Abstract
Manganese (Mn) is an essential heavy metal. However, Mn’s nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and its molecular actions in the brain as well as promising neuroprotective strategies. The authors focused on reporting findings regarding Mn transport mechanisms, Mn effects on cholinergic system, behavioral alterations induced by Mn exposure and studies of neuroprotective strategies against Mn intoxication. We report that exposure to Mn may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such as mutation in the transporter SLC30A10. Accumulation of Mn occurs mainly in the basal ganglia and leads to a syndrome called manganism, whose symptoms of cognitive dysfunction and motor impairment resemble Parkinson’s disease (PD). Various neurotransmitter systems may be impaired due to Mn, especially dopaminergic, but also cholinergic and GABAergic. Several proteins have been identified to transport Mn, including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin and ferroportin and allow its accumulation in the central nervous system. Parallel to identification of Mn neurotoxic properties, neuroprotective strategies have been reported, and these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols and non-characterized components), iron chelating agents, precursors of glutathione (GSH), and synthetic compounds that can experimentally afford protection against Mn-induced neurotoxicity.
Highlights
Mechanisms of Mn uptake into the central nervous system (CNS) As Mn is required for multiple cellular events but becomes toxic at high levels, the intracellular Mn concentration has to be under strict control
Xenopus laevis oocytes expressing human Fpn showed lower intracellular Mn and higher extracellular Mn [63]. These results indicate Fpn may play an important role on Mn homeostasis in the CNS, a direct study to investigate brain Mn levels in human or animal models carrying Fpn mutations has not been reported yet
The interest in researching Mn toxicity has grown in the past few decades
Summary
Manganese (Mn) is a naturally occurring heavy metal present as the fifth most abundant metal in the environment and twelfth most abundant element as a whole. The recommended daily intake of Mn for adult men is 2.3 and 1.8 mg/day for adult women [1] Mn overload may arise from an impaired or not fully developed excretion system, transporter malfunction or exposure to excessive levels of Mn by air, water, food or total parenteral nutrition (TPN). Given the similarities between Mn and iron (Fe), homeostasis of both metals is interdependent, the Fe status influences Mn accumulation This is noted in cases of anemia, for example, when low levels of Fe facilitate Mn uptake [8]. We will discuss the behavioral aspects of Mn intoxication and possible neuroprotective strategies
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