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

INTRODUCTION

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.

METHODS

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.

RESULTS

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.

DISCUSSION AND

CONCLUSION

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.