PMID- 18824032
OWN - NLM
STAT- MEDLINE
DCOM- 20090326
LR  - 20231213
IS  - 0161-813X (Print)
IS  - 0161-813X (Linking)
VI  - 29
IP  - 6
DP  - 2008 Nov
TI  - The protective effect of neuronal nitric oxide synthase (nNOS) against alcohol 
      toxicity depends upon the NO-cGMP-PKG pathway and NF-kappaB.
PG  - 1080-91
LID - 10.1016/j.neuro.2008.08.007 [doi]
AB  - Fetal alcohol syndrome (FAS) stems from maternal alcohol abuse during pregnancy 
      and is an important cause of mental retardation and hyperactivity in children. In 
      the developing brain, alcohol can kill neurons, leading to microencephaly. 
      However, due to their genetic makeup, some individuals are less vulnerable than 
      others to alcohol's neurotoxic effects. Animal studies have demonstrated that one 
      particular gene, neuronal nitric oxide synthase (nNOS), protects developing 
      neurons in vivo against alcohol-induced death. We utilized pharmacologic 
      techniques to demonstrate that nNOS protects neurons against alcohol toxicity by 
      activating the NO-cGMP-PKG signaling pathway. Cerebellar granule cell cultures 
      derived from mice carrying a null mutation for nNOS (nNOS-/- mice) were 
      substantially more vulnerable than cultures from wild-type mice to 
      alcohol-induced cell death. However, activation of the pathway at sites 
      downstream of nNOS protected the cultures against alcohol toxicity. Conversely, 
      blockade of the pathway rendered wild-type cultures vulnerable to alcohol-induced 
      death. We further identified NF-kappaB as the downstream effector through which 
      nNOS and the NO-cGMP-PKG pathway signal their neuroprotective effects. Tumor 
      necrosis factor-alpha (TNF-alpha), which activates NF-kappaB, ameliorated 
      alcohol-induced cell death in nNOS-/- and wild-type cultures, while an NF-kappaB 
      inhibitor (NFi) blocked the protective effects of TNF-alpha and worsened 
      alcohol-induced cell death. Furthermore, NFi blocked the protective effects of 
      NO-cGMP-PKG pathway activators, demonstrating that NF-kappaB is downstream of the 
      NO-cGMP-PKG pathway. As wild-type neurons matured in culture, they became 
      resistant to alcohol toxicity. However, this maturation-dependent alcohol 
      resistance did not occur in nNOS-/- mice and could be reversed in wild-type mice 
      with NFi, demonstrating that nitric oxide and NF-kappaB are crucial for the 
      development of alcohol resistance with age. Thus, nNOS protects developing 
      neurons against alcohol toxicity by activating the NO-cGMP-PKG-NF-kappaB pathway 
      and is crucial for the acquisition of maturation-dependent alcohol resistance.
FAU - Bonthius, Daniel J
AU  - Bonthius DJ
AD  - Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, IA, 
      USA. daniel-bonthius@uiowa.edu
FAU - Bonthius, Nancy E
AU  - Bonthius NE
FAU - Li, Shenglan
AU  - Li S
FAU - Karacay, Bahri
AU  - Karacay B
LA  - eng
GR  - K08 NS002007/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080909
PL  - Netherlands
TA  - Neurotoxicology
JT  - Neurotoxicology
JID - 7905589
RN  - 0 (Central Nervous System Depressants)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 3K9958V90M (Ethanol)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type I)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - H2D2X058MU (Cyclic GMP)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Animals, Newborn
MH  - Cell Death/drug effects
MH  - Cells, Cultured
MH  - Central Nervous System Depressants/*toxicity
MH  - Cerebellum/cytology
MH  - Cyclic GMP/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Drug Interactions
MH  - Enzyme Inhibitors/pharmacology
MH  - Ethanol/*toxicity
MH  - Mice
MH  - Mice, Knockout
MH  - Neurons/*drug effects
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase Type I/deficiency/*physiology
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Time Factors
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - NF-kappaB-Inducing Kinase
EDAT- 2008/10/01 09:00
MHDA- 2009/03/27 09:00
CRDT- 2008/10/01 09:00
PHST- 2008/04/07 00:00 [received]
PHST- 2008/08/26 00:00 [revised]
PHST- 2008/08/31 00:00 [accepted]
PHST- 2008/10/01 09:00 [pubmed]
PHST- 2009/03/27 09:00 [medline]
PHST- 2008/10/01 09:00 [entrez]
AID - S0161-813X(08)00148-4 [pii]
AID - 10.1016/j.neuro.2008.08.007 [doi]
PST - ppublish
SO  - Neurotoxicology. 2008 Nov;29(6):1080-91. doi: 10.1016/j.neuro.2008.08.007. Epub 
      2008 Sep 9.