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The Antitumor Peptide ERα17p Exerts Anti-Hyperalgesic and Anti-Inflammatory Actions Through GPER in Mice.

ABSTRACT: Persistent inflammation and persistent pain are major medical, social and economic burdens. As such, related pharmacotherapy needs to be continuously improved. The peptide ERα17p, which originates from a part of the hinge region/AF2 domain of the human estrogen receptor α (ERα), exerts anti-proliferative effects in breast cancer cells through a mechanism involving the hepta-transmembrane G protein-coupled estrogen receptor (GPER). It is able to decrease the size of xenografted human breast tumors, in mice. As GPER has been reported to participate in pain and inflammation, we were interested in exploring the potential of ERα17p in this respect. We observed that the peptide promoted anti-hyperalgesic effects from 2.5 mg/kg in a chronic mice model of paw inflammation induced by the pro-inflammatory complete Freund's adjuvant (CFA). This action was abrogated by the specific GPER antagonist G-15, leading to the conclusion that a GPER-dependent mechanism was involved. A systemic administration of a Cy5-labeled version of the peptide allowed its detection in both, the spinal cord and brain. However, ERα17p-induced anti-hyperalgesia was detected at the supraspinal level, exclusively. In the second part of the study, we have assessed the anti-inflammatory action of ERα17p in mice using a carrageenan-evoked hind-paw inflammation model. A systemic administration of ERα17p at a dose of 2.5 mg/kg was responsible for reduced paw swelling. Overall, our work strongly suggests that GPER inverse agonists, including ERα17p, could be used to control hyperalgesia and inflammation.

SUBMITTER: Mallet C

PROVIDER: S-EPMC8011567 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPoncirin is flavanone derivative (isolated from Poncirus trifoliata) with known pharmacological activities such as anti-tumor, anti-osteoporotic, anti-inflammatory and anti-colitic. The present study aimed to explore the anti-allodynic and anti-hyperalgesic potentials of poncirin in murine models of inflammatory pain.MethodsThe analgesic potential of poncirin was evaluated in formalin-, acetic acid-, carrageenan- and Complete Freund's Adjuvant (CFA)-induced inflammatory pain models in mice. Anti-allodynic and anti-hyperalgesic activities were measured using Von Frey filaments, Randall Selitto, hotplate and cold acetone tests. The serum nitrite levels were determined using Griess reagent. The Quantitative Real-time PCR (qRT-PCR) was performed to assess the effect of poncirin on mRNA expression levels of inflammatory cytokines and anti-oxidant enzymes.ResultsIntraperitoneal administration of poncirin (30 mg/kg) markedly reduced the pain behavior in both acetic acid-induced visceral pain and formalin-induced tonic pain models used as preliminary screening tools. The poncirin (30 mg/kg) treatment considerably inhibited the mechanical hyperalgesia and allodynia as well as thermal hyperalgesia and cold allodynia. The qRT-PCR analysis showed noticeable inhibition of pro-inflammatory cytokines (mRNA expression levels of TNF-α, IL-1β and IL-6) (p < 0.05) in poncirin treated group. Similarly, poncirin treatment also enhanced the mRNA expressions levels of anti-oxidant enzymes such as transcription factor such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) (p < 0.05), heme oxygenase (HO-1) (p < 0.05) and superoxide dismutase (SOD2) (p < 0.05). Chronic treatment of poncirin for 6 days did not confer any significant hepatic and renal toxicity. Furthermore, poncirin treatment did not altered the motor coordination and muscle strength in CFA-induced chronic inflammatory pain model.ConclusionThe present study demonstrated that poncirin treatment significantly reduced pain behaviors in all experimental models of inflammatory pain, suggesting the promising analgesic potential of poncirin in inflammatory pain conditions.

Project description:BackgroundEndometriosis is well known as a chronic inflammatory disease. The development of endometriosis is heavily influenced by the estrogen receptor β (ERβ), while NOD-like receptors (NLRs) family CARD domain-containing 5 (NLRC5) exhibits anti-inflammatory properties during endometriosis. However, whether NLRC5-mediated anti-inflammation is involved in the ERβ-mediated endometriosis is still uncertain. This study aimed to assess that relation.MethodsNine cases of eutopic endometrial tissue and ten cases of ectopic endometrial tissue were collected from patients with endometriosis, and endometrial samples from ten healthy fertile women were analyzed, and the expression levels of ERβ were quantified using immunohistochemistry (IHC). Subsequently, we constructed mouse model of endometriosis by intraperitoneal injection. We detected the expression of ERβ, NLRC5, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-10 and measured the volume of ectopic lesions in mice with endometriosis. In vitro, human endometrial stromal cells (hESCs) were transfected respectively with ERβ-overexpressing and NLRC5-overexpressing plasmids. We then assessed the expression of ERβ and NLRC5 using quantitative real-time PCR (qRT-PCR) and western blot analysis. Furthermore, we measured the concentrations of TNF-α, IL-6, and IL-10 in the cell culture supernatant through enzyme-linked immunosorbent assay (ELISA). Additionally, we evaluated the migration and invasion ability of hESCs using transwell and wound healing assays.ResultsInhibition of NLRC5 expression promotes the development of ectopic lesions in mice with endometriosis, upregulates the expression of pro-inflammatory factors TNF-α and IL-6, and downregulates the expression of anti-inflammatory factor IL-10. The high expression of NLRC5 in endometriosis depended on the ERβ overexpression. And ERβ promoted the migration of hESCs partially depend on inflammatory microenvironment. Lastly, NLRC5 overexpression inhibited ERβ-mediated development and inflammatory response of endometriosis.ConclusionsOur results suggest that the innate immune molecule NLRC5-mediated anti-inflammation participates in ERβ-mediated endometriosis development, and partly clarifies the pathological mechanism of endometriosis, expanding our knowledge of the specific molecules related to the inflammatory response involved in endometriosis and potentially providing a new therapeutic target for endometriosis.

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The Antitumor Peptide ERα17p Exerts Anti-Hyperalgesic and Anti-Inflammatory Actions Through GPER in Mice.

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