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Ethanol neurotoxicity in the developing cerebellum: underlying mechanisms and implications.

Kumar A, LaVoie HA, DiPette DJ, Singh US - Brain Sci (2013)

Bottom Line: Ethanol's harmful effects include neuronal cell death, impaired differentiation, reduction of neuronal numbers, and weakening of neuronal plasticity.In combination, these ethanol effects disrupt cellular homeostasis, reduce the survival and migration of neurons, and lead to various developmental defects in the brain.Here we review the signaling mechanisms that are required for proper neuronal development, and how these processes are impaired by ethanol resulting in harmful consequences to brain development.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA. ambrish.kumar@uscmed.sc.edu.

ABSTRACT
Ethanol is the main constituent of alcoholic beverages that exerts toxicity to neuronal development. Ethanol affects synaptogenesis and prevents proper brain development. In humans, synaptogenesis takes place during the third trimester of pregnancy, and in rodents this period corresponds to the initial few weeks of postnatal development. In this period neuronal maturation and differentiation begin and neuronal cells start migrating to their ultimate destinations. Although the neuronal development of all areas of the brain is affected, the cerebellum and cerebellar neurons are more susceptible to the damaging effects of ethanol. Ethanol's harmful effects include neuronal cell death, impaired differentiation, reduction of neuronal numbers, and weakening of neuronal plasticity. Neuronal development requires many hormones and growth factors such as retinoic acid, nerve growth factors, and cytokines. These factors regulate development and differentiation of neurons by acting through various receptors and their signaling pathways. Ethanol exposure during development impairs neuronal signaling mechanisms mediated by the N-methyl-d-aspartate (NMDA) receptors, the retinoic acid receptors, and by growth factors such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-I), and basic fibroblast growth factor (bFGF). In combination, these ethanol effects disrupt cellular homeostasis, reduce the survival and migration of neurons, and lead to various developmental defects in the brain. Here we review the signaling mechanisms that are required for proper neuronal development, and how these processes are impaired by ethanol resulting in harmful consequences to brain development.

No MeSH data available.


Related in: MedlinePlus

In ethanol metabolism, the enzyme alcohol dehydrogenase oxidizes ethanol to acetaldehyde, while cytochrome P450-2E1 enzyme converts ethanol to acetaldehyde and H2O2. Acetaldehyde interacts with proteins and forms protein-acetaldehyde adducts (acetaldehyde-hemocyanin adduct). Hydrogen peroxide and acetaldehyde (via transcriptional activation of NADPH oxidase, xanthine oxidase, and iNOS) generate free radicals (reactive oxygen species, ROS/reactive nitrogen species, RNS), which oxidize proteins, lipids, and DNA leading to apoptotic cell death in the developing cerebellum.
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brainsci-03-00941-f002: In ethanol metabolism, the enzyme alcohol dehydrogenase oxidizes ethanol to acetaldehyde, while cytochrome P450-2E1 enzyme converts ethanol to acetaldehyde and H2O2. Acetaldehyde interacts with proteins and forms protein-acetaldehyde adducts (acetaldehyde-hemocyanin adduct). Hydrogen peroxide and acetaldehyde (via transcriptional activation of NADPH oxidase, xanthine oxidase, and iNOS) generate free radicals (reactive oxygen species, ROS/reactive nitrogen species, RNS), which oxidize proteins, lipids, and DNA leading to apoptotic cell death in the developing cerebellum.

Mentions: Under normal physiological conditions, a proper balance between free radicals (reactive oxygen species, ROS, and reactive nitrogen species, RNS) and the levels of antioxidants is required for cell survival. Increased generation of ROS/RNS (such as superoxide anion, hydroxyl radical, and peroxynitrite, etc.), and failure of antioxidative mechanisms (including superoxide dismutase, catalase, glutathione peroxidase, etc.) to remove excess ROS/RNS generates oxidative stress. Increased levels of free radicals damage DNA, oxidize cellular proteins and lipids, and disrupt the membrane permeability of mitochondria. Oxidative damage of mitochondria releases cytochrome C and activates caspase pathways, which lead to cell death. Various in vitro, as well as in vivo, data suggest that prenatal and postnatal ethanol induces elevated level of oxidative stress either by generation of free radicals (ROS/RNS) or disruption of antioxidative defense mechanisms and, thereby, promotes apoptotic cell death in the cerebellum of rodent brains [5,22,23,24,25,26,27,28,29]. Ethanol exposure to in vitro cultures of cortical neurons [26] and fetal rhombencephalic neurons [30] generates ROS and induces mitochondrial membrane depolarization and apoptosis (Figure 2). Pretreatment of cultured fetal cortical neurons with N-acetylcysteine inhibits ethanol-mediated reduction in cellular glutathione level and prevents cell death, indicating a role for oxidative stress in ethanol toxicity [26].


