TY - JOUR
T1 - The inhibitory effect of manganese on acetylcholinesterase activity enhances oxidative stress and neuroinflammation in the rat brain
AU - Santos, Dinamene
AU - Milatovic, Dejan
AU - Andrade, Vanda
AU - Batoreu, M. Camila
AU - Aschner, Michael
AU - Marreilha dos Santos, A. P.
N1 - Funding Information:
This study was funded by FCT (Foundation for Science and Technology of Portugal; SFRH/BD/64128/2009) , by i-Med.UL, Faculty of Pharmacy, University of Lisbon , and a grant from the National Institute of Environmental Health Sciences ES R01 10563 (MA). I would like to thank Prof. Daiana Silva Ávila and Dr. M. Sidoryk-Wegrzynowicz for their support at Vanderbilt University.
PY - 2012/2/26
Y1 - 2012/2/26
N2 - Background: Manganese (Mn) is a naturally occurring element and an essential nutrient for humans and animals. However, exposure to high levels of Mn may cause neurotoxic effects. The pathological mechanisms associated with Mn neurotoxicity are poorly understood, but several reports have established it is mediated, at least in part, by oxidative stress. Objectives: The present study was undertaken to test the hypothesis that a decrease in acetylcholinesterase (AChE) activity mediates Mn-induced neurotoxicity. Methods: Groups of 6 rats received 4 or 8 intraperitoneal (i.p.) injections of 25mg MnCl 2/kg/day, every 48h. Twenty-four hours after the last injection, brain AChE activity and the levels of F 2-isoprostanes (F 2-IsoPs) and F 4-neuroprostanes (F 4-NPs) (biomarkers of oxidative stress), as well as prostaglandin E 2 (PGE 2) (biomarker of neuroinflammation) were analyzed. Results: The results showed that after either 4 or 8 Mn doses, brain AChE activity was significantly decreased (p<0.05), to 60±16% and 55±13% of control levels, respectively. Both treated groups exhibited clear signs of neurobehavioral toxicity, characterized by a significant (p<0.001) decrease in ambulation and rearings in open-field. Furthermore, Mn treatment caused a significant increase (p<0.05) in brain F 2-IsoPs and PGE 2 levels, but only after 8 doses. In rats treated with 4 Mn doses, a significant increase (p<0.05) in brain F 4-NPs levels was found. To evaluate cellular responses to oxidative stress, we assessed brain nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and Mn-superoxide dismutase (Mn-SOD, SOD2) protein expression levels. A significant increase in Mn-SOD protein expression (p<0.05) and a trend towards increased Nrf2 protein expression was noted in rat brains after 4 Mn doses vs. the control group, but the expression of these proteins was decreased after 8 Mn doses. Taken together, these results suggest that the inhibitory effect of Mn on AChE activity promotes increased levels of neuronal oxidative stress and neuroinflammatory biomarkers.
AB - Background: Manganese (Mn) is a naturally occurring element and an essential nutrient for humans and animals. However, exposure to high levels of Mn may cause neurotoxic effects. The pathological mechanisms associated with Mn neurotoxicity are poorly understood, but several reports have established it is mediated, at least in part, by oxidative stress. Objectives: The present study was undertaken to test the hypothesis that a decrease in acetylcholinesterase (AChE) activity mediates Mn-induced neurotoxicity. Methods: Groups of 6 rats received 4 or 8 intraperitoneal (i.p.) injections of 25mg MnCl 2/kg/day, every 48h. Twenty-four hours after the last injection, brain AChE activity and the levels of F 2-isoprostanes (F 2-IsoPs) and F 4-neuroprostanes (F 4-NPs) (biomarkers of oxidative stress), as well as prostaglandin E 2 (PGE 2) (biomarker of neuroinflammation) were analyzed. Results: The results showed that after either 4 or 8 Mn doses, brain AChE activity was significantly decreased (p<0.05), to 60±16% and 55±13% of control levels, respectively. Both treated groups exhibited clear signs of neurobehavioral toxicity, characterized by a significant (p<0.001) decrease in ambulation and rearings in open-field. Furthermore, Mn treatment caused a significant increase (p<0.05) in brain F 2-IsoPs and PGE 2 levels, but only after 8 doses. In rats treated with 4 Mn doses, a significant increase (p<0.05) in brain F 4-NPs levels was found. To evaluate cellular responses to oxidative stress, we assessed brain nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and Mn-superoxide dismutase (Mn-SOD, SOD2) protein expression levels. A significant increase in Mn-SOD protein expression (p<0.05) and a trend towards increased Nrf2 protein expression was noted in rat brains after 4 Mn doses vs. the control group, but the expression of these proteins was decreased after 8 Mn doses. Taken together, these results suggest that the inhibitory effect of Mn on AChE activity promotes increased levels of neuronal oxidative stress and neuroinflammatory biomarkers.
KW - Acetylcholinesterase
KW - F -isoprostanes
KW - Manganese neurotoxicity
KW - Mn-SOD
KW - Prostaglandin E
KW - Rat brain
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U2 - 10.1016/j.tox.2011.11.017
DO - 10.1016/j.tox.2011.11.017
M3 - Article
C2 - 22154916
AN - SCOPUS:84856113283
SN - 0300-483X
VL - 292
SP - 90
EP - 98
JO - Toxicology
JF - Toxicology
IS - 2-3
ER -