Glyceraldehyde-3-phosphate dehydrogenase-monoamine oxidase B-mediated cell death-induced by ethanol is prevented by rasagiline and 1-R-aminoindan.

Abstract

The inhibitors of monoamine oxidase B (MAO B) are effectively used as therapeutic drugs for neuropsychiatric and neurodegenerative diseases. However, their mechanism of action is not clear, since the neuroprotective effect of MAO B inhibitors is associated with the blockage of glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-death cascade, rather than the inhibition of MAO B. Here, we provide evidence that GAPDH potentiates the ethanol-induced activity of MAO B and brain cell toxicity. The levels of nuclear GAPDH and MAO B activity are significantly increased in brain-derived cell lines upon 75 mM ethanol-induced cell death. Over-expression of GAPDH in cells enhances ethanol-induced cell death, and also increases the ethanol-induced activation of MAO B. In contrast, the MAO B inhibitors rasagiline and selegiline (0.25 nM) and the rasagiline metabolite, 1-R-aminoindan (1 muM) decreases the ethanol-induced MAO B, prevents nuclear translocation of GAPDH and reduces cell death. In addition, GAPDH interacts with transforming growth factor-beta-inducible early gene (TIEG2), a transcriptional activator for MAO B, and this interaction is increased in the nucleus by ethanol but reduced by MAO B inhibitors and 1-R-aminoindan. Furthermore, silencing TIEG2 using RNAi significantly reduces GAPDH-induced MAO B upregulation and neurotoxicity. In summary, ethanol-induced cell death, attenuated by MAO B inhibitors, may result from disrupting the movement of GAPDH with the transcriptional activator into the nucleus and secondly inhibit MAO B gene expression. Thus, the neuroprotective effects of rasagiline or 1-R-aminoindan on ethanol-induced cell death mediated by a novel GAPDH-MAO B pathway may provide a new insight in the treatment of neurobiological diseases including alcohol-use disorders.

• Authors: Xiao-Ming Ou, Deyin Lu, Chandra Johnson, Kevin Chen, Moussa B H Youdim, Grazyna Rajkowska, Jean C Shih
• Journal: Neurotoxicity research (Neurotox Res) Vol. 16 Issue 2 Pg. 148-59 (Aug 2009) ISSN: 1476-3524 [Electronic] United States
• PMID: 19526291 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Cell Cycle Proteins
• Central Nervous System Depressants
• Enzyme Inhibitors
• Indans
• KLF11 protein, human
• Neuroprotective Agents
• RNA, Small Interfering
• Repressor Proteins
• aminoindanol
• rasagiline
• Ethanol
• Hydrogen Peroxide
• Glyceraldehyde-3-Phosphate Dehydrogenases
• Monoamine Oxidase

Topics

• Analysis of Variance
• Apoptosis Regulatory Proteins
• Cell Cycle Proteins (genetics)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Central Nervous System Depressants (pharmacology)
• Dose-Response Relationship, Drug
• Drug Interactions
• Enzyme Inhibitors (pharmacology)
• Ethanol (pharmacology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Glyceraldehyde-3-Phosphate Dehydrogenases (metabolism)
• Humans
• Hydrogen Peroxide (metabolism)
• Immunoprecipitation (methods)
• Indans (pharmacology)
• Monoamine Oxidase (genetics, metabolism)
• Neuroprotective Agents (pharmacology)
• Protein Transport (drug effects)
• RNA, Small Interfering (pharmacology)
• Repressor Proteins (genetics)