PMID- 28267559
OWN - NLM
STAT- MEDLINE
DCOM- 20170328
LR  - 20170328
IS  - 1879-3169 (Electronic)
IS  - 0378-4274 (Linking)
VI  - 271
DP  - 2017 Apr 5
TI  - Site-specific neural hyperactivity via the activation of MAPK and PKA/CREB 
      pathways triggers neuronal degeneration in methylmercury-intoxicated mice.
PG  - 66-73
LID - S0378-4274(17)30094-2 [pii]
LID - 10.1016/j.toxlet.2017.03.001 [doi]
AB  - Methylmercury (MeHg) induces site-specific neurotoxicity in the adult brain. In 
      this study, we investigated the site-specific expression of the signaling cascade 
      related to neural activity in a mouse model of MeHg intoxication showing 
      neurodegeneration only in the deep layer of the cerebral cortex, especially layer 
      IV. We performed time course studies of c-fos and brain-derived neurotrophic 
      factor (BDNF) expression levels which are proper markers of neural activity. We 
      showed that upregulation of both markers preceded the neuronal degeneration in 
      the cerebral cortex. Immunohistochemical analysis revealed the site-specific 
      upregulation of c-fos in the deep layer of the cerebral cortex. Western blot 
      analysis showed that c-fos and BDNF expression was associated with CREB 
      phosphorylation, which was triggered by the activation of the p44/42 MAPK, p38 
      MAPK and PKA pathways. However, we did not detect any changes in the expression 
      levels of c-fos and BDNF proteins and no signs of neuronal degeneration in the 
      hippocampus and cerebellum, despite the fact that we could detect accumulation of 
      MeHg in these two brain regions. These results suggested an intriguing 
      possibility that MeHg-induced neuronal degeneration was caused by site-specific 
      neural hyperactivity triggered by the activation of MAPK and PKA/CREB pathways 
      followed by c-fos and BDNF upregulation.
CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
FAU - Fujimura, Masatake
AU  - Fujimura M
AD  - Department of Basic Medical Sciences, National Institute for Minamata Disease, 
      4058-18 Hama, Minamata, Kumamoto 867-0008, Japan. Electronic address: 
      fujimura@nimd.go.jp.
FAU - Usuki, Fusako
AU  - Usuki F
AD  - Department of Clinical Medicine, National Institute for Minamata Disease, 
      Kumamoto, Japan.
LA  - eng
PT  - Journal Article
DEP - 20170304
PL  - Netherlands
TA  - Toxicol Lett
JT  - Toxicology letters
JID - 7709027
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Creb1 protein, mouse)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Methylmercury Compounds)
RN  - 0 (Proto-Oncogene Proteins c-fos)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cerebral Cortex/*drug effects/enzymology/pathology/physiopathology
MH  - Cyclic AMP Response Element-Binding Protein/*metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/*metabolism
MH  - Disease Models, Animal
MH  - Enzyme Activation
MH  - Immunohistochemistry
MH  - Male
MH  - Mercury Poisoning, Nervous 
      System/enzymology/pathology/physiopathology/*prevention & control
MH  - *Methylmercury Compounds
MH  - Mice, Inbred ICR
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - *Nerve Degeneration
MH  - Neurons/*drug effects/enzymology/pathology
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-fos/metabolism
MH  - Signal Transduction
MH  - Time Factors
MH  - Up-Regulation
OTO - NOTNLM
OT  - C-fos
OT  - Deep layer of cerebral cortex
OT  - MAPK and PKA/CREB pathways
OT  - Methylmercury
OT  - Neural activity
OT  - Site-specific neurotoxicity
EDAT- 2017/03/08 06:00
MHDA- 2017/03/30 06:00
CRDT- 2017/03/08 06:00
PHST- 2016/11/05 00:00 [received]
PHST- 2017/01/17 00:00 [revised]
PHST- 2017/03/02 00:00 [accepted]
PHST- 2017/03/08 06:00 [pubmed]
PHST- 2017/03/30 06:00 [medline]
PHST- 2017/03/08 06:00 [entrez]
AID - S0378-4274(17)30094-2 [pii]
AID - 10.1016/j.toxlet.2017.03.001 [doi]
PST - ppublish
SO  - Toxicol Lett. 2017 Apr 5;271:66-73. doi: 10.1016/j.toxlet.2017.03.001. Epub 2017 
      Mar 4.