Influence of the route of administration and the chemical form (MnCl 2 , MnO 2 ) on the absorption and cerebral distribution of manganese in rats

Abstract

The absorption and cerebral distribution of manganese (Mn) have been studied with respect to the route of administration and the chemical form of the Mn compound. Different groups of adult male rats received either MnCl2, 4H2O or MnO2 once a week for 4 weeks at a dose of 24.3 mg Mn/kg body wt. (b.w.) by oral gavage (g.) or 1.22 mg Mn/kg b.w. by intraperitoneal injection (i.p.) or intratracheal instillation (i.t.). Control rats were treated with 0.9% saline. Four days after the last administration the rats were killed and the concentration of Mn measured in blood, hepatic and cerebral tissues (cortex, cerebellum, and striatum). The liver Mn concentration was not affected by the treatments whatever the chemical form or the route of administration of the Mn compound. Administration of MnCl2 by g., i.p., and i.t. routes produced equivalent steady-state blood Mn concentrations (about 1000 ng Mn/100 ml), representing increases of 68, 59, and 68% compared with controls, respectively. Mn concentrations were significantly increased in the cortex but to a lesser extent (g., 22%; i.p., 36%; i.t., 48%) and were higher in the cerebellum after i.p. and i.t. administrations than after oral gavage. Rats treated i.t. with MnCl2 showed an elective increase of the striatal Mn concentration (205%). In contrast, MnO2 given orally did not significantly increase blood and cerebral tissue Mn concentrations; the low bioavailability is most likely due to the lack of intestinal resorption. Administration of MnO2 i.p. and i.t., however, led to significant increases of Mn concentrations in blood and cerebral tissues. These increments were not significantly different from those measured after MnCl2 administration, except for striatal Mn after i.t. which was markedly less (48%) after MnO2 administration. A comparison of the blood Mn kinetics immediately after g. and i.t. treatment with MnCl2 or MnO2 indicated that the higher elevation of blood Mn concentration (> 2000 ng Mn/100 ml) after i.t. administration of MnCl2 could account for the elective uptake of Mn in the striatum observed in repeated dosing experiments. It is concluded that the modulation of Mn distribution in brain regions according to the route of administration and the chemical form of the Mn compound may be explained on the basis of different blood Mn kinetics and regional anatomic specificities of the striatal region.

Adequacy and Consistency of Animal Studies to Evaluate the Neurotoxicity of Chronic Low-Level Manganese Exposure in Humans

“…For example, there is evidence that increases in brain manganese are larger when exposures occur via nasal instillation or inhalation than via other routes (oral or i.p. ), even at the same blood manganese levels (Roels et al 1997), or even in the absence of a measured increase in blood manganese levels (Vitarella et al 2000). Notably though, the observations of a consistent manganese effect on striatal GABA levels over the whole range of cumulative dose, and an emerging effect of manganese on striatal dopamine levels at medium to high doses are equally supported by the evidence presented here, even if inhalation studies, which are a minority, are excluded from the analysis.…”

Direct effects of manganese compounds on dopamine and its metabolite Dopac: An in vitro study

“…However, MnPO 4 does not appear to gain access to or accumulate in the basal ganglia as selectively as MnSO 4 in rats (Vitarella et al, 2000). Apparently, the distribution of the different forms of Mn to various brain regions depends, in part, on the solubility of each Mn compound (Roels et al, 1997;Dorman et al, 2001) and MnPO 4 is much less soluble than the chloride and sulfate forms of Mn (Vitarella et al, 2000). This is important to take into account when considering MMT exposure.…”

Contribution of metals to brain MR signal intensity: review articles

“…Iron deficiency anemia promotes manganese absorption in the intestine and elevation of the manganese concentration in the blood, but the signal intensity of the globus pallidus on T1WI is not affected [33]. In this way, manganese neurotoxicity is caused by mine dust inhalation or intravenous administration but rarely by oral intake [34,35]. The manganese metabolic pathway adapts to oral MRI contrast agents containing manganese, and the contrast effect of this oral contrast agent based on manganese is limited to liver and intestine [36,37].…”