Journal article
Deficiency of neuronal nitric oxide synthase (nNOS) worsens alcohol-induced microencephaly and neuronal loss in developing mice
Brain research. Developmental brain research, Vol.138(1), pp.45-59
2002
DOI: 10.1016/S0165-3806(02)00458-3
PMID: 12234657
Abstract
Previous work conducted in vitro suggests that nitric oxide (NO) protects developing neurons against the toxic effects of alcohol. We tested the hypothesis that neonatal mice carrying a null mutation for neuronal nitric oxide synthase (nNOS), the enzyme which synthesizes NO in neurons, have increased vulnerability to alcohol-induced microencephaly and neuronal loss. Wild-type mice and mutant (nNOS
−/−) mice received a single intraperitoneal injection of ethanol (0.0, 2.2, 3.3, or 4.4 g/kg) daily over postnatal days (PD) 4–9 and were sacrificed on PD10. Peak blood alcohol concentrations were approximately 170, 280, and 385 mg/dl for the 2.2, 3.3 and 4.4 g/kg/day treatment groups, respectively, and did not differ significantly between wild-type and nNOS
−/− strains. Exposure to alcohol induced dose-dependent reductions in total brain weight, forebrain weight and cerebellum weight in both strains of mice. However, the reductions in brain weight were significantly more severe in the nNOS
−/− mice than in wild type. Quantification of cerebellar neurons revealed that alcohol-induced losses of Purkinje cells and granule cells were both significantly greater in the nNOS
−/− mice than in wild type. The increased vulnerability of nNOS-deficient neurons to alcohol-induced cell death was confirmed in vitro. Cerebellar granule cell cultures derived from nNOS
−/− and wild-type mice were exposed for 24 h to 0, 100, 200 or 400 mg/dl ethanol. At each alcohol concentration, the nNOS
−/− neurons had a significantly greater cell loss than did the wild-type neurons. The results demonstrate that deficiency of nNOS decreases the ability of developing neurons to survive the toxic effects of alcohol. Because NO upregulates intracellular cGMP, which can activate cGMP-dependent protein kinase (PKG), we hypothesize that the NO–cGMP–PKG pathway has a neuroprotective role against alcohol toxicity within the developing brain.
Details
- Title: Subtitle
- Deficiency of neuronal nitric oxide synthase (nNOS) worsens alcohol-induced microencephaly and neuronal loss in developing mice
- Creators
- Daniel J Bonthius - Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA 52242, USAGeorgios Tzouras - Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA 52242, USABahri Karacay - Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA 52242, USAJolonda Mahoney - Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA 52242, USAAna Hutton - Neuroscience Program, University of Iowa College of Medicine, Iowa City, IA 52242, USARoss McKim - Neuroscience Program, University of Iowa College of Medicine, Iowa City, IA 52242, USANicholas J Pantazis - Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Brain research. Developmental brain research, Vol.138(1), pp.45-59
- Publisher
- Elsevier B.V
- DOI
- 10.1016/S0165-3806(02)00458-3
- PMID
- 12234657
- ISSN
- 0165-3806
- Language
- English
- Date published
- 2002
- Academic Unit
- Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984065737202771
Metrics
17 Record Views