Ethanol neurotoxicity in the developing cerebellum: underlying mechanisms and implications.

Kumar A, LaVoie HA, DiPette DJ, Singh US - Brain Sci (2013)

In ethanol metabolism, the enzyme alcohol dehydrogenase oxidizes ethanol to acetaldehyde, while cytochrome P450-2E1 enzyme converts ethanol to acetaldehyde and H2O2. Acetaldehyde interacts with proteins and forms protein-acetaldehyde adducts (acetaldehyde-hemocyanin adduct). Hydrogen peroxide and acetaldehyde (via transcriptional activation of NADPH oxidase, xanthine oxidase, and iNOS) generate free radicals (reactive oxygen species, ROS/reactive nitrogen species, RNS), which oxidize proteins, lipids, and DNA leading to apoptotic cell death in the developing cerebellum.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061865&req=5

brainsci-03-00941-f002: In ethanol metabolism, the enzyme alcohol dehydrogenase oxidizes ethanol to acetaldehyde, while cytochrome P450-2E1 enzyme converts ethanol to acetaldehyde and H2O2. Acetaldehyde interacts with proteins and forms protein-acetaldehyde adducts (acetaldehyde-hemocyanin adduct). Hydrogen peroxide and acetaldehyde (via transcriptional activation of NADPH oxidase, xanthine oxidase, and iNOS) generate free radicals (reactive oxygen species, ROS/reactive nitrogen species, RNS), which oxidize proteins, lipids, and DNA leading to apoptotic cell death in the developing cerebellum.
Mentions: Under normal physiological conditions, a proper balance between free radicals (reactive oxygen species, ROS, and reactive nitrogen species, RNS) and the levels of antioxidants is required for cell survival. Increased generation of ROS/RNS (such as superoxide anion, hydroxyl radical, and peroxynitrite, etc.), and failure of antioxidative mechanisms (including superoxide dismutase, catalase, glutathione peroxidase, etc.) to remove excess ROS/RNS generates oxidative stress. Increased levels of free radicals damage DNA, oxidize cellular proteins and lipids, and disrupt the membrane permeability of mitochondria. Oxidative damage of mitochondria releases cytochrome C and activates caspase pathways, which lead to cell death. Various in vitro, as well as in vivo, data suggest that prenatal and postnatal ethanol induces elevated level of oxidative stress either by generation of free radicals (ROS/RNS) or disruption of antioxidative defense mechanisms and, thereby, promotes apoptotic cell death in the cerebellum of rodent brains [5,22,23,24,25,26,27,28,29]. Ethanol exposure to in vitro cultures of cortical neurons [26] and fetal rhombencephalic neurons [30] generates ROS and induces mitochondrial membrane depolarization and apoptosis (Figure 2). Pretreatment of cultured fetal cortical neurons with N-acetylcysteine inhibits ethanol-mediated reduction in cellular glutathione level and prevents cell death, indicating a role for oxidative stress in ethanol toxicity [26].

Bottom Line: Ethanol's harmful effects include neuronal cell death, impaired differentiation, reduction of neuronal numbers, and weakening of neuronal plasticity.In combination, these ethanol effects disrupt cellular homeostasis, reduce the survival and migration of neurons, and lead to various developmental defects in the brain.Here we review the signaling mechanisms that are required for proper neuronal development, and how these processes are impaired by ethanol resulting in harmful consequences to brain development.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA. ambrish.kumar@uscmed.sc.edu.

ABSTRACT
Ethanol is the main constituent of alcoholic beverages that exerts toxicity to neuronal development. Ethanol affects synaptogenesis and prevents proper brain development. In humans, synaptogenesis takes place during the third trimester of pregnancy, and in rodents this period corresponds to the initial few weeks of postnatal development. In this period neuronal maturation and differentiation begin and neuronal cells start migrating to their ultimate destinations. Although the neuronal development of all areas of the brain is affected, the cerebellum and cerebellar neurons are more susceptible to the damaging effects of ethanol. Ethanol's harmful effects include neuronal cell death, impaired differentiation, reduction of neuronal numbers, and weakening of neuronal plasticity. Neuronal development requires many hormones and growth factors such as retinoic acid, nerve growth factors, and cytokines. These factors regulate development and differentiation of neurons by acting through various receptors and their signaling pathways. Ethanol exposure during development impairs neuronal signaling mechanisms mediated by the N-methyl-d-aspartate (NMDA) receptors, the retinoic acid receptors, and by growth factors such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-I), and basic fibroblast growth factor (bFGF). In combination, these ethanol effects disrupt cellular homeostasis, reduce the survival and migration of neurons, and lead to various developmental defects in the brain. Here we review the signaling mechanisms that are required for proper neuronal development, and how these processes are impaired by ethanol resulting in harmful consequences to brain development.

No MeSH data available.


Related in: MedlinePlus