| Calcium-stimulated adenylyl cyclases modulate ethanol-induced neurodegeneration in the neonatal brain. | |
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MedLine Citation:
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PMID: 15745964 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Fetal alcohol exposure results in cognitive and neurobehavioral deficits, but the effects of modifying genetic loci on the severity of these sequelas have not been well characterized. Although the cAMP signaling pathway has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in modulating ethanol-induced neurodegeneration has not been examined. Adenylyl cyclases (ACs) 1 and 8 produce cAMP in response to intracellular calcium elevation and modulate several aspects of neuronal function, including ethanol sensitivity. AC1 and AC8 are expressed widely throughout the brain of neonatal mice, and genetic deletion of both AC1 and AC8 in double-knock-out (DKO) mice enhances ethanol-induced neurodegeneration in the brains of neonatal mice. In addition, ethanol treatment induces significantly greater levels of caspase-3 activation in the brains of DKO mice compared with wild-type (WT) mice, reflecting higher numbers of apoptotic neurons. Administration of the NMDA receptor antagonist MK801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine hydrogen maleate] or the GABA(A) receptor potentiator phenobarbital, which mimics components of the effects of ethanol on neurons, results in significantly greater neurodegeneration in the brains of neonatal DKO mice than WT mice. Furthermore, loss of a single calcium-stimulated AC isoform potentiates neurodegeneration after administration of ethanol, MK801, or phenobarbital. In contrast, the levels of physiological cell death, death after hypoxia/ischemia, and excitotoxic cell death are not increased in the brains of DKO mice. Thus, AC1 and AC8 are critical modulators of neurodegeneration induced by activity blockade in the neonatal brain and represent genetic loci that may potentially modify the severity of fetal alcohol syndrome. |
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Authors:
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James W Maas; Ricardo A Indacochea; Lisa M Muglia; Timothy T Tran; Sherri K Vogt; Tim West; Ann Benz; Amanda A Shute; David M Holtzman; Steven Mennerick; John W Olney; Louis J Muglia |
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Publication Detail:
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Type: Comparative Study; In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of neuroscience : the official journal of the Society for Neuroscience Volume: 25 ISSN: 1529-2401 ISO Abbreviation: J. Neurosci. Publication Date: 2005 Mar |
Date Detail:
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Created Date: 2005-03-04 Completed Date: 2006-03-31 Revised Date: 2009-09-03 |
Medline Journal Info:
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Nlm Unique ID: 8102140 Medline TA: J Neurosci Country: United States |
Other Details:
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Languages: eng Pagination: 2376-85 Citation Subset: IM |
Affiliation:
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Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenylate Cyclase
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metabolism* Anilides / metabolism Animals Animals, Newborn Anoxia / metabolism, pathology Behavior, Animal Blotting, Western / methods Brain / drug effects*, growth & development, pathology Calcium / pharmacology* Caspase 3 Caspases / metabolism Dizocilpine Maleate / pharmacology Dose-Response Relationship, Drug Drug Interactions Ethanol* / blood GABA Modulators / pharmacology Hippocampus / drug effects, metabolism, pathology, physiopathology In Situ Hybridization / methods Mice Mice, Inbred C57BL Neurodegenerative Diseases / chemically induced*, drug therapy, metabolism, pathology Neurons / metabolism, physiology Neuroprotective Agents / pharmacology Oligopeptides / metabolism Phenobarbital / pharmacology Silver Staining / methods Time Factors |
| Grant Support | |
ID/Acronym/Agency:
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AA12952/AA/NIAAA NIH HHS; AA12957/AA/NIAAA NIH HHS; AG18876/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anilides; 0/GABA Modulators; 0/Neuroprotective Agents; 0/Oligopeptides; 0/aspartyl-glutamyl-valyl-aspartyl-p-nitroanilide; 50-06-6/Phenobarbital; 64-17-5/Ethanol; 7440-70-2/Calcium; 77086-22-7/Dizocilpine Maleate; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases; EC 4.6.1.1/Adenylate Cyclase; EC 4.6.1.1/adenylyl cyclase 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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