Manganese: recent advances in understanding its transport and neurotoxicity

Abstract

The present review is based on presentations from the meeting of the Society of Toxicology in San Diego, CA (March 2006). It addresses recent developments in the understanding of the transport of manganese (Mn) into the central nervous system (CNS), as well as brain imaging and neurocognitive studies in non-human primates aimed at improving our understanding of the mechanisms of Mn neurotoxicity. Finally, we discuss potential therapeutic modalities for treating Mn intoxication in humans.

Figure 1. Mn Transport into the CNS

Mechanisms of Mn transport across the blood-brain barrier (BBB) under physiological exposure levels (physiological Mn plasma levels). Transporters associated with Mn transport (relevant to its oxidation state) are indicated. Mn bound to albumin is excluded from passing the BBB given its size. Arrow size depicts the relative importance of each of the transporters in this process, bolder arrows representing more prominent transport mechanisms. Please refer to the discussion for additional details. Since it has yet to be determined whether ZIP8 functions to transport Mn across the BBB, the process has been annotated with a question mark.

Figure 2

Fig. 2. Effect of chronic Mn exposure on [¹¹C]-raclopride BP and AMPH-induced dopamine release. (A) Representative pseudocolor trans-axial images of [¹¹C]-raclopride binding to D2-DAR in the striatum of one animal at baseline and at the Mn-1 and Mn-2 time points. Red areas represent high levels of binding and green areas represent low levels of [¹¹C]-raclopride binding to D2-DAR. Note the progressive lack of a change in [¹¹C]-raclopride levels in the striatum after AMPH administration from baseline to Mn-2. (B) [¹¹C]-raclopride time–activity curves in the striatum and cerebellum before and after AMPH in the same animal as in panel A. Each graph corresponds to the adjacent images in panel A. At baseline (top graph in B), there is a dramatic decrease in [¹¹C]-raclopride levels in the striatum after AMPH administration. Increasing Mn exposure reduces the effectiveness of AMPH-induced DA released to displace [¹¹C]-raclopride from the striatum (see middle and lower graph in B). (C) Quantitative data on [¹¹C]-raclopride BP and AMPH-induced in vivo DA release for all animals. For dopamine release, the numbers in parenthesis are the mean percent change from baseline. Each value is the mean ± SEM of 4 Mn-exposed animals. *p < 0.05. (Reprinted from: Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates Experimental Neurology 202:381-390, 2006 with permission from Elsevier).