The role of glycogen synthase kinase 3 beta in multiple sclerosis

Noori, Tayebeh; Dehpour, Ahmad Reza; Sureda, Antoni; Fakhri, Sajad; Sobarzo‐Sánchez, Eduardo; Farzaei, Mohammad Hosein; Akkol, Esra Küpeli; Khodarahmi, Zahra; Hosseini, Seyede Zahra; Alavi, Seyede Darya; Shirooie, Samira

doi:10.1016/j.biopha.2020.110874

Cited by 30 publications

(17 citation statements)

References 142 publications

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“…Peripheral nerve injury induced by axotomy and TG extraction during our experiments do not rule out the transcriptional alterations of neuroregeneration and neuroprotection genes in neuron. Moreover, the hub genes, such as Actb , Gsk3b , and mt-Co1 , were identified, which are closely correlated with pain development ( Liu et al, 2017 ; Noori et al, 2020 ; Segelcke et al, 2020 ). And the roles and mechanisms of several potential novel targets in orofacial inflammatory pain, such as Scn7a and Zbtb20 in PEP1, Rgs7bp in PEP2, and Bhlha9 in cLTMR, require further exploration.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Alterations of Mouse Trigeminal Ganglion Neurons Following Orofacial Inflammation Revealed by Single-Cell Analysis

Liu

Mai

Yang

et al. 2022

Front. Cell. Neurosci.

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Orofacial inflammation leads to transcriptional alterations in trigeminal ganglion (TG) neurons. However, diverse alterations and regulatory mechanisms following orofacial inflammatory pain in different types of TG neurons remain unclear. Here, orofacial inflammation was induced by injection of complete Freund’s adjuvant (CFA) in mice. After 7 days, we performed single-cell RNA-sequencing on TG cells of mice from control and treatment groups. We identified primary sensory neurons, Schwann cells, satellite glial cells, oligodendrocyte-like cells, immune cells, fibroblasts, and endothelial cells in TG tissue. After principal component analysis and hierarchical clustering, we identified six TG neuronal subpopulations: peptidergic nociceptors (PEP1 and PEP2), non-peptidergic nociceptors (NP1 and NP2), C-fiber low-threshold mechanoreceptors (cLTMR) and myelinated neurons (Nefh-positive neurons, NF) based on annotated marker gene expression. We also performed differential gene expression analysis among TG neuronal subtypes, identifying several differential genes involved in the inflammatory response, neuronal excitability, neuroprotection, and metabolic processes. Notably, we identified several potential novel targets associated with pain modulation, including Arl6ip1, Gsk3b, Scn7a, and Zbtb20 in PEP1, Rgs7bp in PEP2, and Bhlha9 in cLTMR. The established protein–protein interaction network identified some hub genes, implying their critical involvement in regulating orofacial inflammatory pain. Our study revealed the heterogeneity of TG neurons and their diverse neuronal transcriptomic responses to orofacial inflammation, providing a basis for the development of therapeutic strategies for orofacial inflammatory pain.

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Section: Discussionmentioning

confidence: 99%

Transcriptional Alterations of Mouse Trigeminal Ganglion Neurons Following Orofacial Inflammation Revealed by Single-Cell Analysis

Liu

Mai

Yang

et al. 2022

Front. Cell. Neurosci.

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“…[79,80] p38 Mitogen-activated protein kinase (MAPK) triggers the inactivation of GSK3β, via phosphorylation on Ser-389. [81] Kihadanin B (9) is a much less known compound, but it has been shown to reduce phosphorylation of the forkhead transcriptional factor FOXO1 [62] and this effect could be linked to GSK-3β. [82] The two natural products nomilin (7) and kihadanin B (9) should be further considered as potential GSK-3β…”

Section: Discussionmentioning

confidence: 99%

“…Next, we tested four other natural products bearing also a furyl-δ-lactone core: the parent compound limonin (6) (also known as obaculactone and evodin), [59] the anti-inflammatory tetracyclic triterpenoid nomilin (7) [60] and the two limonoids kihadanins A (8) and B ( 9), isolated from the bark of D.s dasycarpus. [61] Kihadanin B (9) functions as a repressor of adipogenesis, decreasing lipid accumulation through the suppression of the Akt-FOXO1-PPARγ signaling axis. [62] The GSK-3β binding capacity of limonin ( 6) was found to be equivalent to that obacunone (5) (Table 1).…”

