Iron-Responsive Olfactory Uptake of Manganese Improves Motor Function Deficits Associated with Iron Deficiency

Abstract

Iron-responsive manganese uptake is increased in iron-deficient rats, suggesting that toxicity related to manganese exposure could be modified by iron status. To explore possible interactions, the distribution of intranasally-instilled manganese in control and iron-deficient rat brain was characterized by quantitative image analysis using T1-weighted magnetic resonance imaging (MRI). Manganese accumulation in the brain of iron-deficient rats was doubled after intranasal administration of MnCl 2 for 1- or 3-week. Enhanced manganese level was observed in specific brain regions of iron-deficient rats, including the striatum, hippocampus, and prefrontal cortex. Iron-deficient rats spent reduced time on a standard accelerating rotarod bar before falling and with lower peak speed compared to controls; unexpectedly, these measures of motor function significantly improved in iron-deficient rats intranasally-instilled with MnCl 2 . Although tissue dopamine concentrations were similar in the striatum, dopamine transporter (DAT) and dopamine receptor D 1 (D1R) levels were reduced and dopamine receptor D 2 (D2R) levels were increased in manganese-instilled rats, suggesting that manganese-induced changes in post-synaptic dopaminergic signaling contribute to the compensatory effect. Enhanced olfactory manganese uptake during iron deficiency appears to be a programmed “rescue response” with beneficial influence on motor impairment due to low iron status.

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“…Manganese neurotoxicity resembles Parkinson's disease and has been well-documented in people drinking contaminated water, workers employed in mining and Mn ore processing and agricultural workers exposed to Mncontaining pesticide [13]. The use of methylcyclopentadienyl manganese tricarbonyl (MMT), an octane enhancer in gasoline, continues to be a huge concern about potential neurological damage due to inhalable Mn particles after combustion [14] Mn intoxication has also been observed in children under long-term parenteral nutrition and patients with chronic liver diseases [15].Advances in molecular physiology and toxicology have revealed that Mn neurotoxicity is, at least, mediated by dopaminergic dysfunction [16][17][18][19]. The dopaminergic neurotransmission is also impaired by iron deficiency.…”

“…Treating adult rats and mice with Mn also increases the number of D 2 binding sites in the dorsal striatum [27]. In addition, rats exposed to Mn during PND 1-21 demonstrated a significant reduction in DAT levels that can persist into adulthood [19,28].An accumulating body of evidence has indicated that Mn absorption is enhanced in iron-deficient anemia (IDA) due to iron-responsive up-regulation of divalent metal transporter-1 (DMT1) which is expressed in intestinal and olfactory epithelium [17,[29][30][31]. Our previous study demonstrated that iron deficiency impairs motor coordination, which was corrected by olfactory Mn exposure, suggesting a possibility that Mn could modulate or compensate for some detrimental effects resulting from an irondeficient state [17].…”

“…The rotarod device was cleaned between trials using Quatricide TB (Pharmaceutical Research Laboratories Inc., Waterbury, CT). The time of the first drop was recorded and the better score of the two trials was used for analysis [17]. …”

“…It might be speculated that Mn could serve as iron for growth when the body is deficient in iron. For example, under iron deficiency some iron-requiring components (e.g., tyrosine hydroxylase) could incorporate and utilize excessive Mn, which would otherwise be toxic and inhibit cellular metabolism [17]. It is also equally possible that a greater availability of iron transport molecules (e.g., transferrin) under iron deficiency [34] could capture manganese in excess and store/transport as an inactive and less toxic form.…”

“…However, dopamine-related synaptic proteins, including dopamine transporter (DAT), dopamine receptor 1 (D 1 R) and D 2 R, were not associated with Mn effect on iron deficiency [17]. Therefore, it was hypothesized that the reversing effect of intranasal Mn instillation on motor dysfunction in iron deficiency could result from altered activity of intracellular proteins related to dopamine homeostasis [17] Since tyrosine hydroxylase (TH) is the critical enzyme for dopamine synthesis and since both iron and Mn can support TH activity [41], we characterized the interaction effect between olfactory Mn exposure and iron deficiency on the expression of TH in the striatum.We found that both iron and manganese influenced the levels of striatal TH ( Figure 5). First, olfactory Mn instillation significantly down-regulated TH by 78% in iron-adequate rats ( Figure 5A; P< 0.001) and by 70% in iron-deficient rats (P< 0.001; n = 4 per group), which is in agreement with Zhang et al [42], who showed that chronic manganese exposure (0.1-1 µM for 24 h) induced a dose-dependent decrease in TH activity of dopaminergic neuronal cell line.…”