Alkaloids of Peganum harmala L. and their Pharmacological Activity

Aidos Doskaliyev; Roza Seidakhmetova; D. S. Tutai; Kristina Goldaeva; V.K. Surov; S.M. Adekenov

doi:10.3889/oamjms.2021.6654

Authors

Aidos Doskaliyev JSC “International Research and Production Holding Phytochemistry”, Karaganda, Republic of Kazakhstan; JSC “National Centre for Neurosurgery”, Nur-Sultan, Republic of Kazakhstan https://orcid.org/0000-0001-8727-567X
Roza Seidakhmetova JSC “International Research and Production Holding Phytochemistry”, Karaganda, Republic of Kazakhstan
D. S. Tutai JSC “International Research and Production Holding Phytochemistry”, Karaganda, Republic of Kazakhstan
Kristina Goldaeva JSC “International Research and Production Holding Phytochemistry”, Karaganda, Republic of Kazakhstan https://orcid.org/0000-0002-4082-1247
V.K. Surov JSC “National Centre for Neurosurgery”, Nur-Sultan, Republic of Kazakhstan
S.M. Adekenov JSC “International Research and Production Holding Phytochemistry”, Karaganda, Republic of Kazakhstan

DOI:

https://doi.org/10.3889/oamjms.2021.6654

Keywords:

Harmine hydrochloride, Neurotropic, Antidepressant, Antiparkinsonian, Antihypoxic, Bioavailability

Abstract

Peganum harmala L. contains 17 alkaloids of quinazoline and indole structure types. Of these, harmaline, harmine, harmalol and L-peganin (vazicin) are pharmacologically active. It was established that of the alkaloids contained in the seeds, 50-95% is dominated by harmaline, harmine is dominated in the roots (67-74% of the total of extractive substances), and in the aerial part, the main mass is peganin (up to 78% of the total of alkaloids). Beta-carboline alkaloids of Peganum harmala L. inhibit monoamine oxidase, thereby exerting a neuroprotective effect.

This article is devoted to the results of studies of the neurotropic action of harmine hydrochloride, when compared with the activity of the reference drug “Amitriptyline”. It was shown that the use of harmine hydrochloride helps to reduce the level of anxiety in animals under conditions of experimental psychoemotional chronic stress with prolonged administration. In the study of acute and chronic toxicity, it was determined that harmine hydrochloride belongs to the category of moderately toxic substances (hazard class II). According to the results of molecular docking, the presence of strong bonds in harmine hydrochloride with the serotonin 5-HT_2C receptor, dopamine D₂ receptor, as well as monoamine oxidase A and B was revealed, which indicates the implementation of the mechanism of neurotropic action of harmine hydrochloride at the level of synaptic neurotransmission of monoamines (dopamine, serotonin and others). It was also established that harmine hydrochloride eliminates haloperidol-induced catalepsy in rats, reduces oligokinesia and rigidity in the Parkinson’s test, has antihypoxic activity in the hypobaric hypoxia test, and exhibits pronounced antidepressant activity in the Porsolt’s test. In the course of the study of pharmacokinetics and bioavailability, it was revealed that with the administration of harmine hydrochloride, the quantitative content is quickly achieved and the concentration of the active substance in the blood significantly increases. The relative bioavailability of harmine hydrochloride is 112.7%.

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References

Shahrajabian MH, Sun W, Cheng Q.A review of ginseng species in different regions as a multipurpose herb in traditional Chinese medicine, modern herbology and pharmacological science.J Med Plants Res. 2019;13(10):213-26.

Sun W, Shahrajabian MH, Khoshkharam M, Cheng Q. Adaptation of acupuncture and traditional Chinese herbal medicines because of climate change.J Stress Physiol Biochem. 202;16(1):85-90. https://doi.org/10.5530/pc.2020.1.10 DOI: https://doi.org/10.5530/pc.2020.1.10

Adekenov SM, Baitulin IO, Egeubayeva RА, Saparbayeva NА. The current state of natural thickets of Peganum harmala L. on the territory of South Kazakhstan. News NAS RK Biol Ser 2010;5:55-61.

