Rat brain endothelial cells are a target of manganese toxicity

Ana Paula Marreilha dos Santos, Dejan Milatovic, Catherine Au, Zhaobao Yin, Maria Camila C. Batoreu, Michael Aschner

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Manganese (Mn) is an essential trace metal; however, exposure to high Mn levels can result in neurodegenerative changes resembling Parkinson's disease (PD). Information on Mn's effects on endothelial cells of the blood-brain barrier (BBB) is lacking. Accordingly, we tested the hypothesis that BBB endothelial cells are a primary target for Mn-induced neurotoxicity. The studies were conducted in an in vitro BBB model of immortalized rat brain endothelial (RBE4) cells. ROS production was determined by F2-isoprostane (F2-IsoPs) measurement. The relationship between Mn toxicity and redox status was investigated upon intracellular glutathione (GSH) depletion with diethylmaleate (DEM) or l-buthionine sulfoximine (BSO). Mn exposure (200 or 800 μM MnCl2 or MnSO4) for 4 or 24 h led to significant decrease in cell viability vs. controls. DEM or BSO pre-treatment led to further enhancement in cytotoxicity vs. exposure to Mn alone, with more pronounced cell death after 24-h DEM pre-treatment. F2-IsoPs levels in cells exposed to MnCl2 (200 or 800 μM) were significantly increased after 4 h and remained elevated 24 h after exposure compared with controls. Consistent with the effects on cell viability and F2-IsoPs, treatment with MnCl2 (200 or 800 μM) was also associated with a significant decrease in membrane potential. This effect was more pronounced in cells exposed to DEM plus MnCl2 vs. cells exposed to Mn alone. We conclude that Mn induces direct injury to mitochondria in RBE4 cells. The ensuing impairment in energy metabolism and redox status may modify the restrictive properties of the BBB compromising its function.

Original languageEnglish (US)
Pages (from-to)152-161
Number of pages10
JournalBrain research
StatePublished - Apr 22 2010
Externally publishedYes


  • F-isoprostanes
  • Glutathione
  • Manganese neurotoxicity
  • Mitochondria cytotoxicity
  • Oxidative stress
  • RBE4 cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology


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