Neurochemical Research

, Volume 37, Issue 10, pp 2117–2124 | Cite as

Phenelzine (Monoamine Oxidase Inhibitor) Increases Production of Nitric Oxide and Proinflammatory Cytokines via the NF-κB Pathway in Lipopolysaccharide-Activated Microglia Cells

  • Hwan-Suck Chung
  • Hyunseong Kim
  • Hyunsu BaeEmail author
Original Paper


Phenelzine is a potent monoamine oxidase inhibitor that is used in patients with depression. It is also well known that nitric oxide (NO) synthase inhibitors show preclinical antidepressant-like properties, which suggests that NO is involved in the pathogenesis of depression. The purpose of this study was to determine if phenelzine affects the production of NO and tumor necrosis factor-alpha (TNF-α) in activated microglia cells. BV-2 microglia cells and primary microglia cells were cultured in DMEM and DMEM/F12 and then cells were treated with LPS or LPS plus phenelzine for 24 h. The culture medium was collected for determination of NO, TNF-α, and IL-6 and cells were harvested by lysis buffer for Western blot analysis. Phenelzine increased the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS), as well as the release of TNF-α and IL-6 in BV-2 microglia cells. It is also confirmed that phenelzine increased the levels of NO, TNF-α and IL-6 in LPS-activated primary microglia cells. Phenelzine increased nuclear translocation of NF-κB by phosphorylation of IκB-α in LPS-activated microglia cells. These findings suggest that high doses of phenelzine could aggravate inflammatory responses in microglia cells that are mediated by NO and TNF-α.


Phenelzine Nitric oxide Microglia Tumor necrosis factor-α NF-κB 



This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government [MEST] (No. 2011-0006220).


