Skip to main content
Log in

Glyceraldehyde-3-Phosphate Dehydrogenase–Monoamine Oxidase B-Mediated Cell Death-Induced by Ethanol is Prevented by Rasagiline and 1-R-Aminoindan

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

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 μM) 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

MAO:

Monoamine oxidase

Co-IP:

Co-immunoprecipitation assay

TIEG2:

Transforming growth factor-beta-inducible early gene 2

MTT:

3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide

siRNA:

Small interfering RNA

PBS:

Phosphate buffered saline

DTT:

Dithiothreitol

EDTA:

Ethylenediaminetetraacetic acid disodium salt dehydrate

References

  • Adickes ED, Mollner TJ, Lockwood SK (1988) Closed chamber system for delivery of ethanol to cell cultures. Alcohol Alcohol 23:377–381

    PubMed  CAS  Google Scholar 

  • Alexander-Kaufman K, James G, Sheedy D, Harper C, Matsumoto I (2006) Differential protein expression in the prefrontal white matter of human alcoholics: a proteomics study. Mol Psychiatry 11:56–65

    Article  PubMed  CAS  Google Scholar 

  • Ansari KS, Yu PH, Kruck TP, Tatton WG (1993) Rescue of axotomized immature rat facial motoneurons by R(-)-deprenyl: stereospecificity and independence from monoamine oxidase inhibition. J Neurosci 13:4042–4053

    PubMed  CAS  Google Scholar 

  • Bae BI, Hara MR, Cascio MB, Wellington CL, Hayden MR, Ross CA, Ha HC, Li XJ, Snyder SH, Sawa A (2006) Mutant huntingtin: nuclear translocation and cytotoxicity mediated by GAPDH. Proc Natl Acad Sci U S A 103:3405–3409

    Article  PubMed  CAS  Google Scholar 

  • Bar-Am O, Amit T, Youdim MB (2007) Aminoindan and hydroxyaminoindan, metabolites of rasagiline and ladostigil, respectively, exert neuroprotective properties in vitro. J Neurochem 103:500–508

    Article  PubMed  CAS  Google Scholar 

  • Blandini F (2005) Neuroprotection by rasagiline: a new therapeutic approach to Parkinson’s disease? CNS Drug Rev 11:183–194

    PubMed  CAS  Google Scholar 

  • Blandini F, Armentero MT, Fancellu R, Blaugrund E, Nappi G (2004) Neuroprotective effect of rasagiline in a rodent model of Parkinson’s disease. Exp Neurol 187:455–459

    Article  PubMed  CAS  Google Scholar 

  • Carlile GW, Chalmers-Redman RM, Tatton NA, Pong A, Borden KE, Tatton WG (2000) Reduced apoptosis after nerve growth factor and serum withdrawal: conversion of tetrameric glyceraldehyde-3-phosphate dehydrogenase to a dimer. Mol Pharmacol 57:2–12

    PubMed  CAS  Google Scholar 

  • Carlsson A, Adolfsson R, Aquilonius SM, Gottfries CG, Oreland L, Svennerholm L, Winblad B (1980) Biogenic amines in human brain in normal aging, senile dementia, and chronic alcoholism. Adv Biochem Psychopharmacol 23:295–304

    PubMed  CAS  Google Scholar 

  • Checkoway H, Powers K, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD (2002) Parkinson’s disease risks associated with cigarette smoking, alcohol consumption, and caffeine intake. Am J Epidemiol 155:732–738

    Article  PubMed  Google Scholar 

  • Chuang DM, Hough C, Senatorov VV (2005) Glyceraldehyde-3-phosphate dehydrogenase, apoptosis, and neurodegenerative diseases. Annu Rev Pharmacol Toxicol 45:269–290

    Article  PubMed  CAS  Google Scholar 

  • Cook T, Urrutia R (2000) TIEG proteins join the Smads as TGF-beta-regulated transcription factors that control pancreatic cell growth. Am J Physiol Gastrointest Liver Physiol 278:G513–G521

    PubMed  CAS  Google Scholar 

  • Ekblom J, Zhu QS, Chen K, Shih JC (1996) Monoamine oxidase gene transcription in human cell lines: treatment with psychoactive drugs and ethanol. J Neural Transm 103:681–692

    Article  PubMed  CAS  Google Scholar 

  • Fang C, Lindros KO, Badger TM, Ronis MJ, Ingelman-Sundberg M (1998) Zonated expression of cytokines in rat liver: effect of chronic ethanol and the cytochrome P450 2E1 inhibitor, chlormethiazole. Hepatology 27:1304–1310

    Article  PubMed  CAS  Google Scholar 

  • Fernandez HH, Chen JJ (2007) Monamine oxidase inhibitors: current and emerging agents for Parkinson disease. Clin Neuropharmacol 30:150–168

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Zapico ME, Mladek A, Ellenrieder V, Folch-Puy E, Miller L, Urrutia R (2003) An mSin3A interaction domain links the transcriptional activity of KLF11 with its role in growth regulation. EMBO J 22:4748–4758

