ArticleFrontiers in pharmacology2025
Dopaminergic REST is implicated in the tamoxifen-induced neuroprotection against manganese toxicity in female mice.
Article in Frontiers in pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Introduction: Chronic manganese (Mn) overexposure causes manganism, a Parkinson's disease-like neurological disorder, due to its preferential accumulation in the basal ganglia. Tamoxifen (TX), a selective estrogen receptor modulator (SERM), afforded neuroprotection against Mn toxicity, and RE1-silencing transcription factor (REST) in dopaminergic neurons mitigated Mn-induced neurotoxicity. Methods: This study investigated whether dopaminergic REST played a role in TX's protection against Mn toxicity in the nigrostriatal regions using wild-type (WT) and dopaminergic REST-deleted (REST cKO) female mice. Behavioral studies, including open-field, rotarod, and novel object recognition tests, were conducted with molecular biology assays. Results: TX mitigated Mn-induced deficits in several motor functions and cognition, as well as dopaminergic neuronal injury, parallel with the attenuation of Mn-decreased tyrosine hydroxylase (TH) and Mn-increased proapoptotic Bax in REST cKO mice. However, several Mn-dysregulated genes associated with oxidative stress and mitochondrial function, including catalase, superoxide dismutase 2 (SOD2), and optic atrophy 1 (OPA1), were attenuated by TX only in WT, but not in REST cKO. At the epigenetic levels, TX attenuated Mn-reduced acetylation of H3K27 in both WT and REST cKO, but Mn-decreased H3K27ac interaction with promoters of catalase, SOD2, and OPA1 was attenuated by TX only in WT, not REST cKO. TX attenuated Mn-decreased estrogen receptor (ER)-α and ER-β protein levels in both WT and REST cKO mice. Discussion: Our findings suggest that TX significantly attenuated Mn-induced TH reduction and behavioral deficits in REST cKO, not to the levels of its protection in WT, since several genes involved in TX-induced protective pathways required dopaminergic REST. Taken together, while TX has some REST-independent protective effects, dopaminergic REST is critical for full neuroprotection.
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