  1. 1.
    Johnson MR, Lydiard RB, Ballenger JC (1995) Panic disorder. Pathophysiology and drug treatment. Drugs 49:328–344PubMedCrossRefGoogle Scholar
  2. 2.
    Casacalenda N, Perry JC, Looper K (2002) Remission in major depressive disorder: a comparison of pharmacotherapy, psychotherapy, and control conditions. Am J Psychiatry 159:1354–1360PubMedCrossRefGoogle Scholar
  3. 3.
    Michael-Titus AT, Bains S, Jeetle J, Whelpton R (2000) Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex—a possible mechanism of neuroprotection in major depression? Neuroscience 100:681–684PubMedCrossRefGoogle Scholar
  4. 4.
    Parent MB, Master S, Kashlub S, Baker GB (2002) Effects of the antidepressant/antipanic drug phenelzine and its putative metabolite phenylethylidenehydrazine on extracellular gamma-aminobutyric acid levels in the striatum. Biochem Pharmacol 63:57–64PubMedCrossRefGoogle Scholar
  5. 5.
    Chiche F, Le Guillou M, Chetrite G, Lasnier F, Dugail I, Carpene C, Moldes M, Feve B (2009) Antidepressant phenelzine alters differentiation of cultured human and mouse preadipocytes. Mol Pharmacol 75:1052–1061PubMedCrossRefGoogle Scholar
  6. 6.
    Lee CS, Han ES, Lee WB (2003) Antioxidant effect of phenelzine on mpp+-induced cell viability loss in differentiated pc12 cells. Neurochem Res 28:1833–1841PubMedCrossRefGoogle Scholar
  7. 7.
    Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A (2011) The role of microglia in the healthy brain. J Neurosci 31:16064–16069PubMedCrossRefGoogle Scholar
  8. 8.
    Wyss-Coray T, Mucke L (2002) Inflammation in neurodegenerative disease—a double-edged sword. Neuron 35:419–432PubMedCrossRefGoogle Scholar
  9. 9.
    Ehde DM, Bombardier CH (2005) Depression in persons with multiple sclerosis. Phys Med Rehabil Clin N Am 16:437–448, ixGoogle Scholar
  10. 10.
    Marshall PS (1993) Allergy and depression: a neurochemical threshold model of the relation between the illnesses. Psychol Bull 113:23–43PubMedCrossRefGoogle Scholar
  11. 11.
    Katon W, Sullivan MD (1990) Depression and chronic medical illness. J Clin Psychiatry 51Suppl:3–11 (discussion 12–14)Google Scholar
  12. 12.
    Schrott LM, Crnic LS (1996) Anxiety behavior, exploratory behavior, and activity in nzb x nzw f1 hybrid mice: role of genotype and autoimmune disease progression. Brain Behav Immun 10:260–274PubMedCrossRefGoogle Scholar
  13. 13.
    Asnis GM, De La Garza R II (2006) Interferon-induced depression in chronic hepatitis c: a review of its prevalence, risk factors, biology, and treatment approaches. J Clin Gastroenterol 40:322–335PubMedCrossRefGoogle Scholar
  14. 14.
    Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, Lalla D, Woolley M, Jahreis A, Zitnik R et al (2006) Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase iii trial. Lancet 367:29–35PubMedCrossRefGoogle Scholar
  15. 15.
    Sluzewska A, Rybakowski J, Bosmans E, Sobieska M, Berghmans R, Maes M, Wiktorowicz K (1996) Indicators of immune activation in major depression. Psychiatry Res 64:161–167PubMedCrossRefGoogle Scholar
  16. 16.
    Gantt KR, Goldman TL, McCormick ML, Miller MA, Jeronimo SM, Nascimento ET, Britigan BE, Wilson ME (2001) Oxidative responses of human and murine macrophages during phagocytosis of leishmania chagasi. J Immunol 167:893–901PubMedGoogle Scholar
  17. 17.
    Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL et al (2000) Inflammation and alzheimer’s disease. Neurobiol Aging 21:383–421PubMedCrossRefGoogle Scholar
  18. 18.
    McGeer PL, McGeer EG (2004) Inflammation and neurodegeneration in parkinson’s disease. Parkinsonism Relat Disord 10(Suppl 1):S3–S7PubMedCrossRefGoogle Scholar
  19. 19.
    Danton GH, Dietrich WD (2003) Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 62:127–136PubMedGoogle Scholar
  20. 20.
    Chao CC, Hu S, Peterson PK (1995) Glia, cytokines, and neurotoxicity. Crit Rev Neurobiol 9:189–205PubMedGoogle Scholar
  21. 21.
    Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A (1987) Anti-cachectin/tnf monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330:662–664PubMedCrossRefGoogle Scholar
  22. 22.
    Baker SJ, Reddy EP (1998) Modulation of life and death by the tnf receptor superfamily. Oncogene 17:3261–3270PubMedCrossRefGoogle Scholar
