Nitric oxide utilizes NF-kappaB to signal its neuroprotective effect against alcohol toxicity.
Alcohol damages the developing brain and can lead to fetal alcohol syndrome. One of alcohol's most important neuropathologic effects is neuronal death. As neurons mature, they become less vulnerable to alcohol-induced death because they acquire a protective signaling pathway, mediated by nitric oxide (NO). This pathway is the NO-cGMP-cyclic GMP-dependent protein kinase G (NO-cGMP-PKG) pathway. The goal of the present studies was to determine whether nuclear factor kappa B (NF-kappaB) is the downstream effector through which the NO-cGMP-PKG pathway signals its neuroprotective effects against alcohol. An activator of NF-kappaB, tumor necrosis factor-alpha (TNF-alpha), protected immature cerebellar granule neuron cultures against alcohol-induced cell death in a dose-dependent fashion. The protective effect of TNF-alpha was similar in magnitude to the protective effects of NMDA and DETA-NONOate, both of which are NO-cGMP-PKG pathway activators. Blockade of the pathway at its first step with NAME, second step with LY83583, or third step with PKG inhibitor increased alcohol-induced cell death and the vulnerability of mature neurons to alcohol toxicity. TNF-alpha protected the neurons, even when the NO-cGMP-PKG pathway was blocked at upstream sites. NF-kappaB activation inhibitor (NFi) worsened alcohol-induced cell death and blocked the protective effects of NO-cGMP-PKG pathway activators and TNF-alpha. TNF-alpha reduced the alcohol vulnerability of immature neurons, while NFi increased the vulnerability of mature neurons. Both NMDA and TNF-alpha led to the phosphorylation and degradation of IkappaBalpha, demonstrating that both agents can activate NF-kappaB in cerebellar granule cells. Thus, NF-kappaB plays a critical role in the acquisition of alcohol resistance by maturing neurons and is a key downstream effector through which the NO-cGMP-PKG pathway signals its neuroprotective effects against alcohol.
Bonthius
Daniel J
DJ
Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, IA 52242, USA. daniel-bonthius@uiowa.edu
Luong
Thirath
T
Bonthius
Nancy E
NE
Hostager
Bruce S
BS
Karacay
Bahri
B
D000818:Animals; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002531:Cerebellum / Q000503:physiopathology; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D011506:Proteins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000431:Ethanol; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C454819:Nfkbid protein, mouse