Tetramethylpyrazine: A promising drug candidate for treating endometriosis
Endometriosis is a debilitating gynecologic disease affecting women of reproductive age; a major contributing cause of dysmenorrhea, chronic pelvic pain, and infertility. Due to the poorly understood pathogenesis and pathophysiology, the clinical management of endometriosis is still a challenge. All existing hormonal therapies interfere with pituitary–gonadal stimulation, induce anovulation and/or a steady hormonal milieu, and reduce or suppress menstrual flow. Given this mechanism of action, these therapies work during treatment but often experience recurrence after discontinuation. In addition, these medications have various side effects and some, such as the GnRH agonists, are restricted by short-term usage. While surgery is efficacious in relieving endometriosis-associated pain, it nonetheless carries certain risks of complications, recurrence and elevated risk of adhesion, organ injury, and premature ovarian failure. Consequently, more efficacious medical treatment of endometriosis is still an unmet need begging to be fulflled.
Tetramethylpyrazine (TMP), also known as ligustrazine, is a natural alkaloid derived from Rhizoma Chuanxiong, and an herb also used in traditional Chinese medicine as a remedy for blood stasis.
TMP has been shown to inhibit platelet aggregation, oxidative stress and inflammation and attenuate fbrosis. In endometriosis, in particular, it has been shown that, as one major ingredient in a concocted herbal formula, TMP suppresses lesional growth, infammation, and epithelial-mesenchymal transition (EMT) and induces apoptosis. Given the excellent safety profles of TMP, it seems to be an admissible candidate compound for treating endometriosis.
Shenghui Huang and team tested the hypothesis that TMP can decelerate lesional progression through arresting epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), and fibrogenesis. Their study showed that TMP treatment stalls lesional progression and fbrogenesis through suppression of platelet activation, platelet-induced EMT, FMT, cellular contractility, and collagen production.
They first investigated whether TMP could suppress platelet-induced changes in morphology, expression of genes involved in EMT of endometriotic epithelial cells (11Z). They co-cultured 11Z cells with buffer (PBS) or activated platelets, induced by thrombin, for 48 h, and confirmed that activated platelets induced dramatic morphological changes suggestive of EMT, with the morphology changed from round-shaped to spindle-like and became dispersed. Study also found that treatment with low-dose (L-TMP) or high-dose TMP (H-TMP) attenuated platelet-induced morphological changes of EMT in 11Z. Based on linear regression analysis using the concentration of TMP as the co-variable, study found that, consistently, treatment with L-TMP and H-TMP concentration-dependently suppressed platelet-induced activation of TGF-β1, vimentin and fbronectin in endometriotic epithelial cells (all p values<0.030).
In addition, Western blot analysis confirmed that the treatment of TMP concentration dependently increased platelet-suppressed protein expression of E-cadherin (p=0.0063).
TMP Suppresses Platelet‑Induced FMT in Endometriotic Stromal Cells; Abrogates Platelet‑Induced Contractility and Collagen Production in Endometriotic Stromal Cells; Treatment with TMP Decreases Lesion Weight and the Extent of Lesional Fibrosis and Improves Hyperalgesia; Suppresses the Aggregation of Platelets, the Expression of TGF‑β1, NK1R, α‑SMA, and Collagen I, and the Extent of Fibrosis in Mouse Endometriotic Lesions; The Extent of Lesional Fibrosis Correlates with the Lesion Weight, Hotplate Latency, and Lesional TGF‑β1, NK1R, α‑SMA, and Collagen I Expression Levels.
Given the growing evidence for the role of platelets in driving the progression of endometriosis and for the hypercoagulant state in women with endometriosis, it is not surprising to see that platelet depletion and antiplatelet treatment effectively suppress lesion growth in mouse with induced endometriosis.
"Our data strongly suggest that TMP is a compound with promising therapeutic potential for treating endometriosis. Naturally, more investigation on its mechanism of action is warranted, and more clinical studies are badly needed.
In summary, our study has shown that TMP treatment stalls lesional progression and fbrogenesis through suppression of platelet activation, platelet-induced EMT, FMT, cellular contractility, and collagen production. Our in vivo experiment demonstrates that treatment with TMP signifcantly reduced lesion weight and the extent of lesional fbrosis, and alleviated hyperalgesia. Thus, our fndings indicate that TMP could be an excellent drug candidate for treating endometriosis."
Source: Shenghui Huang; Fengyi Xiao; Sun‑Wei Guo et al; Reproductive Sciences (2022) 29:1170–1187
