title: The inhibitory effect of manganese on acetylcholinesterase activity enhances oxidative stress and neuroinflammation in the rat brain.
abstract: 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.
  
  
  OBJECTIVE
  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 48 h. 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.
authors.affiliation: I-Med.UL, Department of Toxicology and Food Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
authors.forename: Dinamene
authors.initials: D
authors.lastname: Santos
authors.forename: Dejan
authors.initials: D
authors.lastname: Milatovic
authors.forename: Vanda
authors.initials: V
authors.lastname: Andrade
authors.forename: M Camila
authors.initials: MC
authors.lastname: Batoreu
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.forename: A P
authors.initials: AP
authors.lastname: Marreilha dos Santos
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002712:Chlorides / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D015232:Dinoprostone / Q000378:metabolism; D004660:Encephalitis / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D028441:F2-Isoprostanes / Q000378:metabolism; D008297:Male; D017895:Manganese Compounds; D009043:Motor Activity / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002712:Chlorides; D002800:Cholinesterase Inhibitors; D028441:F2-Isoprostanes; D017895:Manganese Compounds; D051267:NF-E2-Related Factor 2; D013482:Superoxide Dismutase; D000110:Acetylcholinesterase; D015232:Dinoprostone; C025340:manganese chloride