Possible Loss of GABAergic Inhibition in Mice With Induced Adenomyosis and Treatment With Epigallocatechin-3-Gallate Attenuates the Loss With Improved Hyperalgesia

Chen, Yumei; Zhu, Bo; Zhang, Hongping; Ding, Ding; Liu, Xishi; Guo, Sun‐Wei

doi:10.1177/1933719113518984

Cited by 25 publications

(32 citation statements)

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“…Our previous study also showed that the recruitment and degranulation of mast cells play an important role in endometriosis-related dysmenorrhea [14]. In addition, recent research found adenomyosis-induced pain resembles neuropathic pain [15]. We also proved that the density of nerve fibers in the functional layer endometrium of adenomyosis patients was correlated with dysmenorrhea, suggesting the nerve fibers play an important role in the mechanisms of pain generation in adenomyosis [16].…”

Section: Ivyspringsupporting

confidence: 67%

The new application of mifepristone in the relief of adenomyosis-caused dysmenorrhea

Che

Wang

et al. 2020

Int. J. Med. Sci.

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Background: Adenomyosis is a quite common gynecological disorder and above 30% of patients have typical secondary and progressive dysmenorrhea. Current treatments still have many disadvantages and thereby the novel treatment aiming to relieve dysmenorrhea still needs to be further investigated. Mifepristone is a wonderful drug because it is effective, safe and cheap in many diseases including adenomyosis. In this study, we aim to investigate if mifepristone could be used in the treatment of adenomyosis-associated dysmenorrhea. Methods: Human primary endometrial epithelial and stromal cells from adenomyosis patients were isolated and treated with mifepristone. RNA-sequencing was then performed to detect the gene changes of pain-related inflammatory mediators. Meanwhile, the effect of mifepristone on the infiltration and degranulation of mast cells were investigated in adenomyosis lesions. Additionally, the role of mifepristone on the density of nerve fibers was also studied in the ectopic endometrium. At last, to evaluate the therapeutic efficacy of mifepristone on dysmenorrhea of adenomyosis, twenty participants were included and the visual analog scale (VAS) score was assessed and compared before and after treatment with mifepristone. Results: We demonstrated that mifepristone reduced the secretion of IL-6 and TNF-α from endometrial epithelial and stromal cells, restricted the infiltration and degranulation of mast cells in eutopic and ectopic endometrium and decreased the density of nerve fibers by inhibiting the migration capacity of nerve cells in adenomyosis. Meanwhile, we found that mifepristone could significantly relieve dysmenorrhea of adenomyosis. Conclusion: The findings demonstrated that mifepristone could be applied in the treatment of dysmenorrhea for the adenomyosis patients.

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Section: Ivyspringsupporting

confidence: 67%

The new application of mifepristone in the relief of adenomyosis-caused dysmenorrhea

Che

Wang

et al. 2020

Int. J. Med. Sci.

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“…8b ). A multiple linear regression analysis (the number of cells was square-root transformed to improve normality) indicated that while adenomyosis induction was associated with the reduction in the number of GAD65-positive neurons in the NRM ( p < 0.001) as previously reported [ 26 ] while both Ozagrel treatment and platelet depletion were associated dose-dependently with a significant increase of the number of GAD65-positive neurons (both p -values <0.001; R 2 = 0.92).…”

Section: Resultsmentioning

confidence: 54%

“…The procedure has been reported previously in [ 26 ]. Briefly, the mouse brains containing the nucleus raphe magnus (NRM) were harvested and immediately embedded in O.C.…”

Section: Methodsmentioning

confidence: 99%

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Anti-platelet therapy holds promises in treating adenomyosis: experimental evidence