  23. 23.
    Vilcek J, Lee TH (1991) Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions. J Biol Chem 266:7313–7316PubMedGoogle Scholar
  24. 24.
    Sweet MJ, Hume DA (1996) Endotoxin signal transduction in macrophages. J Leukoc Biol 60:8–26PubMedGoogle Scholar
  25. 25.
    Kuprash DV, Udalova IA, Turetskaya RL, Rice NR, Nedospasov SA (1995) Conserved kappa b element located downstream of the tumor necrosis factor alpha gene: distinct nf-kappa b binding pattern and enhancer activity in lps activated murine macrophages. Oncogene 11:97–106PubMedGoogle Scholar
  26. 26.
    Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27:229–237PubMedCrossRefGoogle Scholar
  27. 27.
    Chung HS, Lee JH, Kim H, Lee HJ, Kim SH, Kwon HK, Im SH, Bae H (2010) Foxp3 is a novel repressor of microglia activation. Glia 58:1247–1256PubMedGoogle Scholar
  28. 28.
    Saura J, Tusell JM, Serratosa J (2003) High-yield isolation of murine microglia by mild trypsinization. Glia 44:183–189PubMedCrossRefGoogle Scholar
  29. 29.
    Xie QW, Cho HJ, Calaycay J, Mumford RA, Swiderek KM, Lee TD, Ding A, Troso T, Nathan C (1992) Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science 256:225–228PubMedCrossRefGoogle Scholar
  30. 30.
    Chung HS, Kang M, Cho C, Parvez S, Park CH, Kim D, Oh J, Kim H, Shin M, Hong M et al (2007) Inhibition of nitric oxide and tumor necrosis factor-alpha by moutan cortex in activated mouse peritoneal macrophages. Biol Pharm Bull 30:912–916PubMedCrossRefGoogle Scholar
  31. 31.
    Stoll G, Jander S (1999) The role of microglia and macrophages in the pathophysiology of the cns. Prog Neurobiol 58:233–247PubMedCrossRefGoogle Scholar
  32. 32.
    Kreutzberg GW (1996) Microglia: a sensor for pathological events in the cns. Trends Neurosci 19:312–318PubMedCrossRefGoogle Scholar
  33. 33.
    Vila M, Jackson-Lewis V, Guegan C, Wu DC, Teismann P, Choi DK, Tieu K, Przedborski S (2001) The role of glial cells in parkinson’s disease. Curr Opin Neurol 14:483–489PubMedCrossRefGoogle Scholar
  34. 34.
    Sriram K, Matheson JM, Benkovic SA, Miller DB, Luster MI, O’Callaghan JP (2006) Deficiency of tnf receptors suppresses microglial activation and alters the susceptibility of brain regions to mptp-induced neurotoxicity: role of tnf-alpha. FASEB J 20:670–682PubMedCrossRefGoogle Scholar
  35. 35.
    Lawrence T, Gilroy DW, Colville-Nash PR, Willoughby DA (2001) Possible new role for nf-kappab in the resolution of inflammation. Nat Med 7:1291–1297PubMedCrossRefGoogle Scholar
  36. 36.
    Makarov SS (2001) Nf-kappa b in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction. Arthritis Res 3:200–206PubMedCrossRefGoogle Scholar
  37. 37.
    Boje KM, Arora PK (1992) Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res 587:250–256PubMedCrossRefGoogle Scholar
  38. 38.
    Majumder S, Zhou LZ, Chaturvedi P, Babcock G, Aras S, Ransohoff RM (1998) P48/stat-1alpha-containing complexes play a predominant role in induction of ifn-gamma-inducible protein, 10 kDa (ip-10) by ifn-gamma alone or in synergy with tnf-alpha. J Immunol 161:4736–4744PubMedGoogle Scholar
  39. 39.
    Piao HZ, Choi IY, Park JS, Kim HS, Cheong JH, Son KH, Jeon SJ, Ko KH, Kim WK (2008) Wogonin inhibits microglial cell migration via suppression of nuclear factor-kappa b activity. Int Immunopharmacol 12:1658–1662CrossRefGoogle Scholar
  40. 40.
    Henry JA, Antao CA (1992) Suicide and fatal antidepressant poisoning. Eur J Med 1:343–348PubMedGoogle Scholar
  41. 41.
    Ciocatto E, Fagiano G, Bava GL (1972) Clinical features and treatment of overdosage of monoamine oxidase inhibitors and their interaction with other psychotropic drugs. Resuscitation 1:69–72PubMedCrossRefGoogle Scholar
  42. 42.
    Linden CH, Rumack BH, Strehlke C (1984) Monoamine oxidase inhibitor overdose. Ann Emerg Med 13:1137–1144PubMedCrossRefGoogle Scholar
  43. 43.
    Waring WS, Wallace WA (2007) Acute myocarditis after massive phenelzine overdose. Eur J Clin Pharmacol 63:1007–1009PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Physiology, College of Oriental MedicineKyung Hee UniversitySeoulRepublic of Korea

Personalised recommendations