Overexpression of NGF ameliorates ethanol neurotoxicity in the developing cerebellum

Heaton, Marieta Barrow; Mitchell, J.Jean; Paiva, Michael

doi:10.1002/1097-4695(20001105)45:2<95::aid-neu4>3.0.co;2-y

Cited by 43 publications

(10 citation statements)

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“…The importance of these trophic substances and their potential to modulate ethanol toxicity are underscored not only by observations of NTF rescue of cultured cells from a number of CNS regions from ethanol-induced cell death, but also by investigations of ethanol effects in NTF gene-altered animals. In BDNF knockouts, for example, the developing cerebellum exhibits increased ethanol-mediated cell loss, while overproduction of the related NTF, nerve growth factor (NGF), in transgenic animals, appears to blunt cell death in this region during early periods of maximal ethanol susceptibility (Heaton et al, 2000b). Basal levels of BDNF tend to be at appreciably higher during period of ethanol resistance in the early CNS, relative to earlier, ethanol sensitive periods (e.g., Heaton et al, 2003a; b).…”

Section: Discussionmentioning

confidence: 99%

“…In agreement with this hypothesis, a number of studies have found that supplementation of ethanol-treated cultured neurons with a range of NTFs, particularly those of the neurotrophin gene family, mitigate ethanol neurotoxicity (e.g., NGF, Brodie et al, 1991; Luo et al, 1997; BDNF, Mitchell et al, 1999c; Bhave et al, 1999]). Also, reductions in the availability of certain NTFs during CNS development (e.g., in BDNF gene-deleted animals) exacerbate ethanol toxicity in certain regions (e.g., cerebellum), while increased availability (via NGF transgenic overexpression) serves a protective function (Heaton et al, 2000b; 2002b). There are important interactions between NTFs and both apoptosis-related substances and oxidative processes, which may act to at least partially counter the deleterious effects of ethanol: Both NGF and BDNF, for example, have been shown to up-regulate expression of anti-apoptotic proteins, while suppressing expression or activation of pro-apoptotic molecules (e.g., Katoh et al, 1996; Muller et al, 1997; Aloyz et al, 1998; Liu et al, 1999; Rong et al, 1999]; Perez-Navarro et al, 2005]).…”

Section: Introductionmentioning

confidence: 99%

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Ethanol Influences on Bax Translocation, Mitochondrial Membrane Potential, and Reactive Oxygen Species Generation Are Modulated by Vitamin E and Brain‐Derived Neurotrophic Factor

Heaton

Paiva

Siler-Marsiglio

2011

Alcoholism Clin & Exp Res

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Background-This study investigated ethanol influences on intracellular events which predispose developing neurons toward apoptosis, and the capacity of the antioxidant α-tocopherol (vitamin E) and the neurotrophin brain-derived neurotrophic factor (BDNF) to modulate these effects. Assessments were made of the following: (1) ethanol-induced translocation of the proapoptotic Bax protein to the mitochondrial membrane, a key upstream event in the initiation of apoptotic cell death; (2) disruption of the mitochondrial membrane potential (MMP) as a result of ethanol exposure, an important process in triggering the apoptotic cascade; and (3) generation of damaging reactive oxygen species (ROS) as a function of ethanol exposure.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ethanol Influences on Bax Translocation, Mitochondrial Membrane Potential, and Reactive Oxygen Species Generation Are Modulated by Vitamin E and Brain‐Derived Neurotrophic Factor

Heaton

Paiva

Siler-Marsiglio

2011

Alcoholism Clin & Exp Res

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“…Ethanol-induced cell loss has been shown to be caused by apoptotic cell death due to ethanol toxicity (Ikonomidou et al, 2000; Tenkova et al, 2003). Exposure to alcohol during development may also alter neurotrophin levels and/or function (Climent et al, 2002; Heaton et al, 1999: 2000(a); 2000(b); Parks, et al, 2008), and change expression of neurotropic receptors (Dohrman et al, 1997; Light et al, 2002). Neurotrophins and their receptors are important for the survival and differentiation of neurons in the chick retina (Frade et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Effects of Early Postnatal Exposure to Ethanol on Retinal Ganglion Cell Morphology and Numbers of Neurons in the Dorsolateral Geniculate in Mice

