Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression

Eren-Koçak, Emine; Dalkara, Turgay

doi:10.3389/fphar.2021.777607

Cited by 21 publications

(11 citation statements)

References 193 publications

(295 reference statements)

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“…When NF‐κB binding protein IκB is phosphorylated, the p65 subunit of NF‐κB (NF‐κB‐p65) is freed and translocated to the nucleus, where it initiates transcription of several inflammatory molecules, including cytokines and chemokines (Shih et al., 2015). Thus, nuclear translocation of NF‐κB‐p65 is widely used as an indicator of increased neuroinflammatory signalling (Eren‐Koçak & Dalkara, 2021; Liu et al., 2017). We investigated whether NUDT6 overexpression induced activation of NF‐κB‐p65 in our samples by quantifying the ratio of NF‐κB‐p65 positive nuclei‐to‐total nuclei in immunostained hippocampal sections from NUDT6‐AAV2 and blank‐AAV2 groups.…”

Section: Resultsmentioning

confidence: 99%

FGF2 gene's antisense protein, NUDT6, plays a depressogenic role by promoting inflammation and suppressing neurogenesis without altering FGF2 signalling

Uzay,

Bahadır‐Varol,

Hökelekli

et al. 2024

The Journal of Physiology

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Fibroblast growth factor‐2 (FGF2) is involved in the regulation of affective behaviour and shows antidepressant effects through the Akt and extracellular signal regulated kinase (ERK) 1/2 pathways. Nudix hydrolase 6 (NUDT6) protein is encoded from FGF2 gene's antisense strand and its role in the regulation of affective behaviour is unknown. Here, we overexpressed NUDT6 in the hippocampus and investigated its behavioural effects and the underlying molecular mechanisms affecting the behaviour. We showed that increasing hippocampal NUDT6 results in depression‐like behaviour in rats without changing FGF2 levels or activating its downstream effectors, Akt and ERK1/2. Instead, NUDT6 acted by inducing inflammatory signalling, specifically by increasing S100 calcium binding protein A9 (S100A9) levels, activating nuclear factor‐kappa B‐p65 (NF‐κB‐p65), and elevating microglia numbers along with a reduction in neurogenesis. Our results suggest that NUDT6 could play a role in major depression by inducing a proinflammatory state. This is the first report of an antisense protein acting through a different mechanism of action than regulation of its sense protein. The opposite effects of NUDT6 and FGF2 on depression‐like behaviour may serve as a mechanism to fine‐tune affective behaviour. Our findings open up new venues for studying the differential regulation and functional interactions of sense and antisense proteins in neural function and behaviour, as well as in neuropsychiatric disorders. imageKey points Hippocampal overexpression of nudix hydrolase 6 (NUDT6), the antisense protein of fibroblast growth factor‐2 (FGF2), increases depression‐like behaviour in rats. Hippocampal NUDT6 overexpression triggers a neuroinflammatory cascade by increasing S100 calcium binding proteinA9 (S100A9) expression and nuclear NF‐κB‐p65 translocation in neurons, in addition to microglial recruitment and activation. Hippocampal NUDT6 overexpression suppresses neurogenesis. NUDT6 exerts its actions without altering the levels or downstream signalling pathways of FGF2.

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Section: Resultsmentioning

confidence: 99%

FGF2 gene's antisense protein, NUDT6, plays a depressogenic role by promoting inflammation and suppressing neurogenesis without altering FGF2 signalling

Uzay,

Bahadır‐Varol,

Hökelekli

et al. 2024

The Journal of Physiology

Self Cite

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show abstract

“…When NF-κB binding protein IκB is phosphorylated, the p65 subunit of NF-κB is freed and translocated to the nucleus, where it initiates transcription of several inflammatory molecules, including cytokines and chemokines (Shih et al, 2015). Thus, nuclear translocation of NF-κB-p65 is widely used as an indicator of increased neuroinflammatory signaling (Eren-Koçak and Dalkara, 2021; Liu et al, 2017). We investigated whether NUDT6 overexpression induced activation of NF-κB-p65 in our samples by quantifying the ratio of NF-κB-p65 positive nuclei-to-total nuclei in immunostained hippocampal sections from NUDT6-AAV2 and blank-AAV2 groups.…”

Section: Resultsmentioning

confidence: 99%

NUDT6, the Antisense Protein of FGF2 Gene, Plays a Depressogenic Role by Promoting Inflammation and Suppressing Neurogenesis without Altering FGF2 Signaling