Mashreghi M, Niknia S. The effect of Peganum harmala L. and Teucrium polium alcoholic extracts on growth of Escherichia coli 0157. Jundishapur J Microbiol. 2012;5(3):511-5. https://doi.org/10.5812/jjm.3665 DOI: https://doi.org/10.5812/jjm.3665

Ababou A, Chouieb M, Bouthiba A, Saidi D, Hamedi Bouzina MM, Mederbal K. Spatial pattern analysis of Peganum harmala L. on the salted lower Chelif plain, Algeria. Turk J Bot. 2013;37:111-21. https://doi.org/10.17129/botsci.2303 DOI: https://doi.org/10.17129/botsci.2303

Astulla A, Zaima K, Matsuno Y, Hirasawa Y, Ekasari W, Widyawaruyanti A, et al. Alkaloids from the seeds of Peganum harmala showing antiplasmodial and vasorelaxant activities.J Nat Med. 2008;62(2):470-2. https://doi.org/10.1007/s11418-008-0259-7 PMid:18523842 DOI: https://doi.org/10.1007/s11418-008-0259-7

Berrougui H, Lopez-Lazaro M, Martin-Cordero C, Mamouchi M, Ettaib A, Herrera MD. Cytotoxic activity of methanolic extract and two alkaloids extracted from seeds of Peganum harmala L.J Natl Remedies. 2005;5:41-5.

Goel N, Singh N, Saini R. Efficient in vitro multiplication of Srian Rue (Peganum harmala L.) using 6-benzylaminopurine preconditioned seedling explants. Nat Sci. 2009;7:129-34.

Nafisi S, Asghari MH, Nezhadi MA, Ekhtiari MS. Possible antidiabetic effect Peganum harmala of streptozocine-induced mouse. World Appl Sci J. 2011;14(4):822-4.

Darabpour E, Bavi AP, Motamedi H, Nejad SM. Antibacterial activity of different parts of Peganum harmala L. growing in Iran against multi-drug resistant bacteria. Excl J. 2011;10:252-263. PMid:29033706

Diba K, Shoar MG, Shabathkhori M, Khorshivand Z. Antifungal activity of alcoholic extract of Peganum harmala seeds.J Med Plants Res. 2011;5(23):5550-4.

Mahmoudian M, Jalipour H, Salehian P. Toxicity of Peganum harmala: Review and a case report. Iran J Pharmacol Ther. 2002;1:1-4.

Massoud M, Jalilpour H, Salehian P. Toxicity of Peganum harmala L.: Review and a case report. Iran J Pharmacol Ther. 2002;1:1-4.

Asgarpanah J, Ramezanloo F. Chemistry, pharmacology and medicinal properties of Peganum harmala L. Afr J Pharm Pharmacol. 2012;6(22):1573-80. https://doi.org/10.5897/ajpp11.876 DOI: https://doi.org/10.5897/AJPP11.876

Patel K, Gadewar M, Tripathi R.A review on medicinal importance, pharmacological activity and bioanalytical aspects of betacarboline alkaloid “Harmine”. Asian Pac J Trop Biomed. 2012;2(8):660-4. https://doi.org/10.1016/s2221-1691(12)60116-6 PMid:23569990 DOI: https://doi.org/10.1016/S2221-1691(12)60116-6

Gammerman AF, Kadaev GN, Yatsenko-Khmelevsky AA. Medicinal Plants. Moscow: Healing Plants, Higher School; 1990. p. 544.

