eIF4E-Dependent Translational Control: A Central Mechanism for Regulation of Pain Plasticity

Uttam, Sonali; Wong, Calvin; Price, Theodore J.; Khoutorsky, Arkady

doi:10.3389/fgene.2018.00470

Cited by 44 publications

(36 citation statements)

References 107 publications

(135 reference statements)

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“…Several studies suggest that AMPK activation reduces eukaryotic translation initiation factor 2 subunit α (eIF2α) phosphorylation in several cell types ( Dong et al., 2010 ; Liang et al., 2013 ; Boß et al., 2016 ). Since eIF2α regulates ternary complex availability (eIF4F complex) ( Trinh and Klann, 2013 ), it has been suggested that metformin also reduces eIF2α-dependent translation initiation ( Price and Géranton, 2009 ; Khoutorsky and Price, 2018 ; Uttam et al., 2018 ; Megat and Price, 2018 ). A recent study from our laboratory shows that metformin diminishes chronic fructose-induced tactile allodynia (a model of insulin resistance).…”

Section: Effects Of Metformin On Painmentioning

confidence: 99%

Metformin: A Prospective Alternative for the Treatment of Chronic Pain

et al. 2020

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Metformin (biguanide) is a drug widely used for the treatment of type 2 diabetes. This drug has been used for 60 years as a highly effective antihyperglycemic agent. The search for the mechanism of action of metformin has produced an enormous amount of research to explain its effects on gluconeogenesis, protein metabolism, fatty acid oxidation, oxidative stress, glucose uptake, autophagy and pain, among others. It was only up the end of the 1990s and beginning of this century that some of its mechanisms were revealed. Metformin induces its beneficial effects in diabetes through the activation of a master switch kinase named AMP-activated protein kinase (AMPK). Two upstream kinases account for the physiological activation of AMPK: liver kinase B1 and calcium/ calmodulin-dependent protein kinase kinase 2. Once activated, AMPK inhibits the mechanistic target of rapamycin complex 1 (mTORC1), which in turn avoids the phosphorylation of p70 ribosomal protein S6 kinase 1 and phosphatidylinositol 3kinase/protein kinase B signaling pathways and reduces cap-dependent translation initiation. Since metformin is a disease-modifying drug in type 2 diabetes, which reduces the mTORC1 signaling to induce its effects on neuronal plasticity, it was proposed that these mechanisms could also explain the antinociceptive effect of this drug in several models of chronic pain. These studies have highlighted the efficacy of this drug in chronic pain, such as that from neuropathy, insulin resistance, diabetic neuropathy, and fibromyalgia-type pain. Mounting evidence indicates that chronic pain may induce anxiety, depression and cognitive impairment in rodents and humans. Interestingly, metformin is able to reverse some of these consequences of pathological pain in rodents. The purpose of this review was to analyze the current evidence about the effects of metformin in chronic pain and three of its comorbidities (anxiety, depression and cognitive impairment).

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Section: Effects Of Metformin On Painmentioning

confidence: 99%

Metformin: A Prospective Alternative for the Treatment of Chronic Pain

et al. 2020

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“…Remarkably, our results for Torin1-and XL388-infused groups showed that the reduced Mn-enhanced signals in the cortical area, such as the IC, S1HL, M1/2, and ACC. These results demonstrate that mTOR inhibition may have an effect on activation of other brain regions as well as pain reduction through the inhibition of phosphorylation by mTOR control [13,37]. Nevertheless, there was no difference in signal enhancement ratios between experimental groups in the V1/2 region.…”

Section: How Can Mtor Inhibition Reduce Brain Activities Of Chronic Pmentioning

confidence: 64%

“…Although the roles of mTOR pathway in cancer research have been extensively studied, there has been no in-depth study on the role of mTOR signaling in pain research. Recent studies have reported that neuropathic pain is related to structural changes in the CNS after nerve injury, known as mTOR-mediated neuronal plasticity [13][14][15][16]. The activation of mTOR regulates protein synthesis and in uences a wide range of physiological and pathological states by phosphorylating downstream effectors [12,17,18].…”

Section: Introductionmentioning

confidence: 99%

Manganese-enhanced MRI depicts a reduction in brain response to nociception by mTOR inhibition in chronic pain rats

