期刊
BIOLOGICAL PSYCHIATRY
卷 67, 期 9, 页码 855-863出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2009.10.032
关键词
Alcoholism; ethanol-induced brain cell dysfunction; glyceraldehyde-3-phosphate dehydrogenase; human brain tissues; monoamine oxidase B; rats fed with an ethanol diet
资金
- Public Health Service [P20 RR 017701, MH67996]
- National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award
- University of Mississippi Medical Center [MH-084018, MH-069853]
- Stanley
- Cure HD Initiative
- High Q
- National Institute of Mental Health [R37 MH39085, RO1 MH67968]
- National Institute on Alcohol Abuse and Alcoholism [R24 AA015512-02]
Background: Alcoholism is a major psychiatric condition at least partly associated with ethanol (EtOH)-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 might contribute to EtOH-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 EtOH. Expression of these proteins was also examined in the prefrontal cortex from human subjects with alcohol dependence and in rats fed with an EtOH diet. Coimmunoprecipitation, subcellular fractionation, and luciferase assay were used to address nuclear GAPDH-mediated MAO B activation. To test the effects of inactivation, RNA interference and pharmacological intervention were used, and cell damage was assessed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP Nick End Labeling (TUNEL) and hydrogen peroxide 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 EtOH. 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 might 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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