Section: In Silico Molecular Docking Proceduresmentioning

confidence: 99%

“…[ 7 ] This serine/threonine kinase regulates a wide range of cellular processes and acts as a master kinase involved in different inflammatory diseases, such as multiple sclerosis and fibrosis. [ 8–10 ] The enzyme plays a role in skeletal muscle activities and their regulation. [ 11 ] For all these reasons, GSK‐3β inhibitors have been actively searched and continue to arouse interest.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular docking study of GSK‐3β interaction with nomilin, kihadanin B, and related limonoids and triterpenes with a furyl‐δ‐lactone core

Vergoten

Bailly

2022

J Biochem & Molecular Tox

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Glycogen synthase kinase‐3β (GSK‐3β) is a target enzyme considered for the treatment of multiple human diseases, from neurodegenerative pathologies to viral infections and cancers. Numerous inhibitors of GSK‐3β have been discovered but thus far only a few have reached clinical trials and only one drug, tideglusib (1), has been registered. Natural products targeting GSK‐3β have been identified, including the two anticancer limonoids obacunone (5) and gedunin (4), both presenting a furyl‐δ‐lactone core. To help identifying novel GSK‐3β ligands, we have performed a molecular docking study with 15 complementary natural products bearing a furyl‐δ‐lactone unit (such as limonin (6) and kihadanins A (8) and B (9)) or a closely related structure (such as cedrelone (10) and nimbolide (11)). The formation of GSK‐3β‐binding complexes for those natural products was compared to reference GSK‐3β ATP‐competitive inhibitors LY2090314 (3) and AR‐A014418 (2). Our in silico analysis led to the identification of two new GSK‐3β‐binding natural products: kihadanin B (9) and nomilin (7). The latter surpassed the reference compounds in terms of calculated empirical energy of interaction (ΔE). Nomilin (7) can possibly bind to the active site of GSK‐3β, notably via the furyl‐δ‐lactone core and its 1‐acetyl group, implicated in the protein interaction. Compound structure‐binding relationships are discussed. The study should help the discovery of novel natural products targeting GSK‐3β.

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“…Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that occurs in two isozymes in mammals: GSK3α and GSK3β. In particular, GSK3β plays a role in neuroinflammation and pain [ 77 , 78 ]. AR-A014418 is an ATP-competitive inhibitor of GSK3 with an IC 50 value of 104 nM ( Figure 18 ).…”

Section: Cmgc Groupmentioning

confidence: 99%

Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

et al. 2021

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The purpose of this review is to underline the protein kinases that have been established, either in fundamental approach or clinical trials, as potential biological targets in pain management. Protein kinases are presented according to their group in the human kinome: TK (Trk, RET, EGFR, JAK, VEGFR, SFK, BCR–Abl), CMGC (p38 MAPK, MEK, ERK, JNK, ASK1, CDK, CLK2, DYRK1A, GSK3, CK2), AGC (PKA, PKB, PKC, PKMζ, PKG, ROCK), CAMK, CK1 and atypical/other protein kinases (IKK, mTOR). Examples of small molecule inhibitors of these biological targets, demonstrating an analgesic effect, are described. Altogether, this review demonstrates the fundamental role that protein kinase inhibitors could play in the development of new pain treatments.

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The role of glycogen synthase kinase 3 beta in multiple sclerosis

Cited by 30 publications

References 142 publications

Transcriptional Alterations of Mouse Trigeminal Ganglion Neurons Following Orofacial Inflammation Revealed by Single-Cell Analysis

Transcriptional Alterations of Mouse Trigeminal Ganglion Neurons Following Orofacial Inflammation Revealed by Single-Cell Analysis

Molecular docking study of GSK‐3β interaction with nomilin, kihadanin B, and related limonoids and triterpenes with a furyl‐δ‐lactone core

Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

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