Ethanol Induces Cell Death and Cell Cycle Delay in Cultures of Pheochromocytoma PC12 Cells

Luo, Jia; West, John C; Cook, Robert T.; Pantazis, Nicholas J.

doi:10.1111/j.1530-0277.1999.tb04166.x

Cited by 41 publications

(14 citation statements)

References 87 publications

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“…Specifically, alcohol may arrest the cells in the G 1 phase of the cell cycle, preventing cells from entering S-phase (Morris et al, 2009b). Alcohol arresting cells in G 1 is consistent with alcohol's effect on the cell cycle in fetal neurogenesis (Li et al, 2001; Luo and Miller, 1998; Luo et al, 1999). Perhaps for neurogenesis, the adolescent brain is more similar to the developing brain than the adult; though much more work is needed to adequately address this question.…”

Section: Alcohol and Adult Neurogenesissupporting

confidence: 62%

Roles of neural stem cells and adult neurogenesis in adolescent alcohol use disorders

Nixon

Morris

Liput

et al. 2010

Alcohol

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This review discusses the contributions of a newly considered form of plasticity, the ongoing production of new neurons from neural stem cells, or adult neurogenesis, within the context of neuropathologies that occur with excessive alcohol intake in the adolescent. Neural stem cells and adult neurogenesis are now thought to contribute to the structural integrity of the hippocampus, a limbic system region involved in learning, memory, behavioral control, and mood. In adolescents with alcohol use disorders, the hippocampus appears to be particularly vulnerable to the neurodegenerative effects of alcohol, but the role of neural stem cells and adult neurogenesis in alcoholic neuropathology has only recently been considered. This review encompasses a brief overview of neural stem cells and the processes involved in adult neurogenesis, how neural stem cells are affected by alcohol, and possible differences in the neurogenic niche between adults and adolescents. Specifically, what is known about developmental differences in adult neurogenesis between the adult and adolescent is gleaned from the literature, as well as how alcohol affects this process differently between the age groups. And finally, this review suggests differences that may exist in the neurogenic niche between adults and adolescents and how these differences may contribute to the susceptibility of the adolescent hippocampus to damage. However, many more studies are needed to discern whether these developmental differences contribute to the vulnerability of the adolescent to developing an alcohol use disorder.

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Section: Alcohol and Adult Neurogenesissupporting

confidence: 62%

Roles of neural stem cells and adult neurogenesis in adolescent alcohol use disorders

Nixon

Morris

Liput

et al. 2010

Alcohol

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“…Ethanol exposure induces the death of certain types of cells under some circumstances (5,23,39,40). Our results indicate that the PKR/ eIF2␣ pathway plays a role in ethanol-mediated cell death.…”

Section: Discussionmentioning

confidence: 62%

Interaction between RAX and PKR Modulates the Effect of Ethanol on Protein Synthesis and Survival of Neurons