    Article  PubMed  CAS  Google Scholar 

  • Geha RM, Rebrin I, Chen K, Shih JC (2001) Substrate and inhibitor specificities for human monoamine oxidase A and B are influenced by a single amino acid. J Biol Chem 276:9877–9882

    Article  PubMed  CAS  Google Scholar 

  • Gerlach M, Double KL, Youdim MB, Riederer P (2006) Potential sources of increased iron in the substantia nigra of parkinsonian patients. J Neural Transm Suppl (70):133–142

  • Goodnick PJ (2007) Seligiline transdermal system in depression. Expert Opin Pharmacother 8:59–64

    Article  PubMed  CAS  Google Scholar 

  • Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y, Takahashi M, Cheah JH, Tankou SK, Hester LD, Ferris CD, Hayward SD, Snyder SH, Sawa A (2005) S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol 7:665–674

    Article  PubMed  CAS  Google Scholar 

  • Hara MR, Thomas B, Cascio MB, Bae BI, Hester LD, Dawson VL, Dawson TM, Sawa A, Snyder SH (2006) Neuroprotection by pharmacologic blockade of the GAPDH death cascade. Proc Natl Acad Sci U S A 103:3887–3889

    Article  PubMed  CAS  Google Scholar 

  • Henriksen JH, Gronbaek M, Moller S, Bendtsen F, Becker U (1997) Carbohydrate deficient transferrin (CDT) in alcoholic cirrhosis: a kinetic study. J Hepatol 26:287–292

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Nowotny P, Holmans P, Smemo S, Kauwe JS, Hinrichs AL, Tacey K, Doil L, van Luchene R, Garcia V, Rowland C, Schrodi S, Leong D, Gogic G, Chan J, Cravchik A, Ross D, Lau K, Kwok S, Chang SY, Catanese J, Sninsky J, White TJ, Hardy J, Powell J, Lovestone S, Morris JC, Thal L, Owen M, Williams J, Goate A, Grupe A (2004) Association of late-onset Alzheimer’s disease with genetic variation in multiple members of the GAPD gene family. Proc Natl Acad Sci U S A 101:15688–15693

    Article  PubMed  CAS  Google Scholar 

  • Liu H, Baliga M, Bigler SA, Baliga R (2003) Role of cytochrome P450 2B1 in puromycin aminonucleoside-induced cytotoxicity to glomerular epithelial cells. Nephron Exp Nephrol 94:e17–e24

    Article  PubMed  CAS  Google Scholar 

  • Lu D, Johnson C, Johnson S, Tazik S, Ou XM (2008) The neuroprotective effect of antidepressant drug via inhibition of TIEG2-MAO B mediated cell death. Drug Discov Ther 2:289–295

    PubMed  Google Scholar 

  • Luo J, Miller MW (1996) Ethanol inhibits basic fibroblast growth factor-mediated proliferation of C6 astrocytoma cells. J Neurochem 67:1448–1456

    PubMed  CAS  Google Scholar 

  • Luo J, Miller MW (1997) Differential sensitivity of human neuroblastoma cell lines to ethanol: correlations with their proliferative responses to mitogenic growth factors and expression of growth factor receptors. Alcohol Clin Exp Res 21:1186–1194

    PubMed  CAS  Google Scholar 

  • Maruyama W, Akao Y, Youdim MB, Davis BA, Naoi M (2001) Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. J Neurochem 78:727–735

    Article  PubMed  CAS  Google Scholar 

  • Ou XM, Partoens PM, Wang JM, Walker JH, Danks K, Vaughan PF, De Potter WP (1998) The storage of noradrenaline, neuropeptide Y and chromogranins in and stoichiometric release from large dense cored vesicles of the undifferentiated human neuroblastoma cell line SH-SY5Y. Int J Mol Med 1:105–112

    PubMed  CAS  Google Scholar 

  • Ou XM, Chen K, Shih JC (2004) Dual functions of transcription factors, transforming growth factor-beta-inducible early gene (TIEG)2 and Sp3, are mediated by CACCC element and Sp1 sites of human monoamine oxidase (MAO) B gene. J Biol Chem 279:21021–21028

    Article  PubMed  CAS  Google Scholar 

  • Ou XM, Chen K, Shih JC (2006a) Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway. Proc Natl Acad Sci U S A 103:10923–10928

    Article  PubMed  CAS  Google Scholar 

  • Ou XM, Chen K, Shih JC (2006b) Glucocorticoid and androgen activation of monoamine oxidase A are regulated differently by R1 and SP1. J Biol Chem 29:54

    Google Scholar 

  • Pantazis NJ, Dohrman DP, Luo J, Goodlett CR, West JR (1992) Alcohol reduces the number of pheochromocytoma (PC12) cells in culture. Alcohol 9:171–180

    Article  PubMed  CAS  Google Scholar 

  • Paterson IA, Barber AJ, Gelowitz DL, Voll C (1997) (-)Deprenyl reduces delayed neuronal death of hippocampal pyramidal cells. Neurosci Biobehav Rev 21:181–186

