PMID- 22154916
OWN - NLM
STAT- MEDLINE
DCOM- 20120321
LR  - 20211021
IS  - 1879-3185 (Electronic)
IS  - 0300-483X (Print)
IS  - 0300-483X (Linking)
VI  - 292
IP  - 2-3
DP  - 2012 Feb 26
TI  - The inhibitory effect of manganese on acetylcholinesterase activity enhances 
      oxidative stress and neuroinflammation in the rat brain.
PG  - 90-8
LID - 10.1016/j.tox.2011.11.017 [doi]
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 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.
CI  - Copyright (c) 2011 Elsevier Ireland Ltd. All rights reserved.
FAU - Santos, Dinamene
AU  - Santos D
AD  - I-Med.UL, Department of Toxicology and Food Sciences, Faculty of Pharmacy, 
      University of Lisbon, Lisbon, Portugal.
FAU - Milatovic, Dejan
AU  - Milatovic D
FAU - Andrade, Vanda
AU  - Andrade V
FAU - Batoreu, M Camila
AU  - Batoreu MC
FAU - Aschner, Michael
AU  - Aschner M
FAU - Marreilha dos Santos, A P
AU  - Marreilha dos Santos AP
LA  - eng
GR  - R01 ES010563/ES/NIEHS NIH HHS/United States
GR  - R01 ES010563-11/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111203
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - 0 (Chlorides)
RN  - 0 (Cholinesterase Inhibitors)
RN  - 0 (F2-Isoprostanes)
RN  - 0 (Manganese Compounds)
RN  - 0 (NF-E2-Related Factor 2)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 3.1.1.7 (Acetylcholinesterase)
RN  - K7Q1JQR04M (Dinoprostone)
RN  - QQE170PANO (manganese chloride)
SB  - IM
CIN - Toxicology. 2012 Aug 16;298(1-3):59-60; author reply 61-2. PMID: 22503707
MH  - Acetylcholinesterase/*metabolism
MH  - Animals
MH  - Blotting, Western
MH  - Brain/*drug effects/enzymology/metabolism
MH  - Chlorides/*toxicity
MH  - Cholinesterase Inhibitors/*toxicity
MH  - Dinoprostone/metabolism
MH  - Encephalitis/*chemically induced/enzymology/metabolism
MH  - F2-Isoprostanes/metabolism
MH  - Male
MH  - Manganese Compounds
MH  - Motor Activity/drug effects
MH  - NF-E2-Related Factor 2/metabolism
MH  - Oxidative Stress/*drug effects
MH  - Random Allocation
MH  - Rats
MH  - Rats, Wistar
MH  - Superoxide Dismutase/metabolism
MH  - Up-Regulation
PMC - PMC3264815
MID - NIHMS342243
COIS- Conflict of interest statement None of the authors has any financial interest or 
      conflict of interest related to the manuscript.
EDAT- 2011/12/14 06:00
MHDA- 2012/03/22 06:00
PMCR- 2013/02/26
CRDT- 2011/12/14 06:00
PHST- 2011/10/11 00:00 [received]
PHST- 2011/11/22 00:00 [revised]
PHST- 2011/11/24 00:00 [accepted]
PHST- 2011/12/14 06:00 [entrez]
PHST- 2011/12/14 06:00 [pubmed]
PHST- 2012/03/22 06:00 [medline]
PHST- 2013/02/26 00:00 [pmc-release]
AID - S0300-483X(11)00502-6 [pii]
AID - 10.1016/j.tox.2011.11.017 [doi]
PST - ppublish
SO  - Toxicology. 2012 Feb 26;292(2-3):90-8. doi: 10.1016/j.tox.2011.11.017. Epub 2011 
      Dec 3.