Movafeghi A, Abedini M, Fathiazad F, Aliasgharpour M, Omidi Y. Floral nectar composition of Peganumharmala L. Nat Prod Res. 2009;23:301-8. https://doi.org/10.1080/14786410802076291 PMid:19235031 DOI: https://doi.org/10.1080/14786410802076291

Faridi P, Younes G, Mohagheghzadeh A. Chemical composition of Peganum harmala L. smoke and volatile oil.J Essent Oil Bearing Plants. 2013;16(6):850-4. https://doi.org/10.1080/0972060x.2013.861993 DOI: https://doi.org/10.1080/0972060X.2013.861993

Khan AM, Qureshi RA, Ullah F, Gilani SA, Nosheen S, Sahreen MK, et al. Phytochemical analysis of selected medicinal plants of Margalla Hills and surroundings.J Med Plants Res. 2011;5(25):6017-23.

Kartal M, Altun ML, Kurucu S. HPLC method for the analysis of harmol, harmalole, harmine and harmaline in the seeds of Peganum harmala L.J Pharm Biomed 2003;311:263-9. https://doi.org/10.1016/s0731-7085(02)00568-x PMid:12609665 DOI: https://doi.org/10.1016/S0731-7085(02)00568-X

Fatma B, Fatiha M, Noureddine D. Phytochemical and antimicrobial study of the seeds and leaves of Peganum harmala L. against urinary tract infection pathogens. Asian Pac J Trop Dis. 2016;6(10):822-6. https://doi.org/10.1016/s2222-1808(16)61139-8 DOI: https://doi.org/10.1016/S2222-1808(16)61139-8

Siddiqui S, Khan OY, Faizi S, Shaheen B. Studies on the chemical constituents of the seeds of Peganum harmala: Isolation and structure elucidation of two β-carboline lactams-harmalanine and harmalacidine. Heterocycles. 1987;26(6):1401-20. https://doi.org/10.3987/com-88-4490 DOI: https://doi.org/10.3987/R-1987-06-1563

Manske F, Perkin V, Robinson R. Harmine and harmaline. Part IX. Synthesis of harmaline.J Chem Soc. 1927;1(14):20-8. https://doi.org/10.1039/jr9270000001 DOI: https://doi.org/10.1039/JR9270000001

Schults EE, Nurmaganbetov ZS, Turmukhanbetov AZ, Adekenov SM. Chemistry, pharmacology, and medical aspects of the plant Peganum harmala L. Pharmaceutical Bulletin. 2014;3:66-76. https//doi.org/10.5897/AJPP11.876

Chen Q, Chao RH, Chen HS, Hou X, Yan H, Zhou S, et al. Antitumor and neurotoxic effects of novel harmine derivatives and structure-activity relationship analysis. Int J Cancer. 2015;114(5):675-82. https://doi.org/10.1002/ijc.20703 DOI: https://doi.org/10.1002/ijc.20703

Vachnadze VY, Suladze TS, Vachnadze NS, Kintsurashvili LG, Novikova ZN. Alkaloids of Peganum harmala L. and their biological activity. Georgian Med News. 2015;6:79-81. PMid:26087737

Réus GZ, Stringari RB, de Souza B, Petronilho F, Dal-Pizzol F. Harmine and imipramine promote antioxidant activities in prefrontal cortex and hippocampus. Oxid Med Cell Longev. 2010;3(5):325-31. https://doi.org/10.4161/oxim.3.5.13109 PMid:21150338 DOI: https://doi.org/10.4161/oxim.3.5.13109

Serrano-Duenas M, Cardoso-Pelaez F, Sanchez-Ramos J. Effects of Banisteriopsis caapi extract on Parkinson’s disease. Sci Rev Altern Med. 2001;5(3):127-32.

