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Cited by 12Fibromyalgia and Chronic Fatigue Syndrome ResearchPain Mechanisms and TreatmentsPain Management and Treatment

Novel Trajectories Towards Possible Effects of Semaglutide for Amelioration of Reserpine-induced Fibromyalgia in Rats: Contribution of cAMP/PKA/p-CREB and M1/M2 Microglia Polarization

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Shafiek, Mena Z., Zaki, Hala F., Mohamed, Ahmed F., Ibrahim, Weam W.·2025·Journal of Neuroimmune Pharmacology
DOI 10.1007/s11481-025-10196-4PMC PMC12003577
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Abstract

Fibromyalgia (FM) is a pain disorder characterized by pervasive musculoskeletal pain associated with exhaustion, depression, and irregular sleep patterns. Semaglutide, an innovative glucagon-like peptide-1 (GLP-1) agonist, has shown analgesic effects by modulating pain hypersensitivity in animal models of inflammatory pain. The objective of this study is to ascertain semaglutide's therapeutic potential against FM-like symptoms caused by reserpine. Reserpine (1 mg/kg/day; SC) was administered into rats for 3 consecutive days, then they were treated daily with semaglutide intraperitoneally in low (5 nmol/kg), intermediate (10 nmol/kg), or high doses (20 nmol/kg), respectively, for 14 consecutive days. Semaglutide alleviated reserpine induced histopathological and immunohistopathological changes in spinal cord of rats evidenced by a remarkable rise in immuno-expression of cluster of differentiation 163 (CD163) contrary to a significant diminution in CD86 level as compared with reserpine group. Semaglutide also had an analgesic effect and improved motor incoordination, and depression brought on by reserpine. Furthermore, it had an anti-inflammatory impact via stimulating cyclic adenosine monophosphate (cAMP)/ protein kinase A (PKA)/ cAMP response element (CRE)-binding protein (CREB) signaling pathway and shifting M1/M2 macrophage polarization towards the M2. Semaglutide's anti-inflammatory actions were manifested through inhibition of inducible nitric oxide synthase and reduction in dorsal root ganglia concentrations of tumor necrosis factor-α together with elevation in the levels of arginase-1 and interleukin-4. Graphical Abstract

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  • This shift is evidenced by nearly fourfold upregulation of iNOS and fivefold downregulation of Arg-1 compared with controls.

    “This shift was further evidenced by a nearly fourfold upregulation of the M1-associated marker inducible nitric oxide synthase (iNOS) and fivefold downregulation of the M2-associated marker arginase-1 (Arg-1) compared with controls (120, 121).”

    From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [121]

    The Results section reports the claimed shift in markers in reserpine-treated rats relative to normal controls, but not the stated magnitudes. i-NOS rose 2.88-fold, rather than nearly fourfold, and arginase-1 fell to 44.9% of the control level, rather than showing a fivefold decrease. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In a reserpine-induced FMS model, microglia rapidly shift toward the M1 phenotype, resulting in an increased M1/M2 ratio.

    “In a reserpine-induced FMS model, microglia rapidly shifted toward the M1 phenotype, resulting in an increased M1/M2 ratio.”

    From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [121]

    The Results section, “Semaglutide Mitigated the Dysregulation of M1/M2 Macrophage Polarization Induced by Reserpine” (page unavailable), attributes the reserpine group’s inflammatory response to a shift toward M1; its increased M1 markers and decreased M2 markers are consistent with an increased M1/M2 balance. The paper does not establish that this shift happened rapidly: the Experimental Design describes a single later assessment of these markers, not a time course. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Shafiek, M. Z., Zaki, H. F., Mohamed, A. F., & Ibrahim, W. W.
Affiliations
  • Misr International University (EG)
  • Cairo University (EG)
Corresponding author
Shafiek, Mena Z.
ORCID
Venue
Journal of Neuroimmune Pharmacology
Publisher
Springer Science and Business Media LLC
Published
2025-04-17
Volume
20
Issue
1
Pages
43-43
ISSN
  • 1557-1890 (ISSN-L)
  • 1557-1904
DOI
10.1007/s11481-025-10196-4
PMC
PMC12003577
OpenAlex
W4409488957
Cited by
12
References
5
Citations by year
2026: 10 · 2025: 2
FWCI
8.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroimmune Pharmacology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Misr International University
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
Keywords
semaglutide, fibromyalgia, GLP-1 receptor agonists, cAMP/PKA/CREB signaling, microglial polarization, M2 macrophage polarization, CD163, CD86, spinal cord, analgesia, anti-inflammatory activity, inducible nitric oxide synthase, TNF-α, arginase-1, IL-4, depression, motor incoordination
MeSH terms
Semaglutide, Cyclic AMP, Animals, Glucagon-Like Peptides, Fibromyalgia, Male, Reserpine, Signal Transduction, Rats, Wistar, Cyclic AMP Response Element-Binding Protein, Microglia, Cyclic AMP-Dependent Protein Kinases, Rats, Glucagon-Like Peptide 1

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