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Manganese Flux Across the Blood–Brain Barrier

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Abstract

Manganese (Mn) is essential for brain growth and metabolism, but in excess can be a neurotoxicant. The chemical form (species) of Mn influences its kinetics and toxicity. Significant Mn species entering the brain are the Mn2+ ion and Mn citrate which, along with Mn transferrin, enter the brain by carrier-mediated processes. Although the divalent metal transporter (DMT-1) was suggested to be a candidate for brain Mn uptake, brain Mn influx was not different in Belgrade rats, which do not express functional DMT-1, compared to controls. Brain Mn influx was not sodium dependent or dependent on ATP hydrolysis, but was reduced by mitochondrial energy inhibitors. Mn and Fe do not appear to compete for brain uptake. Brain Mn uptake appears to be mediated by a Ca uptake mechanism, thought to not be a p-type ATPase, but a store-operated calcium channel. Efflux of Mn from the brain was found to be slower than markers used as membrane impermeable reference compounds, suggesting diffusion mediates brain Mn efflux. Owing to carrier-mediated brain Mn influx and diffusion-mediated efflux, slow brain Mn clearance and brain Mn accumulation with repeated excess exposure would be predicted, and have been reported. This may render the brain susceptible to Mn-induced neurotoxicity from excessive Mn exposure.

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Abbreviations

BBB:

Blood–brain barrier

BMEC:

Brain microvascular endothelial cell

D o/a :

Octanol/aqueous partitioning coefficient

J :

Influx

K d :

Diffusion constant

K el :

Apparent elimination rate constant

K in :

Influx transfer coefficient

K m :

Michaelis–Menten constant

K out :

Brain capillary efflux

MMT:

Methylcyclopentadienyl manganese tricarbonyl

Mn:

Manganese

MW:

Molecular weight

P diffusion :

Estimated permeability due to diffusion

PS:

Permeability-surface area product

S:

Surface area of rat brain capillaries

Tf:

Transferrin

TfR-ME:

Transferrin receptor mediated endocytosis

V brain :

Brain distribution volume

V max :

Maximum velocity of carrier-mediated transport

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Acknowledgments

This work was supported by Health Effects Institute Assistance Award R-824835, NIH Grant T32 ES7266 and the University of Kentucky Graduate School. The author thanks Matt Hazzard, University of Kentucky Teaching & Academic Support Center, for preparing Fig. 1.

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  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky Academic Medical Center, 511C Pharmacy Building, 725 Rose Street, Lexington, KY, 40536-0082, USA

    Robert A. Yokel

  2. Graduate Center for Toxicology, University of Kentucky Academic Medical Center, Lexington, KY, 40506-9983, USA

    Robert A. Yokel

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Yokel, R.A. Manganese Flux Across the Blood–Brain Barrier. Neuromol Med 11, 297–310 (2009). https://doi.org/10.1007/s12017-009-8101-2

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