Uzay

Hökelekli

Yılmaz

et al. 2022

Preprint

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Fibroblast growth factor-2 (FGF2) is involved in the regulation of affective behavior and shows antidepressant effects through Akt and ERK1/2 pathways. NUDT6 is a protein encoded from the antisense strand of the FGF2 gene and its role in the regulation of affective behavior is unclear. Here, we show that increasing NUDT6 expression in the hippocampus results in depression-like behavior in rats without changing FGF2 levels or activating its downstream effectors, Akt and ERK1/2. Instead, NUDT6 acts by inducing inflammatory signaling, specifically by increasing S100A9 levels, activating NF-kB, and rising microglia number along with a reduction in neurogenesis. Conversely, inhibition of hippocampal NUDT6 expression by shRNA results in antidepressant effects and increases neurogenesis without altering FGF2 levels. Together these findings suggest that NUDT6 may play a role in major depression by inducing a proinflammatory state and serve as a novel therapeutic target for antidepressant development. The opposite effects of NUDT6 and FGF2 on depression-like behavior may serve as a mechanism to fine-tune affective behavior. Our findings open up new venues for studying the differential regulation and functional interactions of sense and antisense proteins in neural function and behavior as well as in neuropsychiatric disorders.

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“…Dysfunction in the excitation/inhibition balance could lead to the major depression ( Fee et al, 2017 ). Ion channels play a vital role in regulating the excitability, network activity and plasticity, which can alter the GABAergic and glutamatergic neuron excitability and firing, to change the excitation/inhibition balance in microcircuits ( Eren-Koçak and Dalkara, 2021 ). Drugs targeting ion channels, including voltage-gated Na + (VGSCs) and Ca 2+ channels (VGCCs), are the major treatment for chronic neuropathic pain ( Markman and Dworkin, 2006 ).…”

Section: Discussionmentioning

confidence: 99%

Use of pain-related gene features to predict depression by support vector machine model in patients with fibromyalgia

2023

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The prevalence rate of depression is higher in patients with fibromyalgia syndrome, but this is often unrecognized in patients with chronic pain. Given that depression is a common major barrier in the management of patients with fibromyalgia syndrome, an objective tool that reliably predicts depression in patients with fibromyalgia syndrome could significantly enhance the diagnostic accuracy. Since pain and depression can cause each other and worsen each other, we wonder if pain-related genes can be used to differentiate between those with major depression from those without. This study developed a support vector machine model combined with principal component analysis to differentiate major depression in fibromyalgia syndrome patients using a microarray dataset, including 25 fibromyalgia syndrome patients with major depression, and 36 patients without major depression. Gene co-expression analysis was used to select gene features to construct support vector machine model. The principal component analysis can help reduce the number of data dimensions without much loss of information, and identify patterns in data easily. The 61 samples available in the database were not enough for learning based methods and cannot represent every possible variation of each patient. To address this issue, we adopted Gaussian noise to generate a large amount of simulated data for training and testing of the model. The ability of support vector machine model to differentiate major depression using microarray data was measured as accuracy. Different structural co-expression patterns were identified for 114 genes involved in pain signaling pathway by two-sample KS test (p < 0.001 for the maximum deviation D = 0.11 > Dcritical = 0.05), indicating the aberrant co-expression patterns in fibromyalgia syndrome patients. Twenty hub gene features were further selected based on co-expression analysis to construct the model. The principal component analysis reduced the dimension of the training samples from 20 to 16, since 16 components were needed to retain more than 90% of the original variance. The support vector machine model was able to differentiate between those with major depression from those without in fibromyalgia syndrome patients with an average accuracy of 93.22% based on the expression levels of the selected hub gene features. These findings would contribute key information that can be used to develop a clinical decision-making tool for the data-driven, personalized optimization of diagnosing depression in patients with fibromyalgia syndrome.

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Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression

Cited by 21 publications

References 193 publications

FGF2 gene's antisense protein, NUDT6, plays a depressogenic role by promoting inflammation and suppressing neurogenesis without altering FGF2 signalling

FGF2 gene's antisense protein, NUDT6, plays a depressogenic role by promoting inflammation and suppressing neurogenesis without altering FGF2 signalling

NUDT6, the Antisense Protein of FGF2 Gene, Plays a Depressogenic Role by Promoting Inflammation and Suppressing Neurogenesis without Altering FGF2 Signaling

Use of pain-related gene features to predict depression by support vector machine model in patients with fibromyalgia

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