Targeting α7-nAChR by galantamine mitigates reserpine-induced fibromyalgia-like symptoms in rats: Involvement of cAMP/PKA, PI3K/AKT, and M1/M2 microglia polarization

Atta, Ahd A.; Ibrahim, Weam W.; Mohamed, Abdullah; Abdelkader, Noha F.

doi:10.1016/j.ejphar.2023.175810

Cited by 7 publications

(1 citation statement)

References 105 publications

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“…In various neuropathic pain models, high expression of in ammatory M1 macrophage-speci c molecules and low levels of M2 microglia-speci c molecules indicate M1/M2 microglia polarization shift (Kiguchi et al, 2015(Kiguchi et al, , 2017Atta et al, 2023a). In bromyalgia patients, nociplastic pain arises due to M1 microglia-dependent neuroin ammation [ (Tripathi et al, 2021;Atta et al, 2023b). This aligns with the current study's ndings, as immunohistological results in RIFM rats showed a shift towards the M1 phenotype, as seen in CD163, a marker of M1 microglia.…”

Section: Discussionsupporting

confidence: 88%

Thalamic Purinergic Receptors: A Gateway to Modulating Fibromyalgia Pain via NLRP3 Inflammasome Signaling and Pyroptosis

Kamel,

Mohamed,

Zaki

2024

Preprint

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The high pain sensitivity in fibromyalgia (FM) is processed by the thalamus that presents as a key component in the pain pathway in FM patients. Noteworthy, Purinergic receptors, specifically P2X, are implicated in pain signaling and neuroinflammation via inflammasome signaling. However, there is no available data on the impact of pharmacological intervention on P2X receptor in thalamic pain transmission in FM. To investigate this aspect, the clinically tested P2X inhibitor, Suramin (SURM), was utilized. FM was induced over three days using Reserpine (1 mg/kg/day, s.c.), followed by a single dose of SURM (100 mg/kg, i.p.). At the molecular level, SURM countered the overexpression of P2X7 and P2X4 receptors accompanied by reduced NLRP3 inflammasome complex and pyroptotic markers like gasdermin-D. This was associated by the suppression of the p38-MAPK and NF-κB pathways, along with a decrease in pro-inflammatory cytokines and tumor necrosis factor-α as observed by increased CD86 expression on M1 microglia phenotype, a neuroinflammatory marker. Concurrently, blocking the P2X receptor shifted microglia polarization towards the M2 phenotype, marked by elevated CD163 expression, as a neuroprotective mechanism. This was outlined by increased neurotrophic and anti-inflammatory; IL-10 with normalization of disturbed neurotransmitters. Behaviorally, SURM ameliorated the heightened pain processing, as observed in mechanical and thermal pain tests. Furthermore, it lowered Reserpine-induced motor impairment in the rotarod and open-field tests. This improvement in the somatosensory experience was reflected in alleviating depressive-like behavior in the forced swimming test. These findings highlight the therapeutic potential of blocking thalamic P2X receptors in alleviating fibromyalgia symptoms.

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Section: Discussionsupporting

confidence: 88%

Thalamic Purinergic Receptors: A Gateway to Modulating Fibromyalgia Pain via NLRP3 Inflammasome Signaling and Pyroptosis

Kamel,

Mohamed,

Zaki

2024

Preprint

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Microglia polarization in nociplastic pain: mechanisms and perspectives

et al. 2023

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Nociplastic pain is the third classification of pain as described by the International Association for the Study of Pain (IASP), in addition to the neuropathic and nociceptive pain classes. The main pathophysiological mechanism for developing nociplastic pain is central sensitization (CS) in which pain amplification and hypersensitivity occur. Fibromyalgia is the prototypical nociplastic pain disorder, characterized by allodynia and hyperalgesia. Much scientific data suggest that classical activation of microglia in the spinal cord mediates neuroinflammation which plays an essential role in developing CS. In this review article, we discuss the impact of microglia activation and M1/M2 polarization on developing neuroinflammation and nociplastic pain, besides the molecular mechanisms engaged in this process. In addition, we mention the impact of microglial modulators on M1/M2 microglial polarization that offers a novel therapeutic alternative for the management of nociplastic pain disorders. Graphical abstract Illustrating the mechanisms underlying microglia activation in central sensitization and nociplastic pain. LPS lipopolysaccharide, TNF-α tumor necrosis factor-α, INF-γ Interferon gamma, ATP adenosine triphosphate, 49 P2Y12/13R purinergic P2Y 12/13 receptor, P2X4/7R purinergic P2X 4/7 receptor, SP Substance P, NK-1R Neurokinin 1 receptor, CCL2 CC motif ligand 2, CCR2 CC motif ligand 2 receptor, CSF-1 colony-stimulating factor 1, CSF-1R colony-stimulating factor 1 receptor, CX3CL1 CX3C motif ligand 1, CX3XR1 CX3C motif ligand 1 receptor, TLR toll-like receptor, MAPK mitogen-activated protein kinases, JNK jun N-terminal kinase, ERK extracellular signal-regulated kinase, iNOS Inducible nitric oxide synthase, IL-1β interleukin-1β, IL-6 interleukin-6, BDNF brain-derived neurotrophic factor, GABA γ-Aminobutyric acid, GABAR γ-Aminobutyric acid receptor, NMDAR N-methyl-D-aspartate receptor, AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropi-onic acid receptor, IL-4 interleukin-4, IL-13 interleukin-13, IL-10 interleukin-10, Arg-1 Arginase 1, FGF fibroblast growth factor, GDNF glial cell-derived neurotrophic factor, IGF-1 insulin-like growth factor-1, NGF nerve growth factor, CD Cluster of differentiation.

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Crosstalk Among Glial Cells in the Blood–Brain Barrier Injury After Ischemic Stroke

Lu,

Wen

2024

Mol Neurobiol

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Targeting α7-nAChR by galantamine mitigates reserpine-induced fibromyalgia-like symptoms in rats: Involvement of cAMP/PKA, PI3K/AKT, and M1/M2 microglia polarization

Cited by 7 publications

References 105 publications

Thalamic Purinergic Receptors: A Gateway to Modulating Fibromyalgia Pain via NLRP3 Inflammasome Signaling and Pyroptosis

Thalamic Purinergic Receptors: A Gateway to Modulating Fibromyalgia Pain via NLRP3 Inflammasome Signaling and Pyroptosis

Microglia polarization in nociplastic pain: mechanisms and perspectives

Crosstalk Among Glial Cells in the Blood–Brain Barrier Injury After Ischemic Stroke

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