Dursun

Jakubowska-Doğru

List

et al. 2011

Alcoholism: Clinical and Experimental Research

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Background The adverse effects of fetal and early postnatal ethanol intoxication on peripheral organs and the central nervous system are well documented. Ocular defects have also been reported in about 90% of children with Fetal Alcohol Syndrome (FAS), including microphthalmia, loss of neurons in the retinal ganglion cell layer (GCL), optic nerve hypoplasia and dysmyelination. However, little is known about perinatal ethanol effects on retinal cell morphology. Examination of the potential toxic effects of alcohol on the neuron architecture is important since the changes in dendritic geometry and synapse distribution directly affect the organization and functions of neural circuits. Thus, in the present study estimations of the numbers of neurons in the GCL and dorsolateral geniculate nucleus (dLGN), and a detailed analysis of RGC morphology were carried out in transgenic mice exposed to ethanol during the early postnatal period. Methods The study was carried out in male and female transgenic mice expressing Yellow Fluorescent Protein (YFP) controlled by a Thy-1 (thymus cell antigen 1) regulator on a C57 background. Ethanol (3 g/kg/day) was administered to mouse pups by intragastric intubation throughout postnatal days (PD) 3–20. Intubation control (IC) and untreated control (C) groups were included. Blood alcohol concentration (BAC) was measured in separate groups of pups on PD3, PD10, and PD20 at 4 different time points, 1, 1.5, 2 and 3 h after the second intubation. Numbers of neurons in the GCL and in the dLGN were quantified on PD20 using unbiased stereological procedures. Retinal ganglion cell morphology was imaged by confocal microscopy and analyzed using Neurolucida software. Results Binge-like ethanol exposure in mice during the early postnatal period from PD3 through PD20 altered RGC morphology and resulted in a significant decrease in the numbers of neurons in the GCL and in the dLGN. In the alcohol exposure group, out of 13 morphological parameters examined in RGCs, soma area was significantly reduced and dendritic tortuosity significantly increased. After neonatal exposure to ethanol a decrease in total dendritic field area and an increase in the mean branch angle were also observed. Interestingly, RGC dendrite elongation and a decrease in the spine density were observed in the IC group, as compared to both ethanol-exposed and pure control subjects. There were no significant effects of alcohol exposure on total retinal area. Conclusion Early postnatal ethanol exposure affects development of the visual system, reducing the numbers of neurons in the GCL and in the dLGN, and altering RGCs’ morphology.

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“…A number of potential therapeutics have been identified, primarily based on putative mechanisms of alcohol-induced teratogenesis, including neurotrophic agents [9,18,30,31,46], neuroactive peptides [10,82,91,92,99], antioxidants [11,14,29,44,55] and NMDA receptor antagonists [75,76]. The present study examines whether choline supplementation would be effective when administered during prenatal alcohol exposure.…”

Section: Introductionmentioning

confidence: 99%

Prenatal choline supplementation mitigates the adverse effects of prenatal alcohol exposure on development in rats

Thomas

Abou

Dominguez

2009

Neurotoxicology and Teratology

162

138

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Prenatal alcohol exposure can lead to a range of physical, neurological, and behavioral alterations referred to as fetal alcohol spectrum disorders (FASD). Variability in outcome observed among children with FASD is likely related to various pre-and postnatal factors, including nutritional variables. Choline is an essential nutrient that influences brain and behavioral development. Recent animal research indicates that prenatal choline supplementation leads to long-lasting cognitive enhancement, as well as changes in brain morphology, electrophysiology and neurochemistry. The present study examined whether choline supplementation during ethanol exposure effectively reduces fetal alcohol effects. Pregnant dams were exposed to 6.0 g/kg/day ethanol via intubation from gestational day (GD) 5-20; pair-fed and lab chow controls were included. During treatment, subjects from each group received choline chloride (250 mg/kg/day) or vehicle. Physical development and behavioral development (righting reflex, geotactic reflex, cliff avoidance, reflex suspension and hindlimb coordination) were examined. Subjects prenatally exposed to alcohol exhibited reduced birth weight and brain weight, delays in eye opening and incisor emergence, and alterations in the development of all behaviors. Choline supplementation significantly attenuated ethanol's effects on birth and brain weight, incisor emergence, and most behavioral measures. In fact, behavioral performance of ethanol-exposed subjects treated with choline did not differ from that of controls. Importantly, choline supplementation did not influence peak blood alcohol level or metabolism, indicating that choline's effects were not due to differential alcohol exposure. These data indicate early dietary supplements may reduce the severity of some fetal alcohol effects, findings with important implications for children of women who drink alcohol during pregnancy.

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Overexpression of NGF ameliorates ethanol neurotoxicity in the developing cerebellum

Cited by 43 publications

References 58 publications

Ethanol Influences on Bax Translocation, Mitochondrial Membrane Potential, and Reactive Oxygen Species Generation Are Modulated by Vitamin E and Brain‐Derived Neurotrophic Factor

Ethanol Influences on Bax Translocation, Mitochondrial Membrane Potential, and Reactive Oxygen Species Generation Are Modulated by Vitamin E and Brain‐Derived Neurotrophic Factor

Effects of Early Postnatal Exposure to Ethanol on Retinal Ganglion Cell Morphology and Numbers of Neurons in the Dorsolateral Geniculate in Mice

Prenatal choline supplementation mitigates the adverse effects of prenatal alcohol exposure on development in rats

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