Zhu

Chen

Shen

et al. 2016

Reprod Biol Endocrinol

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BackgroundRecently emerging evidence indicates that endometriotic lesions are wounds undergoing repeated tissue injury and repair (ReTIAR), and platelets induce epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), leading ultimately to fibrosis. Due to the commonality of cyclic bleeding as in endometriosis, adenomyotic lesions are also wounds that undergo ReTIAR, and we have recently provided evidence corroborating platelet-induced EMT, FMT and fibrogenesis in adenomyosis. This study sought to evaluate the effect of antiplatelet therapy in a mouse model of adenomyosis.MethodsAdenomyosis was induced in 57 female ICR mice with neonatal dosing of tamoxifen, while another 12 (group C) were dosed with solvent only, serving as a blank control. Starting from 4 weeks after birth, hotplate test was administrated to all mice every 4 weeks. At the 16th week, all mice with induced adenomyosis were randomly divided into 6 groups: untreated, low- and high-dose Ozagrel, low- and high-dose anti-mouse GPIbα polyclonal IgG antibody to deplete platelets, and isotype-matched inert IgG non-immune antibody. Group C received no treatment. After 3 weeks of treatment, they were hotplate tested again, their uterine horns and brains were harvested, and a blood sample was taken to measure the plasma corticosterone level by ELISA. The left uterine horn was used for immunohistochemistry analysis. The brainstem nucleus raphe magnus (NRM) sections were subjected to immunofluorescence staining for GAD65. The depth of myometrial infiltration and uterine contractility were evaluated.ResultsWe found that both Ozagrel treatment and platelet depletion dose-dependently suppressed myometrial infiltration, improved generalized hyperalgesia, reduced uterine contractility, and lowered plasma corticosterone levels, improved the expression of some proteins known to be involved in adenomyosis and slowed down the process of fibrogenesis. It also elevated the number of GAD65-expressing neurons in the brainstem NRM, possibly boosting the GABAergic inhibition of pain due to adenomyosis.ConclusionThis study further provides evidence that platelets play important roles in the development of adenomyosis. Anti-platelet treatment is efficacious in suppression of myometrial infiltration, improving generalized hyperalgesia, reducing uterine hyperactivity and systemic corticosterone levels. Collectively, these results demonstrate that anti-platelet therapy seems to be promising for treating adenomyosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-016-0198-1) contains supplementary material, which is available to authorized users.

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“…The important role of platelets in the development of endometriosis, as shown in this and our previous studies (Ding et al, 2015;Guo et al, 2015aGuo et al, , 2015bZhang et al, 2015), has practical implications for the development of nonhormonal therapeutics for endometriosis. While it has recently been shown that epigallocatechin-3-gallate is promising for its anti-fibrotic properties in treating endometriosis (Matsuzaki and Darcha, 2014) and also efficacious in treating adenomyosis in mice with induced adenomyosis (Chen et al, 2013(Chen et al, , 2014, it is perhaps no coincidence that epigallocatechin-3-gallate is anti-platelet (Ok et al, 2012). In fact, several compounds that are reported to be promising in treating endometriosis or adenomyosis in preclinical and clinical studies, such as andrographalide (Li et al, 2013;Liu et al, 2014;Mao et al, 2011), valproic acid Guo, 2008, 2011;Liu et al, 2010), curcumin (Zhang et al, 2011), resveratrol (Zhu et al, 2015), puerarin (Chen et al, 2011;Wang et al, 2011) and quercetin (Zhang et al, 2009), turn out to be either anti-platelet or anti-thrombotic (Choo et al, 2002;Davidson et al, 2011;Jin et al, 2008;Lien et al, 2013;Liu et al, 2006;Lu et al, 2011;Mayanglambam et al, 2010;Mosawy et al, 2013aMosawy et al, , 2013bShen et al, 2007).…”

Section: Markermentioning

confidence: 99%

Anti-platelet therapy is efficacious in treating endometriosis induced in mouse

Guo

Ding

Liu

2016

Reproductive BioMedicine Online

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In light of recent findings showing that platelets play important roles in the development of endometriosis in general and in fibrogenesis in particular, this study investigated the efficacy of Ozagrel, a TXA synthase inhibitor, in a murine model of endometriosis. In addition, another mouse experiment was conducted to evaluate the effect of timing of platelet depletion and of sequential depletion of platelets and macrophages on the development of endometriosis. It was found that both the Ozagrel treatment and different platelet depletion schemes resulted in significant reduction in lesion growth (all P-values <0.01) along with improved hyperalgesia in mice with induced endometriosis. They also significantly reduced the expression of markers of proliferation, angiogenesis, inflammation and fibrosis as well as decreased macrophage infiltration in endometriotic lesions (all P-values <0.05). Compared with untreated mice, pre-emptive depletion of platelets as well as platelet depletion after induction resulted in significant reduction in lesion weight (both P-values <0.001), while sequential depletion of platelets and macrophages yielded similar reduction. These results, in conjunction with other roles that platelets play in the development of endometriosis, strongly argue for the potential of anti-platelet therapy in treating endometriosis.

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Possible Loss of GABAergic Inhibition in Mice With Induced Adenomyosis and Treatment With Epigallocatechin-3-Gallate Attenuates the Loss With Improved Hyperalgesia

Cited by 25 publications

References 78 publications

The new application of mifepristone in the relief of adenomyosis-caused dysmenorrhea

The new application of mifepristone in the relief of adenomyosis-caused dysmenorrhea

Anti-platelet therapy holds promises in treating adenomyosis: experimental evidence

Anti-platelet therapy is efficacious in treating endometriosis induced in mouse

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