Chen

Bower

et al. 2006

Journal of Biological Chemistry

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Ethanol exposure inhibits protein synthesis and causes cell death in the developing central nervous system. The double-stranded RNA (dsRNA)-activated protein kinase (PKR), a serine/threonine protein kinase, plays an important role in translational regulation and cell survival. PKR has been well known for its anti-viral response. Upon activation by viral infection or dsRNA, PKR phosphorylates its substrate, the ␣-subunit of eukaryotic translation initiation factor-2 (eIF2␣) leading to inhibition of translation initiation. It has recently been shown that, in the absence of a virus or dsRNA, PKR can be activated by direct interactions with its protein activators, PACT, or its mouse homologue, RAX. We have demonstrated that exposure to ethanol increased the phosphorylation of PKR and eIF2␣ in the developing cerebellum. The effect of ethanol on PKR/eIF2␣ phosphorylation positively correlated to the expression of PACT/RAX in cultured neuronal cells. Using PKR inhibitors and PKR null mouse fibroblasts, we verified that ethanol-induced eIF2␣ phosphorylation was mediated by PKR. Overexpression of a wild-type RAX dramatically enhanced sensitivity to ethanol-induced PKR/eIF2␣ phosphorylation, as well as translational inhibition and cell death. In contrast, overexpression of a mutant (S18A) RAX inhibited ethanol-mediated PKR/eIF2␣ activation. Ethanol promoted PKR and RAX association in cells expressing wild-type RAX but not in cells expressing S18A RAX. S18A RAX functioned as a dominant negative protein and blocked ethanol-induced inhibition of protein synthesis and cell death. Our results suggest that the interactions between PKR and PACT/RAX modulate the effect of ethanol on protein synthesis and cell survival in the central nervous system. Fetal alcohol syndrome is the most common non-hereditary cause of mental retardation (1). Prenatal exposure to alcohol disrupts many events of neuronal development, including neurogenesis, migration, cell survival, protein synthesis, axonal growth, and synaptogenesis (2-5). Neuronal death is a prominent pathologic effect of fetal alcohol exposure. This loss of neurons may underlie many of the behavioral deficits observed in fetal alcohol syndrome. The vulnerability of neurons to alcohol neurotoxicity differs among brain regions and changes with developmental stages (6, 7). The causes for ethanol-induced neuronal loss remain incompletely elucidated, as are the cellular and molecular mechanisms underlying the spatiotemporal window of susceptibility.The double-stranded RNA (dsRNA) 2 -activated protein kinase (PKR) is a serine/threonine protein kinase ubiquitously expressed in mammalian cells (8,9). PKR is initially identified as an interferon-induced protein that is activated in virus-infected cells by dsRNA produced during the virus life cycle (10, 11). PKR consists of two functionally distinct domains, an N-terminal dsRNA binding regulatory domain and a C-terminal catalytic domain. PKR is activated by dsRNA (11); interaction with dsRNA causes PKR to form homodimers and to autophosphoryl...

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“…Reduced volume of brain tissue, increased brain damage accompanied by cognitive deficits, and low density of neuronal and glial cells have been reported in alcoholism (3–8). Ethanol also induces neuronal cell death and cell cycle delay in cell model systems in vitro (9, 10). Therefore, effective treatment against ethanol-induced cellular dysfunction and damage is eagerly awaited.…”

Section: Introductionmentioning

confidence: 99%

A Novel Role for Glyceraldehyde-3-Phosphate Dehydrogenase and Monoamine Oxidase B Cascade in Ethanol-Induced Cellular Damage

Stockmeier

Meltzer

et al. 2010

Biological Psychiatry

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Background Alcoholism is a major psychiatric condition at least partly associated with ethanol-induced cell damage. Although brain cell loss has been reported in subjects with alcoholism, the molecular mechanism is unclear. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and monoamine oxidase B (MAO B) reportedly play a role in cellular dysfunction under stressful conditions and may contribute to ethanol-induced cell damage. Methods Expression of GAPDH and MAO B protein was studied in human glioblastoma and neuroblastoma cell lines exposed to physiological concentrations of ethanol. Expression of these proteins was also examined in the prefrontal cortex from human subjects with alcohol dependence and in rats fed with an ethanol diet. Co-immunoprecipitation, subcellular fractionation, and luciferase assay were used to address nuclear GAPDH-mediated MAO B activation. To test the effects of inactivation, RNAi and pharmacological intervention were used, and cell damage was assessed by TUNEL and H2O2 measurements. Results Ethanol significantly increases levels of GAPDH, especially nuclear GAPDH, and MAO B in neuronal cells as well as in human and rat brains. Nuclear GAPDH interacts with the transcriptional activator, transforming growth factor-beta-inducible early gene 2 (TIEG2), and augments TIEG2-mediated MAO B transactivation, which results in cell damage in neuronal cells exposed to ethanol. Knockdown expression of GAPDH or treatment with MAO B inhibitors selegiline (Deprenyl) and rasagiline (Azilect) can block this cascade. Conclusions Ethanol-elicited nuclear GAPDH augments TIEG2-mediated MAO B, which may play a role in brain damage in subjects with alcoholism. Compounds that block this cascade are potential candidates for therapeutic strategies.

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Ethanol Induces Cell Death and Cell Cycle Delay in Cultures of Pheochromocytoma PC12 Cells

Cited by 41 publications

References 87 publications

Roles of neural stem cells and adult neurogenesis in adolescent alcohol use disorders

Roles of neural stem cells and adult neurogenesis in adolescent alcohol use disorders

Interaction between RAX and PKR Modulates the Effect of Ethanol on Protein Synthesis and Survival of Neurons

A Novel Role for Glyceraldehyde-3-Phosphate Dehydrogenase and Monoamine Oxidase B Cascade in Ethanol-Induced Cellular Damage

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