Tamoxifen induces partial neuroprotection against manganese toxicity in the dopaminergic REST-deleted male mice

Chronic manganese (Mn) exposure leads to manganism, a neurological disorder with Parkinson's disease (PD)-like symptoms. Tamoxifen (TX), a selective estrogen receptor modulator (SERM), and the RE1-silencing transcription factor (REST) have both shown neuroprotective effects against Mn neurotoxicity. Since TX, via Wnt signaling, increases REST and protects dopaminergic (DAergic) neurons against Mn toxicity in vitro, we investigated if DAergic REST is essential for TX-induced neuroprotection, with a potential involvement of Wnt, in Mn-exposed male mice. TX pellets were implanted in wild-type (WT) and DAergic REST knockout (REST cKO) male mice prior to Mn exposure (330 μg MnCl₂, via nostril instillation) for 3 weeks, followed by behavioral and molecular analyses. The findings revealed that TX attenuated Mn-induced impairments of movement and cognition in WT mice, while those effects were diminished in REST cKO mice. The protein levels in the striatum, where DAergic nerve terminals were situated, showed that TX attenuated Mn-induced reductions in tyrosine hydroxylase and REST proteins, as well as Mn's neurotoxicity in WT, while these protections on certain proteins were diminished in REST cKO mice. Mn impaired Wnt signaling by dysregulating Wnt3a and β-catenin proteins in WT and REST cKO mice. TX attenuated these Mn effects in WT, with less attenuation in REST cKO mice, suggesting that DAergic REST contributes to TX's Wnt-mediated neuroprotection against Mn toxicity. These findings demonstrate that TX induces partial protection against Mn-induced toxicity and Wnt signaling disruption in the absence of DAergic REST, but DAergic REST is required for TX-induced full neuroprotection in male mice.