Planta Med 2019; 85(14/15): 1136-1142
DOI: 10.1055/a-1008-9491
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Monoamine Oxidase Inhibition by Kavalactones from Kava (Piper Methysticum)

Denise Prinsloo
Pharmaceutical Chemistry, School of Pharmacy and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa
,
Sandra van Dyk
Pharmaceutical Chemistry, School of Pharmacy and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa
,
Anél Petzer
Pharmaceutical Chemistry, School of Pharmacy and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa
,
Jacobus P. Petzer
Pharmaceutical Chemistry, School of Pharmacy and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa
› Author Affiliations
Further Information

Publication History

received 29 January 2019
revised 13 August 2019

accepted 01 September 2019

Publication Date:
20 September 2019 (online)

Abstract

Monoamine oxidases (MAOs) are key metabolic enzymes for neurotransmitter and dietary amines and are targets for the treatment of neuropsychiatric and neurodegenerative disorders. This study examined the MAO inhibition potential of kavain and other kavalactones from the roots of kava (Piper methysticum), a plant that has been used for its anxiolytic properties. (±)-Kavain was found to be a good potency in vitro inhibitor of human MAO-B with an IC50 of 5.34 µM. (±)-Kavain is a weaker MAO-A inhibitor with an IC50 of 19.0 µM. Under the same experimental conditions, the reference MAO inhibitor, curcumin, displays IC50 values of 5.01 µM and 2.55 µM for the inhibition of MAO-A and MAO-B, respectively. It was further established that (±)-kavain interacts reversibly and competitively with MAO-A and MAO-B with enzyme-inhibitor dissociation constants (Ki) of 7.72 and 5.10 µM, respectively. Curcumin in turn, displays a Ki value of 3.08 µM for the inhibition of MAO-A. Based on these findings, other kavalactones (dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin) were also evaluated as MAO inhibitors in this study. Yangonin proved to be the most potent MAO inhibitor with IC50 values of 1.29 and 0.085 µM for MAO-A and MAO-B, respectively. It may be concluded that some of the central effects (e.g., anxiolytic) of kava may be mediated by MAO inhibition.

