Deficiency of neuronal nitric oxide synthase (nNOS) worsens alcohol-induced microencephaly and neuronal loss in developing mice

Bonthius, Daniel J.; Tzouras, Georgios; Karaçay, Bahri; Mahoney, Jolonda C.; Hutton, Ana M.; McKim, Ross; Pantazis, Nicholas J.

doi:10.1016/s0165-3806(02)00458-3

Cited by 62 publications

(92 citation statements)

References 47 publications

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“…The enzyme that synthesizes NO within neurons is neuronal nitric oxide synthase (nNOS). We have shown previously that mice genetically deficient for nNOS (nNOS−/− mice) have an enhanced vulnerability to alcohol-induced microencephaly and neuronal loss, thus confirming an important role for NO in neuroprotection against alcohol in vivo (Bonthius et al, 2002;. Identification of the upstream signal regulating nNOS expression is critically important for understanding the cascade of events leading to NO-mediated neuroprotection against alcohol.…”

Section: Introductionmentioning

confidence: 88%

“…We have previously reported that genetic deficiency of nNOS worsens alcohol-induced microencephaly and neuronal loss both in vitro and in developing mice (Bonthius et al, 2002;Bonthius et al, 2006). This suggested that nNOS exerts a neuroprotective effect against alcohol toxicity.…”

Section: Transduction Of the Nnos Gene Via An Ad5-nnos Viral Vector Pmentioning

confidence: 96%

“…NO is neuroprotective against alcohol in vivo, as well. Developing mice that are genetically deficient for nNOS, and thus unable to produce NO within their neurons, have more severe alcohol-induced microencephaly and neuronal losses than do wild type mice (Bonthius et al, 2002;. Furthermore, cultured CGN from these nNOS null mice have an enhanced vulnerability to alcohol-induced cell death (Bonthius et al, 2002).…”

Section: The Nnos Gene Is a Downstream Target Of The Camp Pathway Andmentioning

confidence: 99%

“…Developing mice that are genetically deficient for nNOS, and thus unable to produce NO within their neurons, have more severe alcohol-induced microencephaly and neuronal losses than do wild type mice (Bonthius et al, 2002;. Furthermore, cultured CGN from these nNOS null mice have an enhanced vulnerability to alcohol-induced cell death (Bonthius et al, 2002). This enhanced vulnerability is abolished by treating the cultures with the NO generator, DETA-NONOate (unpublished observations), demonstrating that their increased susceptibility to alcohol is due to NO deficiency.…”

Section: The Nnos Gene Is a Downstream Target Of The Camp Pathway Andmentioning

confidence: 99%

“…Based on our previous observation that nNOS protects CGN cultures against alcohol-induced cell death (Bonthius et al, 2002) and that nNOS−/− mice have an enhanced vulnerability to alcohol-induced microencephaly and neuronal loss (Bonthius et al, 2002;Bonthius et al, 2006), we hypothesized that delivery of the nNOS gene into CGN derived from nNOS−/− mice could protect the neurons against alcohol toxicity. The results confirmed this hypothesis.…”

Section: Transduction Of the Nnos Gene Into Cultured Cgn With Ad5-nnomentioning

confidence: 99%

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Stimulation of the cAMP pathway protects cultured cerebellar granule neurons against alcohol-induced cell death by activating the neuronal nitric oxide synthase (nNOS) gene

Karaçay

Pantazis

et al. 2007

Brain Research

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Neuronal loss is a key component of fetal alcohol syndrome pathophysiology. Therefore, identification of molecules and signaling pathways that ameliorate alcohol-induced neuronal death is important. We have previously reported that neuronal nitric oxide synthase (nNOS) can protect developing cerebellar granule neurons (CGN) against alcohol-induced death both in vitro and in vivo. However, the upstream signal controlling nNOS expression in CGN is unknown. Activated cAMP response element binding protein (CREB) has been strongly linked to the survival of multiple cell types, including CGN. Furthermore, the promoter of the nNOS gene contains two cAMP response elements (CRE). Using cultures of CGN, we tested the hypothesis that cAMP mediates nNOS activation and the protective effect of nNOS against alcohol-induced cell death. Forskolin, an activator of the cAMP pathway, stimulated expression of a reporter gene under the control of the nNOS promoter, and this stimulation was substantially reduced when the two CREs were mutated. Forskolin increased nNOS mRNA levels several-fold, increased production of nitric oxide, and abolished alcohol's toxic effect in wild type CGN. Furthermore, forskolin's protective effect was substantially reduced in CGN cultures genetically deficient for nNOS (from nNOS−/− mice). Delivery of nNOS cDNA using a replication-deficient adenoviral vector into nNOS−/− CGN abolished alcohol-induced neuronal death. In addition, over-expression of nNOS in wild type CGN ameliorated alcohol-induced cell death. These results indicate that the neuroprotective effect of the cAMP pathway is mediated, in part, by the pathway's downstream target, the nNOS gene.

