PMID- 25092802
OWN - NLM
STAT- MEDLINE
DCOM- 20150914
LR  - 20171116
IS  - 1098-1136 (Electronic)
IS  - 0894-1491 (Linking)
VI  - 63
IP  - 1
DP  - 2015 Jan
TI  - Ammonia-induced senescence in cultured rat astrocytes and in human cerebral 
      cortex in hepatic encephalopathy.
PG  - 37-50
LID - 10.1002/glia.22731 [doi]
AB  - Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis and is 
      due to a low-grade cerebral edema associated with oxidative/nitrosative stress. 
      Recent reports suggest that cognitive impairment in cirrhotic patients may not 
      resolve completely after an attack of manifest HE. As astrocyte dysfunction is 
      central to the pathogenesis of HE and astrocytes are critically involved in 
      synaptic plasticity, we tested for sustained impairment of astrocyte function by 
      analyzing expression levels of senescence biomarkers in ammonia-treated cultured 
      rat astrocytes and in postmortem brain samples from cirrhotic patients with or 
      without HE. NH4 Cl time- and dose-dependently inhibited proliferation of cultured 
      astrocytes by up to 45% (5 mmol/L, 72 h) and strongly increased 
      senescence-associated beta-galactosidase activity. Inhibition of astrocyte 
      proliferation by ammonia was mediated by a l-methionine sulfoximine-, oxidative 
      stress-, and p38(MAPK) -dependent activation of p53 associated with enhanced 
      transcription of cell cycle inhibitory genes GADD45alpha and p21. Mitochondria and 
      the nucleus were identified as sources of oxygen radical formation after 
      prolonged NH4 Cl exposure. Concurrently, NH4 Cl (5 mmol/L) treatment inhibited 
      both epidermal growth factor- and brain-derived neurotrophic factor 
      (BDNF)-induced proliferation as well as BDNF-mediated astrocyte morphology 
      changes through downregulation of the respective growth factor receptors 
      epidermal growth factor receptor and truncated tyrosine receptor kinase B. 
      Increased mRNA expression levels of senescence-associated genes were also found 
      in post mortem brain samples from patients with liver cirrhosis with HE, but not 
      in those without HE. The data suggest that ammonia toxicity and HE are associated 
      with premature astrocyte senescence, which may impair neurotransmission and 
      contribute to persistence of cognitive disturbances after resolution of episodes 
      of overt HE.
CI  - (c) 2014 Wiley Periodicals, Inc.
FAU - Gorg, Boris
AU  - Gorg B
AD  - Clinic for Gastroenterologogy, Hepatology and Infectious Diseases, Heinrich Heine 
      University, Dusseldorf, Germany.
FAU - Karababa, Ayse
AU  - Karababa A
FAU - Shafigullina, Aygul
AU  - Shafigullina A
FAU - Bidmon, Hans J
AU  - Bidmon HJ
FAU - Haussinger, Dieter
AU  - Haussinger D
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140804
PL  - United States
TA  - Glia
JT  - Glia
JID - 8806785
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Reactive Oxygen Species)
RN  - 7664-41-7 (Ammonia)
SB  - IM
MH  - Ammonia/metabolism/*pharmacology
MH  - Animals
MH  - Astrocytes/*drug effects/*metabolism
MH  - Brain Edema/etiology
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cells, Cultured
MH  - Cellular Senescence/*drug effects
MH  - Cerebral Cortex/*drug effects/metabolism
MH  - Hepatic Encephalopathy/*drug therapy/*metabolism
MH  - Humans
MH  - Mitochondria/drug effects/metabolism
MH  - Oxidative Stress/drug effects
MH  - Rats, Wistar
MH  - Reactive Oxygen Species/metabolism
OTO - NOTNLM
OT  - ammonia
OT  - astrocytes
OT  - glutamine
OT  - senescence
EDAT- 2014/08/06 06:00
MHDA- 2015/09/15 06:00
CRDT- 2014/08/06 06:00
PHST- 2014/03/03 00:00 [received]
PHST- 2014/07/15 00:00 [accepted]
PHST- 2014/08/06 06:00 [entrez]
PHST- 2014/08/06 06:00 [pubmed]
PHST- 2015/09/15 06:00 [medline]
AID - 10.1002/glia.22731 [doi]
PST - ppublish
SO  - Glia. 2015 Jan;63(1):37-50. doi: 10.1002/glia.22731. Epub 2014 Aug 4.