“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

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.

Valproate and sodium butyrate attenuate manganese-decreased locomotor activity and astrocytic glutamate transporters expression in mice

“…Since the symptoms of Mn toxicity or manganism are similar to those in PD, including tremor, gait, frequent falling and problems with posture and agility (Peres et al, 2016), analysis of Mn-induced reduction of locomotor activity and motor coordination are pertinent to test the effects of VPA and NaB in Mn-induced behavioral deficits. The cerebral cortex is a major component of the neural motor pathway in regulating body movements, and cerebellar regions play a critical role in motor coordination and balance.…”

“…Although the molecular mechanisms of these neurological disorders are still not completely understood, their etiology is based on genetic, environmental or gene × environment interactions (Dauncey, 2012; Peres et al, 2016). Genetic abnormalities leading to neurological diseases are associated with rare gene mutations and irregular gene expression (Dauncey, 2012; Karki et al, 2015; Seifert et al, 2006).…”

“…Environmental and idiopathic factors also significantly influence the development and progression of neurodegenerative disorders (Peres et al, 2016; Robison et al, 2012). Previous studies have reported that environmental agents may induce toxicity, which can lead to serious brain injury and damage (Dauncey, 2012; Peres et al, 2016).…”

“…Previous studies have reported that environmental agents may induce toxicity, which can lead to serious brain injury and damage (Dauncey, 2012; Peres et al, 2016). One of the most studied metal toxicants is manganese (Mn), which is an essential trace element, but chronic high level exposures to this metal may cause a neurological disorder referred to as manganism, with similar clinical features to parkinsonism (Peres et al, 2016), characterized by locomotor dysfunction and behavioral abnormality (Peres et al, 2016; Robison et al, 2012). Upon overexposure, Mn accumulates preferentially in specific brain regions (i.e.…”

“…globus pallidus), resulting in motor deficits and neurological disorders (Robison et al, 2012). Several therapeutic approaches have been reported for the treatment of manganism, such as levodopa, antioxidants, plant extracts, iron (Fe)-chelating agents and glutathione precursors (Peres et al, 2016). …”