    Article  PubMed  CAS  Google Scholar 

  • Robinson DS, Amsterdam JD (2008) The selegiline transdermal system in major depressive disorder: a systematic review of safety and tolerability. J Affect Disord 105:15–23

    Article  PubMed  CAS  Google Scholar 

  • Senatorov VV, Charles V, Reddy PH, Tagle DA, Chuang DM (2003) Overexpression and nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase in a transgenic mouse model of Huntington’s disease. Mol Cell Neurosci 22:285–297

    Article  PubMed  CAS  Google Scholar 

  • Shih JC, Chen K, Ridd MJ (1999) Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 22:197–217

    Article  PubMed  CAS  Google Scholar 

  • Speiser Z, Levy R, Cohen S (1998) Effects of N-propargyl-1-(R)aminoindan (rasagiline) in models of motor and cognition disorders. J Neural Transm Suppl 52:287–300

    PubMed  CAS  Google Scholar 

  • Tariot PN, Cohen RM, Sunderland T, Newhouse PA, Yount D, Mellow AM, Weingartner H, Mueller EA, Murphy DL (1987) L-deprenyl in Alzheimer’s disease. Preliminary evidence for behavioral change with monoamine oxidase B inhibition. Arch Gen Psychiatry 44:427–433

    PubMed  CAS  Google Scholar 

  • Tatton WG, Ju WY, Holland DP, Tai C, Kwan M (1994) (-)-Deprenyl reduces PC12 cell apoptosis by inducing new protein synthesis. J Neurochem 63:1572–1575

    PubMed  CAS  Google Scholar 

  • Tatton WG, Chalmers-Redman RM, Elstner M, Leesch W, Jagodzinski FB, Stupak DP, Sugrue MM, Tatton NA (2000) Glyceraldehyde-3-phosphate dehydrogenase in neurodegeneration and apoptosis signaling. J Neural Transm Suppl 7:7–100

    Google Scholar 

  • Tatton W, Chalmers-Redman R, Tatton N (2003) Neuroprotection by deprenyl and other propargylamines: glyceraldehyde-3-phosphate dehydrogenase rather than monoamine oxidase B. J Neural Transm 110:509–515

    Article  PubMed  CAS  Google Scholar 

  • Wang CL, Wan YL, Liu YC, Huang ZQ (2006) TGF-beta1/SMAD signaling pathway mediates p53-dependent apoptosis in hepatoma cell lines. Chin Med Sci J 21:33–35

    PubMed  Google Scholar 

  • Wong WK, Chen K, Shih JC (2001) Regulation of human monoamine oxidase B gene by Sp1 and Sp3. Mol Pharmacol 59:852–859

    PubMed  CAS  Google Scholar 

  • Yao Z, Zhang J, Dai J, Keller ET (2001) Ethanol activates NFkappaB DNA binding and p56lck protein tyrosine kinase in human osteoblast-like cells. Bone 28:167–173

    Article  PubMed  CAS  Google Scholar 

  • Youdim MB (2006) The path from anti Parkinson drug selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and m30. Curr Alzheimer Res 3:541–550

    Article  PubMed  CAS  Google Scholar 

  • Youdim MB, Wadia A, Tatton W, Weinstock M (2001) The anti-Parkinson drug rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition in cell culture and in vivo. Ann N Y Acad Sci 939:450–458

    Article  PubMed  CAS  Google Scholar 

  • Youdim MB, Maruyama W, Naoi M (2005) Neuropharmacological, neuroprotective and amyloid precursor processing properties of selective MAO-B inhibitor anti-parkinsonian drug, rasagiline. Drugs Today (Barc) 41:369–391

    Article  CAS  Google Scholar 

  • Zhang JS, Moncrieffe MC, Kaczynski J, Ellenrieder V, Prendergast FG, Urrutia R (2001) A conserved alpha-helical motif mediates the interaction of Sp1-like transcriptional repressors with the corepressor mSin3A. Mol Cell Biol 21:5041–5049

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by Public Health Service Grants P20 RR17701, a NARSAD Young Investigator Award, NIMH Grant R37 MH39085 (Merit Award), RO1 MH67968, Boyd and Elsie Welin Professor, and by an Intramural Research Support grant from The University of Mississippi Medical Center (Jackson, MS). We thank Dr. Craig. A. Stockmeier from The University of Mississippi Medical Center for his helpful advice, Dr. Warren May from The University of Mississippi Medical Center for statistical analysis, and Hailin Zheng from Rappaport Family Research Institute (Haifa, Israel), for synthesizing rasagiline.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xiao-Ming Ou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ou, XM., Lu, D., Johnson, C. et al. Glyceraldehyde-3-Phosphate Dehydrogenase–Monoamine Oxidase B-Mediated Cell Death-Induced by Ethanol is Prevented by Rasagiline and 1-R-Aminoindan. Neurotox Res 16, 148–159 (2009). https://doi.org/10.1007/s12640-009-9064-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-009-9064-7

Keywords

Navigation