Metformin Acts on Two Different Molecular Pathways to Enhance Adult Neural Precursor Proliferation/Self-Renewal and Differentiation

Fatt, Michael P.; Hsu, Karolynn; He, Liang; Wondisford, Fredric E.; Miller, Freda D.; Kaplan, David R.; Wang, Jing

doi:10.1016/j.stemcr.2015.10.014

Cited by 102 publications

(86 citation statements)

References 20 publications

(36 reference statements)

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“…In our study, metformin reduced apoptosis induced by SE to a greater extent than salubrinal or GSK2656157, despite the similar reductions in CHOP levels in all of the treatment groups. Although both salubrinal and metformin have neuroprotective effects, it has been reported that metformin also has the capability to enhance the proliferation of neural precursors through TAp73 [31], which may result in fewer apoptotic cells after metformin compared to the salubrinal or GSK2656157 treatment. Further studies are necessary to examine the mechanism by which metformin ameliorates apoptosis induced by SE.…”

Section: Discussionmentioning

confidence: 99%

The effect of metformin treatment on endoplasmic reticulum (ER) stress induced by status epilepticus (SE) via the PERK-eIF2α-CHOP pathway

Chen

Guo

et al. 2017

Bosn J of Basic Med Sci

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Status epilepticus (SE) is defined as continuous seizure activity lasting more than 5 minutes. It results in neuronal cell death, mediated by endoplasmic reticulum (ER) stress response. Previously, metformin demonstrated neuroprotective effects in primary cortical neurons. In this study, we analyzed the effect of metformin on ER stress via the pro-apoptotic protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) pathway. SE was induced in rats by pentylenetetrazole. Following SE, the rats were treated with salubrinal, GSK2656157, or metformin. In a control group (normal saline) SE was not induced. CHOP, eIF2α, and PERK expression was determined by Western blot; apoptosis was analyzed by TUNEL assay. CHOP expression was significantly increased at 6 and 24 hours following SE. At both time points, eIF2α and PERK levels were also increased. At 6 hours, CHOP expression was significantly reduced in salubrinal, GSK2656157 and metformin groups versus SE group. eIF2α and PERK levels were decreased in metformin compared to SE group. eIF2α expression was markedly decreased in salubrinal versus SE group, while PERK expression was markedly reduced in GSK2656157 versus SE group. At 6 and 24 hours, the apoptosis rate was significantly increased in SE versus control group, while it was significantly reduced in salubrinal, GSK2656157, and metformin groups compared to SE group. The apoptosis rate also decreased in salubrinal group at 24 hours, although not to the extent observed in metformin group. Overall, CHOP expression and apoptosis induced by SE in rats were reduced with metformin. Further studies are required to evaluate the clinical relevance of metformin for patients with SE.

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Section: Discussionmentioning

confidence: 99%

The effect of metformin treatment on endoplasmic reticulum (ER) stress induced by status epilepticus (SE) via the PERK-eIF2α-CHOP pathway

Chen

Guo

et al. 2017

Bosn J of Basic Med Sci

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“…These events include the amyloid deposition in the brain due to the uncontrolled cleavage of APP and the degeneration of neurotoxic Aβ-42 peptides, hyperphosporhylation of tau protein and the formation of intracellular neurofibrillary tangles, the deficiency of acetylcholine (ACh) due to its increased hydrolysis by acetylcholinesterase (AChE), oxidative stress, and mitochondrial dysfunction Fouad Bulletin of the National Research Centre (2019) 43:52 (Gage 2002) and can be obtained from fetal and postmortem neonatal brain tissues (Martínez-Morales et al 2013) or differentiated from iPSCs and ESCs (Hermann and Storch 2013;Yu et al 2013aYu et al , 2013b. The mechanistic action of NSCs is regulated by metabolic processes such as oxygen consumption and energy production (Almeida and Vieira 2017;Fatt et al 2015;Wang et al 2012a). Mitochondrial dysfunction is implicated in AD progression (Swerdlow et al 2014); therefore, more research is required to estimate the connection between the metabolic switch of NSCs and AD pathogenesis (Fang et al 2018).…”

