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 journalArticle

22 Citations (Scopus)

Abstract

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
Volume1326
DOIs
StatePublished - Apr 22 2010
Externally publishedYes

Fingerprint

diethyl maleate
Manganese
Endothelial Cells
F2-Isoprostanes
Brain
Blood-Brain Barrier
Buthionine Sulfoximine
Oxidation-Reduction
Cell Survival
Membrane Potentials
Energy Metabolism
Glutathione
Parkinson Disease
Mitochondria
Cell Death
Metals
manganese chloride
Wounds and Injuries

Keywords

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

ASJC Scopus subject areas

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

Cite this

Santos, A. P. M. D., Milatovic, D., Au, C., Yin, Z., Batoreu, M. C. C., & Aschner, M. (2010). Rat brain endothelial cells are a target of manganese toxicity. Brain Research, 1326, 152-161. https://doi.org/10.1016/j.brainres.2010.02.016

Rat brain endothelial cells are a target of manganese toxicity. / Santos, Ana Paula Marreilha dos; Milatovic, Dejan; Au, Catherine; Yin, Zhaobao; Batoreu, Maria Camila C; Aschner, Michael.

In: Brain Research, Vol. 1326, 22.04.2010, p. 152-161.

Research output: Contribution to journalArticle

Santos, APMD, Milatovic, D, Au, C, Yin, Z, Batoreu, MCC & Aschner, M 2010, 'Rat brain endothelial cells are a target of manganese toxicity', Brain Research, vol. 1326, pp. 152-161. https://doi.org/10.1016/j.brainres.2010.02.016
Santos, Ana Paula Marreilha dos ; Milatovic, Dejan ; Au, Catherine ; Yin, Zhaobao ; Batoreu, Maria Camila C ; Aschner, Michael. / Rat brain endothelial cells are a target of manganese toxicity. In: Brain Research. 2010 ; Vol. 1326. pp. 152-161.
@article{51803d3f0fb14122ae85dce4b16f63f4,
title = "Rat brain endothelial cells are a target of manganese toxicity",
abstract = "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.",
keywords = "F-isoprostanes, Glutathione, Manganese neurotoxicity, Mitochondria cytotoxicity, Oxidative stress, RBE4 cells",
author = "Santos, {Ana Paula Marreilha dos} and Dejan Milatovic and Catherine Au and Zhaobao Yin and Batoreu, {Maria Camila C} and Michael Aschner",
year = "2010",
month = "4",
day = "22",
doi = "10.1016/j.brainres.2010.02.016",
language = "English (US)",
volume = "1326",
pages = "152--161",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",

}

TY - JOUR

T1 - Rat brain endothelial cells are a target of manganese toxicity

AU - Santos, Ana Paula Marreilha dos

AU - Milatovic, Dejan

AU - Au, Catherine

AU - Yin, Zhaobao

AU - Batoreu, Maria Camila C

AU - Aschner, Michael

PY - 2010/4/22

Y1 - 2010/4/22

N2 - 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.

AB - 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.

KW - F-isoprostanes

KW - Glutathione

KW - Manganese neurotoxicity

KW - Mitochondria cytotoxicity

KW - Oxidative stress

KW - RBE4 cells

UR - http://www.scopus.com/inward/record.url?scp=77950028100&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950028100&partnerID=8YFLogxK

U2 - 10.1016/j.brainres.2010.02.016

DO - 10.1016/j.brainres.2010.02.016

M3 - Article

C2 - 20170646

AN - SCOPUS:77950028100

VL - 1326

SP - 152

EP - 161

JO - Brain Research

JF - Brain Research

SN - 0006-8993

ER -