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Section: Introductionmentioning

confidence: 88%

Section: Transduction Of the Nnos Gene Via An Ad5-nnos Viral Vector Pmentioning

confidence: 96%

Section: The Nnos Gene Is a Downstream Target Of The Camp Pathway Andmentioning

confidence: 99%

Section: The Nnos Gene Is a Downstream Target Of The Camp Pathway Andmentioning

confidence: 99%

Section: Transduction Of the Nnos Gene Into Cultured Cgn With Ad5-nnomentioning

confidence: 99%

See 3 more Smart Citations

Stimulation of the cAMP pathway protects cultured cerebellar granule neurons against alcohol-induced cell death by activating the neuronal nitric oxide synthase (nNOS) gene

Karaçay

Pantazis

et al. 2007

Brain Research

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Oxidative stress and DNA damage in the mechanism of fetal alcohol spectrum disorders

Bhatia

Drake

Miller

et al. 2019

Birth Defects Research

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This review covers molecular mechanisms involving oxidative stress and DNA damage that may contribute to morphological and functional developmental disorders in animal models resulting from exposure to alcohol (ethanol, EtOH) in utero or in embryo culture. Components covered include: (a) a brief overview of EtOH metabolism and embryopathic mechanisms other than oxidative stress; (b) mechanisms within the embryo and fetal brain by which EtOH increases the formation of reactive oxygen species (ROS); (c) critical embryonic/fetal antioxidative enzymes and substrates that detoxify ROS; (d) mechanisms by which ROS can alter development, including ROS-mediated signal transduction and oxidative DNA damage, the latter of which leads to pathogenic genetic (mutations) and epigenetic changes; (e) pathways of DNA repair that mitigate the pathogenic effects of DNA damage; (f) related indirect mechanisms by which EtOH enhances risk, for example by enhancing the degradation of some DNA repair proteins; and, (g) embryonic/fetal pathways like NRF2 that regulate the levels of many of the above components. Particular attention is paid to studies in which chemical and/or genetic manipulation of the above mechanisms has been shown to alter the ability of EtOH to adversely affect development. Alterations in the above components are also discussed in terms of: (a) individual embryonic and fetal determinants of risk and (b) potential risk biomarkers and mitigating strategies. FASD risk is likely increased in progeny which/who are biochemically predisposed via genetic and/or environmental mechanisms, including enhanced pathways for ROS formation and/or deficient pathways for ROS detoxification or DNA repair.

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Animal models of gene–alcohol interactions

Lovely

2019

Birth Defects Research

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Most birth defects arise from complex interactions between multiple genetic and environmental factors. However, our current understanding of how these interactions and their contributions affect birth defects remains incomplete. Human studies are limited in their ability to identify the fundamental causes of birth defects due to ethical and practical limitations. Animal models provide a great number of resources not available to human studies and they have been critical in advancing our understanding of birth defects and the complex interactions that underlie them. In this review, we discuss the use of animal models in the context of gene–environment interactions that underlie birth defects. We focus on alcohol which is the most common environmental factor associated with birth defects. Prenatal alcohol exposure leads to a wide range of cognitive impairments and structural deficits broadly termed fetal alcohol spectrum disorders (FASD). We discuss the broad impact of prenatal alcohol exposure on the developing embryo and elaborate on the current state of gene–alcohol interactions. Additionally, we discuss how animal models have informed our understanding of the genetics of FASD. Ultimately, these topics will provide insight into the use of animal models in understanding gene–environment interactions and their subsequent impact on birth defects.

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Deficiency of neuronal nitric oxide synthase (nNOS) worsens alcohol-induced microencephaly and neuronal loss in developing mice

Cited by 62 publications

References 47 publications

Stimulation of the cAMP pathway protects cultured cerebellar granule neurons against alcohol-induced cell death by activating the neuronal nitric oxide synthase (nNOS) gene

Stimulation of the cAMP pathway protects cultured cerebellar granule neurons against alcohol-induced cell death by activating the neuronal nitric oxide synthase (nNOS) gene

Oxidative stress and DNA damage in the mechanism of fetal alcohol spectrum disorders

Animal models of gene–alcohol interactions

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