 
  • References

  • 1 Glover V, Sandler M, Owen F, Riley GJ. Dopamine is a monoamine oxidase B substrate in man. Nature 1977; 265: 80-81
  • 2 Youdim MB, Bakhle YS. Monoamine oxidase: isoforms and inhibitors in Parkinsonʼs disease and depressive illness. Br J Pharmacol 2006; 147 Suppl 1: S287-S296
  • 3 Bach AW, Lan NC, Johnson DL, Abell CW, Bembenek ME, Kwan SW, Seeburg PH, Shih JC. cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. Proc Natl Acad Sci U S A 1988; 85: 4934-4938
  • 4 Shih JC, Chen K, Ridd MJ. Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 1999; 22: 197-217
  • 5 Youdim MB, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 2006; 7: 295-309
  • 6 Ramsay RR. Inhibitor design for monoamine oxidases. Curr Pharm Des 2013; 19: 2529-2539
  • 7 Shulman KI, Herrmann N, Walker SE. Current place of monoamine oxidase inhibitors in the treatment of depression. CNS Drugs 2013; 27: 789-797
  • 8 LeWitt PA, Taylor DC. Protection against Parkinsonʼs disease progression: clinical experience. Neurotherapeutics 2008; 5: 210-225
  • 9 Henchcliffe C, Schumacher HC, Burgut FT. Recent advances in Parkinsonʼs disease therapy: use of monoamine oxidase inhibitors. Expert Rev Neurother 2005; 5: 811-821
  • 10 Edmondson DE. Hydrogen peroxide produced by mitochondrial monoamine oxidase catalysis: biological implications. Curr Pharm Des 2014; 20: 155-160
  • 11 Umbarkar P, Singh S, Arkat S, Bodhankar SL, Lohidasan S, Sitasawad SL. Monoamine oxidase-A is an important source of oxidative stress and promotes cardiac dysfunction, apoptosis, and fibrosis in diabetic cardiomyopathy. Free Radic Biol Med 2015; 87: 263-273
  • 12 Kaludercic N, Carpi A, Nagayama T, Sivakumaran V, Zhu G, Lai EW, Bedja D, De Mario A, Chen K, Gabrielson KL, Lindsey ML, Pacak K, Takimoto E, Shih JC, Kass DA, Di Lisa F, Paolocci N. Monoamine oxidase B prompts mitochondrial and cardiac dysfunction in pressure overloaded hearts. Antioxid Redox Signal 2014; 20: 267-280
  • 13 Manni ME, Rigacci S, Borchi E, Bargelli V, Miceli C, Giordano C, Raimondi L, Nediani C. Monoamine oxidase is overactivated in left and right ventricles from ischemic hearts: an intriguing therapeutic target. Oxid Med Cell Longev 2016; 2016: 4375418
  • 14 Flamand V, Zhao H, Peehl DM. Targeting monoamine oxidase A in advanced prostate cancer. J Cancer Res Clin Oncol 2010; 136: 1761-1771
  • 15 Lebot V, Merlin M, Lindstrom L. Kava – the pacific Elixir: the definitive Guide to its Ethnobotony, History, and Chemistry. Rochester: Healing Arts Press; 1997: 1-272
  • 16 Cairney S, Maruff P, Clough AR. The neurobehavioural effects of kava. Aust N Z J Psychiatry 2002; 36: 657-662
  • 17 Sarris J, Kavanagh DJ, Byrne G, Bone KM, Adams J, Deed G. The Kava Anxiety Depression Spectrum Study (KADSS): a randomized, placebo-controlled crossover trial using an aqueous extract of Piper methysticum . Psychopharmacology (Berl) 2009; 205: 399-407
  • 18 Sarris J, Stough C, Bousman CA, Wahid ZT, Murray G, Teschke R, Savage KM, Dowell A, Ng C, Schweitzer I. Kava in the treatment of generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol 2013; 33: 643-648
  • 19 Sarris J, Stough C, Teschke R, Wahid ZT, Bousman CA, Murray G, Savage KM, Mouatt P, Ng C, Schweitzer I. Kava for the treatment of generalized anxiety disorder RCT: analysis of adverse reactions, liver function, addiction, and sexual effects. Phytother Res 2013; 27: 1723-1728
  • 20 Savage KM, Stough CK, Byrne GJ, Scholey A, Bousman C, Murphy J, Macdonald P, Suo C, Hughes M, Thomas S, Teschke R, Xing C, Sarris J. Kava for the treatment of generalised anxiety disorder (K-GAD): study protocol for a randomised controlled trial. Trials 2015; 16: 493
  • 21 Wu D, Yu L, Nair MG, DeWitt DL, Ramsewak RS. Cyclooxygenase enzyme inhibitory compounds with antioxidant activities from Piper methysticum (kava kava) roots. Phytomedicine 2002; 9: 41-47
  • 22 Jamieson DD, Duffield PH. The antinociceptive actions of kava components in mice. Clin Exp Pharmacol Physiol 1990; 17: 495-507
  • 23 Keledjian J, Duffield PH, Jamieson DD, Lidgard RO, Duffield AM. Uptake into mouse brain of four compounds present in the psychoactive beverage kava. J Pharm Sci 1988; 77: 1003-1006
  • 24 Pantano F, Tittarelli R, Mannocchi G, Zaami S, Ricci S, Giorgetti R, Terranova D, Busardo FP, Marinelli E. Hepatotoxicity induced by “the 3Ks”: kava, kratom and khat. Int J Mol Sci 2016; 17: 580
  • 25 Smith TE, Djang M, Velander AJ, Downey CW, Carroll KA, van Alphen S. Versatile asymmetric synthesis of the kavalactones: first synthesis of (+)-kavain. Org Lett 2004; 6: 2317-2320
  • 26 Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W. Interaction of various Piper methysticum cultivars with CNS receptors in vitro. Planta Med 2001; 67: 306-311
  • 27 Jussofie A, Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology (Berl) 1994; 116: 469-474
  • 28 Chua HC, Christensen ET, Hoestgaard-Jensen K, Hartiadi LY, Ramzan I, Jensen AA, Absalom NL, Chebib M. Kavain, the major constituent of the anxiolytic kava extract, potentiates GABAA receptors: functional characteristics and molecular mechanism. PLoS One 2016; 11: e0157700
  • 29 Friese J, Gleitz J. Kavain, dihydrokavain, and dihydromethysticin non-competitively inhibit the specific binding of [3H]-batrachotoxinin-A 20-alpha-benzoate to receptor site 2 of voltage-gated Na+ channels. Planta Med 1998; 64: 458-459
  • 30 Schirrmacher K, Busselberg D, Langosch JM, Walden J, Winter U, Bingmann D. Effects of (±)-kavain on voltage-activated inward currents of dorsal root ganglion cells from neonatal rats. Eur Neuropsychopharmacol 1999; 9: 171-176
  • 31 Uebelhack R, Franke L, Schewe HJ. Inhibition of platelet MAO-B by kava pyrone-enriched extract from Piper methysticum Forster (kava-kava). Pharmacopsychiatry 1998; 31: 187-192
  • 32 Khatri DK, Juvekar AR. Kinetics of inhibition of monoamine oxidase using curcumin and ellagic acid. Pharmacogn Mag 2016; 12: S116-S120
  • 33 Novaroli L, Reist M, Favre E, Carotti A, Catto M, Carrupt PA. Human recombinant monoamine oxidase B as reliable and efficient enzyme source for inhibitor screening. Bioorg Med Chem 2005; 13: 6212-6217
  • 34 Son SY, Ma J, Kondou Y, Yoshimura M, Yamashita E, Tsukihara T. Structure of human monoamine oxidase A at 2.2-A resolution: the control of opening the entry for substrates/inhibitors. Proc Natl Acad Sci U S A 2008; 105: 5739-5744
  • 35 Da Prada M, Zurcher G, Wuthrich I, Haefely WE. On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. J Neural Transm Suppl 1988; 26: 31-56
  • 36 Flockhart DA. Dietary restrictions and drug interactions with monoamine oxidase inhibitors: an update. J Clin Psychiatry 2012; 73 (Suppl. 01) 17-24
  • 37 Petzer A, Pienaar A, Petzer JP. The inhibition of monoamine oxidase by esomeprazole. Drug Res (Stuttg) 2013; 63: 462-467
  • 38 Mostert S, Petzer A, Petzer JP. Indanones as high-potency reversible inhibitors of monoamine oxidase. ChemMedChem 2015; 10: 862-873
  • 39 Strydom B, Bergh JJ, Petzer JP. The inhibition of monoamine oxidase by 8-(2-phenoxyethoxy)caffeine analogues. Arzneimittelforschung 2012; 62: 513-518
  • 40 Petzer A, Harvey BH, Wegener G, Petzer JP. Azure B, a metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase. Toxicol Appl Pharmacol 2012; 258: 403-409