Manganese exposure is cytotoxic and alters dopaminergic and GABAergic neurons within the basal ganglia

Abstract

Manganese is an essential nutrient, integral to proper metabolism of amino acids, proteins and lipids. Excessive environmental exposure to manganese can produce extrapyramidal symptoms similar to those observed in Parkinson’s disease (PD). We used in vivo and in vitro models to examine cellular and circuitry alterations induced by manganese exposure. Primary mesencephalic cultures were treated with 10–800 μM manganese chloride which resulted in dramatic changes in the neuronal cytoskeleton even at subtoxic concentrations. Using cultures from mice with red fluorescent protein driven by the tyrosine hydroxylase (TH) promoter, we found that dopaminergic neurons were more susceptible to manganese toxicity. To understand the vulnerability of dopaminergic cells to chronic manganese exposure, mice were given i.p. injections of MnCl2 for 30 days. We observed a 20% reduction in TH‐positive neurons in the substantia nigra pars compacta (SNpc) following manganese treatment. Quantification of Nissl bodies revealed a widespread reduction in SNpc cell numbers. Other areas of the basal ganglia were also altered by manganese as evidenced by the loss of glutamic acid decarboxylase 67 in the striatum. These studies suggest that acute manganese exposure induces cytoskeletal dysfunction prior to degeneration and that chronic manganese exposure results in neurochemical dysfunction with overlapping features to PD.

Structural Elements in the Transmembrane and Cytoplasmic Domains of the Metal Transporter SLC30A10 Are Required for Its Manganese Efflux Activity

“…After a final wash with EDTA-free phosphate-buffered saline, pellets were resuspended in 20 l of phosphate-buffered saline (prior to resuspension in 20 l of phosphate-buffered saline, we reconfirmed that, in each experiment, pellet sizes were similar between transfection conditions). These pellets were transferred to acid-washed vials and digested by the addition of 200 l of 70% metal-free HNO 3 . After digestion, samples were diluted to 2% HNO 3 using ultrapure water.…”

“…However, elevated levels of manganese are cytotoxic and induce oxidative stress, mitochondrial dysfunction, and apoptosis (2,3). In humans, when systemic levels of manganese increase, the metal accumulates in the basal ganglia in the brain and leads to the development of an incurable parkinsonian syndrome (1,4,5).…”

Effect of Manganese Chloride on the Neurochemical Profile of the Rat Hypothalamus

“…Symptoms similar to Parkinson's disease have also been reported (Benedetto et al, 2009;Olanow, 2004;Pal et al, 1999). Moreover, Mn 2 + was also reported to disrupt the astrocytes glutamine transporter expression and function in astrocytic cell cultures (Sidoryk-Wegrzynowicz et al, 2009) and to alter dopaminergic and GABAergic neurons within the basal ganglia (Stanwood et al, 2009). Although the mechanisms underlying Mn 2 + neurotoxicity remain unclear and chronic exposure to Mn 2 + is a topic of interest since neuropathologic changes in humans lead to neuronal loss, gliosis and Alzheimer disease, the present study examined the effects of acute exposure to Mn 2 + in relation to previous Mn 2 + -enhanced magnetic resonance imaging studies in the hypothalamus.…”

“…Recently, magnetic resonance imaging techniques have taken advantage of the paramagnetic properties of this compound identified as a potential indirect noninvasive neuronal marker (Duong et al, 2000) and allowing the identification of various neuronal pathways within the rodent brain in tract tracing studies (Pautler et al, 1998(Pautler et al, , 2004. However, excessive levels of Mn 2 + are toxic for the central nervous system (Stanwood et al, 2009). Silva et al (2004) have reported behavioral disorders such as somnolence, convulsions, tremors, and respiratory effects in both rats and mice at high Mn 2 + doses ( > 90 mg/kg) independent of the route of administration.…”

Imaging neuronal pathways with 52Mn PET: Toxicity evaluation in rats

“…It has been long recognized that prolonged exposure to manganese leads to a disease called manganism (Barbeau, 1983). The basal ganglia, and the dopaminergic neurons in particular, are most vulnerable to manganese (Eriksson et al, 1992, Stanwood et al, 2009, Sriram et al, 2010. As a result, motor extrapyramidal symptoms, resembling those of Parkinson's disease patients, are a common manifestation in humans (Huang et al, 1998, Tuschl et al, 2013 as well as in experimental animals (Eriksson et al, 1987, Olanow et al, 1996.…”