Ge-Gen Decoction alleviates primary dysmenorrhea in rats by modulating HSP90/AKT and NLRP3 inflammasome pathways

Primary dysmenorrhea (PDM) is a common gynecological condition characterized by painful menstrual cramps, significantly impacting quality of life. Current treatments, primarily non-steroidal anti-inflammatory drugs (NSAIDs) and hormonal therapies, often have side effects or are not universally effective. The underlying mechanisms of PDM involve uterine hypercontractility and inflammation, often linked to elevated prostaglandins and pro-inflammatory cytokines like IL-1β and IL-18. Traditional Chinese Medicine (TCM) formulas like Ge-Gen Decoction (GGD) have been historically used for PDM, but their specific molecular mechanisms, particularly concerning inflammatory pathways like the NLRP3 inflammasome and signaling cascades such as HSP90/AKT, remain underexplored, representing a critical gap in understanding their therapeutic potential.

Researchers established a cold-damp stagnation-type primary dysmenorrhea (PDM) model in female Wistar rats using cold stimulation, estradiol benzoate, and oxytocin. The n=30 rats were divided into five groups (n=6 each): control, PDM model, GGD (1.8 g/kg), GGD plus Terazosin (an HSP90 agonist, 0.08 g/kg), and ibuprofen (0.06 g/kg). Treatments were administered orally once daily. Primary endpoints included PDM severity assessed by writhing frequency and latency. Secondary endpoints involved uterine histopathology, serum levels of prostaglandins (PGE2, PGF2α), and inflammatory cytokines (IL-1β, IL-18, IL-6). Uterine expression of HSP90, p-AKT, NLRP3, Caspase-1, and IL-1β was quantified using immunohistochemistry to elucidate mechanistic pathways.

The PDM model group exhibited significantly increased writhing frequency, elevated PGF2α levels, and a higher PGF2α/PGE2 ratio compared to controls, alongside severe uterine damage. Mechanistically, the model group showed marked upregulation of uterine HSP90, p-AKT, NLRP3, Caspase-1, and IL-1β expression, indicating robust inflammatory activation. GGD treatment effectively attenuated all these pathological changes, demonstrating effects comparable to the positive control, ibuprofen. This included a reduction in writhing frequency, normalization of prostaglandin ratios, and improved uterine histopathology. Furthermore, GGD significantly reduced serum levels of pro-inflammatory cytokines, including IL-1β, IL-18, and IL-6.

Notably, co-administration of Terazosin (0.08 g/kg), an HSP90 agonist, effectively reversed the protective and anti-inflammatory effects of GGD, confirming the crucial role of HSP90/AKT pathway modulation in GGD's therapeutic action. This antagonism by Terazosin was observed across all measured parameters, from writhing behavior to cytokine suppression and uterine protein expression.