Manganese (Mn) is a required co-factor for many ubiquitous enzymes; however, chronic Mn overexposure can cause manganism, a parkinsonian-like syndrome. Previous studies showed Mn influx into brain is carrier-mediated, though the putative carrier(s) were not established. Studies conducted with cultured bovine brain microvascular endothelial cells (bBMECs), which comprise the blood–brain barrier, revealed 54Mn (II) uptake positively correlated with pH, was temperature-dependent, and was sodium- and energy-independent. Brain 54Mn uptake correlated inversely with calcium (Ca) concentration, but 45Ca uptake was unaltered by high Mn concentration. Lanthanum (La), a non-selective inhibitor of several Ca channel types, as well as verapamil and amiloride, inhibitors of voltage-operated Ca channels, failed to inhibit Mn uptake into cells. Nickel (Ni), another non-selective inhibitor of several Ca channel types, inhibited Mn and Ca uptake into cells by 88 and 85%, respectively. Cyclopiazonic acid (CPA) and thapsigargin, which activate store-operated calcium channels (SOCCs), increased 54Mn and 45Ca uptake into cultured bBMECs. In situ brain perfusion studies were conducted in adult, male Sprague–Dawley rats to verify the cell culture results. Both nickel and verapamil produced a non-significant decrease in Mn and Ca influx. Lanthanum significantly increased Mn influx to 675 and 450% of control in parietal cortex and caudate, respectively, while producing no significant effect on Ca influx. Vanadate, which inhibits Ca-ATPase, inhibited Mn uptake into cultured blood–brain barrier cells, but not into perfused rat brain. Overall these results suggest that both Ca-dependent and Ca-independent mechanisms play a role in brain Mn influx. This work provides evidence that store-operated Ca channels, as well as another mechanism at the blood–brain barrier, likely play a role in carrier-mediated Mn influx into the brain.
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Research described in this article was conducted under contract to the Health Effects Institute (HEI), an organization jointly funded by the United States Environmental Protection Agency (EPA) (Assistance Award No. R-824835) and certain motor vehicle and engine manufacturers. The contents of this article do not necessarily reflect the views of HEI, or its sponsors, nor do they necessarily reflect the views and policies of EPA or motor vehicle and engine manufacturers. Additional support was given by the University of Kentucky Graduate School (J.S.C.) and National Institute of Environmental Health Sciences, NIH, Grant #T32 ES7266 (J.S.C.).
Crossgrove, Janelle S. and Yokel, Robert A., "Manganese Distribution across the Blood-Brain Barrier. IV. Evidence for Brain Influx through Store-Operated Calcium Channels" (2005). Pharmaceutical Sciences Faculty Publications. 196.