Understanding Nrf2 Function in Manganese Neurotoxicity

The objective of the present review was to summarize and discuss recent findings on the effects of Mn exposure on Nrf2 signaling in the brain and its relationship with other molecular mechanisms of Mn neurotoxicity. The existing data show that Mn exposure interferes with Nrf2 signaling following a biphasic response model. Upon low-to-moderate dose or following short-term exposure, Mn activates Nrf2 signaling with subsequent upregulation of Nrf2-target antioxidant genes, which limit progression of Mn-induced oxidative stress. Evidence from Nrf2-deficient animal models support the essential role of Nrf2 in counteracting Mn-induced neuronal oxidative stress. In contrast, high-dose and/or long-term Mn exposure down-regulates Nrf2 signaling due to inhibition of SIRT1, REST1, and CYP1B1 expression, as well as upregulation of GSK-3β expression. The observed inhibition of Nrf2 signaling is associated not only with oxidative stress, but is also tightly related to Mn-induced neuroinflammation, pyroptosis, neurodegeneration, endoplasmic reticulum stress, ferroptosis, tau and amyloid-β accumulation, and dysregulated heat-shock protein expression. Although the existing data were derived from laboratory studies and environmentally irrelevant doses, it is assumed that Nrf2 signaling may represent a potential therapeutic strategy for preventing Mn neurotoxicity.