2020

BESPS

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Parkinson's disease (PD) is a motor system disorder caused by factors that lead to depletion of dopamine from the dopaminergic neurons in the substantia nigra. Mechanisms of PD include mitochondrial dysfunction, oxidative stress and neuroinflammation. Metformin is an old antidiabetic drug that has recently been shown to offer protective effects against many types of cancer, cardiovascular and neurodegenerative diseases. Indole-3-carbinol (I3C) is a phytochemical derived from the cruciform vegetables. Recently, I3C was proven to have antioxidant, anti-inflammatory and neuroprotective properties. The aim of this work was to study the effect of metformin and/or I3C on 6-hydroxydopamine (6-OHDA)-induced PD in rats. Sixty male Wistar rats were divided into 6 equal groups: Control; 6-OHDA, metformin + 6-OHDA; I3C + 6-OHDA; carboxymethyl cellulose + 6-OHDA and metformin + I3C + 6-OHDA group. Striatal dopamine, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), transforming growth factor beta1 (TGF-β1), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione reductase (GR), mitochondrial complex 1 activity, total swim score and catalepsy score were measured. The striatum was subjected to immunohistochemical examination. The combination between metformin and I3C induced significant increase in striatal SOD, GR, mitochondrial complex 1 activity and dopamine with significant decrease in striatal TNF-α, IL-6, TGF-β1, MDA and nuclear factor kappa-B expression with significant improvement in catalepsy and total swim scores better than the groups that received either I3C or metformin alone. So, metformin/I3C combination may represent a beneficial therapeutic modality for amelioration of 6-OHDAinduced PD in rats..

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Metformin treatment reduces motor and neuropsychiatric phenotypes in the zQ175 mouse model of Huntington disease

Cited by 60 publications

References 58 publications

Reactive Species in Huntington Disease: Are They Really the Radicals You Want to Catch?

Reactive Species in Huntington Disease: Are They Really the Radicals You Want to Catch?

Synergistic activation of AMPK prevents from polyglutamine-induced toxicity in Caenorhabditis elegans

Effect of metformin and indole-3-carbinol on a rat model of Parkinson’s disease induced by 6-hydroxydopamine

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