Yarnell E, Abascal K. Botanical treatments for depression: Part 2-herbal correctives for systemic imbalances. Altern Complement Ther. 2001;7(3):138-43. https://doi.org/10.1089/10762800151125056 DOI: https://doi.org/10.1089/10762800151125056

Zheng XY, Zhang ZJ, Chou GX, Wu T, Cheng XM, Wang CH. Acetylcholinesterase inhibitive activity-guided isolation of two new alkaloids from seeds of Peganum nigellastrum Bunge by an in vitro TLC-bioautographic assay. Arch Pharm Res. 2009;32:1245-51. https://doi.org/10.1007/s12272-009-1910-x DOI: https://doi.org/10.1007/s12272-009-1910-x

Schwarz MJ, HoughtonPJ.Activities of extract and constituents of Banisteriopsis caapi relevant to parkinsonism. Pharmacol Biochem Behav. 2003;75(3):627-33. https://doi.org/10.1016/s0091-3057(03)00129-1 PMid:12895680 DOI: https://doi.org/10.1016/S0091-3057(03)00129-1

Paromita B, Durbadal O, Hemanta M.A dihydro-pyrido-indole potently inhibits HSV-1 infection by interfering the viral immediate early transcriptional events. Antiv Res. 2014;105(1):126-34. https://doi.org/10.1016/j.antiviral.2014.02.007 DOI: https://doi.org/10.1016/j.antiviral.2014.02.007

Blesa J, Przedborski S. Parkinson’s disease: Animal models and dopaminergic cell vulnerability. Front Neuroanat. 2014;8:1-12. https://doi.org/10.3389/fnana.2014.00155 PMid:25565980 DOI: https://doi.org/10.3389/fnana.2014.00155

Tolkachev ON, Tolkachev VN, Sheichenko OP, Fateeva TV, Semenov AV, Abizov EA. Plant preparations based on indole alkaloids: Biological activity. Biol Med Pharm Chem Issues. 2018;9:3-14. https://doi.org/10.29296/25877313-2018-09-01 DOI: https://doi.org/10.29296/25877313-2018-09-01

Farzin D, Haghparast A, Motaman S, Baryar F, Mansouri N. Effects of harmane and other β-carbolines on apomorphineinduced licking behavior in rat. Pharmacol Biochem Behav. 2011;98(2):215-9. https://doi.org/10.1016/j.pbb.2011.01.001 PMid: 21237191 DOI: https://doi.org/10.1016/j.pbb.2011.01.001

Yonezawa T, Hasegawa S, Asai M, Ninomiya T, Sasaki T, Cha BY, et al. Harmine, a β-carboline alkaloid, inhibits osteoclast differentiation and bone resorptionin vitroandin vivo. Eur J Pharmacol.2011;650(2-3):511-8. https://doi.org/10.1016/j.ejphar.2010.10.048 PMid:21047508 DOI: https://doi.org/10.1016/j.ejphar.2010.10.048

Egusa H, Doi M, Saeki M, Fukuyasu S, Akashi Y, Yokota Y, et al. The small molecule harmine regulates NFATc1 and Id2 expression in osteoclast progenitor cells. Bone. 2011;49(2):264-74. https://doi.org/10.1016/j.bone.2011.04.003 PMid:21504804 DOI: https://doi.org/10.1016/j.bone.2011.04.003

Iurlo M, Leone M, Schilström B, Linnér L, Nomikos L, Hertel P, et al. Effects of harmine on dopamine output and metabolism in rat striatum: Role of monoamine oxidase-a inhibition. Psychopharmacology.2001;159(1):98–104. https://doi.org/10.1007/s002130100879 PMid:11797076 DOI: https://doi.org/10.1007/s002130100879

Jiménez J, Riverón-Negrete L, Abdullaev F, Espinosa-Aguirre J, Rodríguez-Arnaiz R. Cytotoxicity of the β-carboline alkaloids harmine and harmaline in human cell assays in vitro. Exp Toxicol Pathol. 2008;60(4-5):381-9.https://doi.org/10.1016/j.etp.2007.12.003 PMid:18430551 DOI: https://doi.org/10.1016/j.etp.2007.12.003