Section: Stem Cell-based Therapy For Admentioning

confidence: 99%

Stem cells as a promising therapeutic approach for Alzheimer’s disease: a review

Fouad

2019

Bull Natl Res Cent

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Alzheimer's disease (AD) is a neurodegenerative disorder that impairs memory formation and disrupts neurocognitive function. This neuropathy is characterized by neural loss, neurodegeneration, and formation of amyloid plaques and neurofibrillary tangles. Approved medications provide only symptomatic relief without affecting AD progression. Because of the multifactorial nature of AD and the absence of effective treatment, stem cell-based therapy has been regarded as an effective, safe, and innovative therapeutic approach to overcome AD. Different sources of stem cells are employed for AD treatment, such as neural stem cells (NSCs), mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). There is a growing body of evidence supporting the promising therapeutic potential of stem cell transplantation, which might be attributed to the mechanistic actions exerted by stem cells such as inducing hippocampal neurogenesis, secreting paracrine factors, exerting anti-inflammatory activity, showing anti-amyloidogenic potential, and finally resulting in cognitive recovery. Although stem cell-based therapy faces potential hurdles, it holds a potential hope to provide a safe, effective, and feasible clinical application of stem cells in AD patients.

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“…The functional role of AMPK in neuron and glial cells has been intensively studied, and it has been identified that the AMPK may affect neuronal differentiation and synaptic connectivity (Fatt et al, ). Aberrant activity of AMPK in the nervous system is associated with the neurodegenerative diseases, for example ALS, Alzheimer's disease, Parkinson's disease, and Huntington's disease (Hang, Thundyil, & Lim, ; Ju et al, ; Vingtdeux et al, ).…”

Section: Discussionmentioning

confidence: 99%

Reduced sirtuin 1/adenosine monophosphate‐activated protein kinase in amyotrophic lateral sclerosis patient‐derived mesenchymal stem cells can be restored by resveratrol

Yun

Jeong

Kim

et al. 2018

J Tissue Eng Regen Med

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neuron system. Our previous study has shown that bone marrowmesenchymal stem cells (BM-MSCs) from ALS patients have functional limitations in releasing neurotrophic factors and exhibit the senescence phenotype. In this study, we examined sirtuin 1/adenosine monophosphate-activated protein kinase (SIRT1/ AMPK) activities and identified significant decreases in the ALS-MSCs compared with normal healthy control originated BM-MSCs. This decline was restored by pretreatment with resveratrol (RSV), measured using quantitative polymerase chain reaction, NAD/NADH assay, and immunoblot analysis. Neuroprogenitor markers were increased in RSV-treated ALS-MSCs (RSV/ALS-MSCs). The differentiated ALS-MSCs (ALS-dMSCs) exhibited a cell body and dendritic shape similar to neurons. RSV/ALS-MSCs showed significantly increased differentiation rate as compared with the untreated ALS-dMSCs. The neurite numbers and lengths were also significantly increased. This was confirmed with immunoblot analysis using neuron specific markers such as nestin, NF-M, Tuj-1, and Map-2 in RSV/ALS-dMSCs. Thus, this study shows that ALS-MSCs showed down-regulation of AMPK/SIRT1 signalling, which was recovered by treatment with RSV. This data suggest that RSV can be one of the candidate agents for improving therapeutic efficacy of ALS patients' originated MSCs.

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Metformin Acts on Two Different Molecular Pathways to Enhance Adult Neural Precursor Proliferation/Self-Renewal and Differentiation

Cited by 102 publications

References 20 publications

The effect of metformin treatment on endoplasmic reticulum (ER) stress induced by status epilepticus (SE) via the PERK-eIF2α-CHOP pathway

The effect of metformin treatment on endoplasmic reticulum (ER) stress induced by status epilepticus (SE) via the PERK-eIF2α-CHOP pathway

Stem cells as a promising therapeutic approach for Alzheimer’s disease: a review

Reduced sirtuin 1/adenosine monophosphate‐activated protein kinase in amyotrophic lateral sclerosis patient‐derived mesenchymal stem cells can be restored by resveratrol

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