Thioredoxin-1 Regulates Microglia Polarization to Ameliorate Neuroinflammation and Cognitive Impairment Following...

Neuroinflammation is a key driver of cognitive deficits after surgical menopause, a state commonly triggered by oophorectomy for oncological purposes. This intervention is routinely performed in premenopausal patients with hormone receptor-positive (HR+) breast cancer, constitutes foundational therapy for epithelial ovarian carcinoma, and is indicated for risk reduction in carriers of hereditary mutations such as breast cancer susceptibility gene 1/2 (BRCA1/2). As highly efficient immune cells, microglia play a central role in the onset of neurodegenerative diseases. Our study explored the role of thioredoxin-1 (Trx-1) in suppressing microglial activation and its potential for ameliorating postmenopausal cognitive decline.

Female C57BL/6J mice underwent ovariectomy (OVX) to model tumor-therapeutic oophorectomy. They were intraperitoneally injected with recombinant human Trx-1 (rhTrx-1) at a dose of 200 μg/30 g or PBS once weekly for five weeks following OVX. A Y-maze active avoidance task and trace fear conditioning were used to assess cognitive function. Levels of neuroinflammation were evaluated through immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and real-time polymerase chain reaction (PCR). Trx-1 levels in the hippocampus of OVX mice were measured by western blot and immunohistochemical analysis. Furthermore, the impact of Trx-1 on microglial activation was assessed in vitro.

OVX induced the production of inflammatory factors and microglial activation in the brain, resulting in cognitive deficits in mice. However, intraperitoneal injection of rhTrx-1 inhibited these effects by improving cognitive function, reducing inflammatory cytokines, and promoting microglial polarization. In vitro studies also showed that rhTrx-1 attenuated lipopolysaccharide (LPS)-stimulated microglial activation through mitogen-activated protein kinase (MAPK) pathway signaling.

Due to its inhibitory effect on neuroinflammation and microglial activation, Trx-1 may represent a promising therapeutic candidate for managing cancer therapy-related cognitive impairment, particularly in patients undergoing estrogen-deprivation therapies such as oophorectomy.