Cha

Choi

Kim

et al. 2020

Preprint

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Neuropathic pain induced by a nerve injury could lead to chronic pain. Recent studies have reported hyperactive neural activities in the nociceptive-related area of the brain as a result of chronic pain. Although cerebral activities associated with hyperalgesia and allodynia in the chronic pain model were difficult to represent with functional imaging techniques, advances in manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) could facilitate the visualization of the activation of pain-specific neural responses in the cerebral cortex. In order to investigate the alleviation of pain nociception by mammalian target of rapamycin (mTOR) modulation, we observed the cerebrocortical excitability changes and compared the regional Mn 2+ enhancement after mTOR inhibitions. At day 7 after nerve injury, drugs were applied into the intracortical area, and drug (Vehicle, Torin1 and XL388) effects were compared within groups using MEMRI. In the results, signal intensities of the insular cortex (IC), primary somatosensory cortex of the hind limb region (S1HL), motor cortex 1/2 (M1/2), and anterior cingulate cortex (ACC) regions were significantly reduced after application of mTOR inhibitors (Torin1 and XL388). Furthermore, the rostral-caudal analysis of the IC indicated that the rostral region of the IC was more associated with pain perception than caudal region. Our data suggest that MEMRI could present the pain-related signal changes in the brain, and mTOR inhibition is closely correlated with pain modulation in chronic pain rats.

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“…Translation regulation plays a major role in synaptic plasticity, memory formation and related circuitry changes and occurs via multiple mechanisms [49][50][51] . Notably, dendrites contain a large amount of locally pre-positioned ribosomes and mRNA ready for rapid onset on translation occurring during LTP [52][53][54] .…”

Section: Hypothesis: Rna G4 May Play a Key Role In Neuroplasticity Thmentioning

confidence: 99%

Hypothesis: Regulation of neuroplasticity may involve I-motif and G-quadruplex DNA formation modulated by epigenetic mechanisms

Todorov

Cunha

2019

Medical Hypotheses

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Recent studies demonstrated the existence in vivo of various functional DNA structures that differ from the double helix. The G-quadruplex (G4) and intercalated motif (I-motif or IM) DNA structures are formed as knots where, correspondingly, guanines or cytosines on the same strand of DNA bind to each other. There are grounds to believe that G4 and IM sequences play a significant role in regulating gene expression considering their tendency to be found in or near regulatory sites (such as promoters, enhancers, and telomeres) as well as the correlation between the prevalence of G4 or IM conformations and specific phases of cell cycle. Notably, G4 and IM capable sequences tend to be found on the opposite strands of the same DNA site with at most one of the two structures formed at any given time. The recent evidence that K + , Mg 2+ concentrations directly affect IM formation (and likely G4 formation indirectly) lead us to believe that these structures may play a major role in synaptic plasticity of neurons, and, therefore, in a variety of central nervous system (CNS) functions including memory, learning, habitual behaviors, pain perception and others. Furthermore, epigenetic mechanisms, which have an important role in synaptic plasticity and memory formation, were also shown to influence formation and stability of G4s and IMs. Our hypothesis is that non-canonical DNA and RNA structures could be an integral part of neuroplasticity control via gene expression regulation at the level of transcription, translation and splicing. We propose that the regulatory activity of DNA IM and G4 structures is modulated by DNA methylation/demethylation of the IM and/or G4 sequences, which facilitates the switch between canonical and non-canonical conformation. Other neuronal mechanisms interacting with the formation and regulatory activity of non-canonical DNA and RNA structures, particularly G4, IM and triplexes, may involve microRNAs as well as ion and proton fluxes. We are proposing experiments in acute brain slices and in vivo to test our hypothesis. The proposed studies would provide new insights into fundamental neuronal mechanisms in health and disease and potentially open new avenues for treating mental health disorders. I-motif and G-quadruplexWhile double helix DNA structure (B-form) is the most common conformation, a variety of other forms are known to exist in vitro 1-5 . Some forms also appear to exist in vivo and were shown to have physiological significance 6 . Of those, G-quadruplex (G4) and intercalated motif (I-motif or IM) appear to be the most interesting. G4 is found in G-rich regulatory regions of the genome and was demonstrated to exist in vivo in several studies 6,7 . There is also evidence of its involvement in regulatory pathways 8 .IM, a form occurring primarily in C-rich regulatory regions and are characterized by C:C+ pairs. Hence IMs form more easily at lower pH. However, IMs can form at normal pH and are also affected by other factors, including ionic strengths (K + , Mg 2+ concentration in particula...

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eIF4E-Dependent Translational Control: A Central Mechanism for Regulation of Pain Plasticity

Cited by 44 publications

References 107 publications

Metformin: A Prospective Alternative for the Treatment of Chronic Pain

Metformin: A Prospective Alternative for the Treatment of Chronic Pain

Manganese-enhanced MRI depicts a reduction in brain response to nociception by mTOR inhibition in chronic pain rats

Hypothesis: Regulation of neuroplasticity may involve I-motif and G-quadruplex DNA formation modulated by epigenetic mechanisms

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