Boeira JM, da Silva J, Erdtmann B, Henriques JA. Genotoxic effects of the alkaloids harman and harmine assessed by comet assay and chromosome aberration test in mammalian cells in vitro. Pharmacol Toxicol. 2001;89(6):287-94. https://doi.org/10.1034/j.1600-0773.2001.d01-162.x DOI: https://doi.org/10.1034/j.1600-0773.2001.d01-162.x

Boeira JM, Viana AF, Picada JN, Henriques JA. Genotoxic and recombinogenic activities of the two beta-carboline alkaloids harman and harmine in Saccharomyces cerevisiae. Mutat Res. 2002;500(1-2):39-48. https://doi.org/10.1016/s0027-5107(01)00294-9 PMid: 11890933 DOI: https://doi.org/10.1016/S0027-5107(01)00294-9

Reza VR, Abbas H. Cytotoxicity and antimicrobial activity of harman alkaloids.J Pharmacol Toxicol. 2007;2(7):677-80. https//doi.org/10.3109/13880209.2010.519390 DOI: https://doi.org/10.3923/jpt.2007.677.680

Hamsa TP, Kuttan G. Harmine activates intrinsic and extrinsic pathways of apoptosis in B16F-10 melanoma. Chin Med. 2011;6(1):11. https://doi.org/10.1186/1749-8546-6-11 PMid:21429205 DOI: https://doi.org/10.1186/1749-8546-6-11

Hamsa TP, Kuttan G. Harmine inhibits tumour specific neovessel formation by regulating VEGF, MMP, TIMP and pro-inflammatory mediators both in vivo and in vitro. Eur J Pharmacol. 2010;649(1-3):64-73. https://doi.org/10.1016/j.ejphar.2010.09.010 DOI: https://doi.org/10.1016/j.ejphar.2010.09.010

Ma Y, Wink M. The beta-carboline alkaloid harmine inhibits BCRP and can reverse resistance to the anticancer drugs mitoxantrone and camptothecin in breast cancer cells. Phytother Res. 2010;24(1):146-9. https://doi.org/10.1002/ptr.2860 PMid:19548284 DOI: https://doi.org/10.1002/ptr.2860

Song Y, Kesuma D, Wang J, Deng Y, Duan J, Wang JH, et al. Specific inhibition of cyclin-dependent kinases and cell proliferation by harmine.Biochem Biophys Res Commun.2004;317(1):128-32. https://doi.org/10.1016/j.bbrc.2004.03.019 PMid:15047157 DOI: https://doi.org/10.1016/j.bbrc.2004.03.019

Jahaniani F, Ebrahimi SA, Rahbar-Roshandel N, Mahmoudian M. Xanthomicrol is the main cytotoxic component of Dracocephalum kotschyiiand a potential anti-cancer agent. Phytochemistry.2005;66(13):1581-92. https://doi.org/10.1016/j.phytochem.2005.04.035 PMid:15949825 DOI: https://doi.org/10.1016/j.phytochem.2005.04.035

Adayev T, Wegiel J, Hwanga YW. Harmine is an ATP-competitive inhibitor for dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A). Arch Biochem Biophys. 2011;507(2):212-8. https://doi.org/10.1016/j.abb.2010.12.024 PMid:21185805 DOI: https://doi.org/10.1016/j.abb.2010.12.024

Owaisat S, Robert B, Scott M. In vivo comparison of harmine efficacy against psychostimulants: Preferential inhibition of the cocaine response through a glutamatergic mechanism. Neurosci Lett. 2012;525(1):12-6. https://doi.org/10.1016/j.neulet.2012.07.052 PMid:22877698 DOI: https://doi.org/10.1016/j.neulet.2012.07.052

Zhong Z, Tao Y. Treatment with harmine ameliorates functional impairment and neuronal death following traumatic brain injury. Mol Med Rep. 2015;12(6):7985-91. https://doi.org/10.3892/mmr.2015.4437 DOI: https://doi.org/10.3892/mmr.2015.4437

Mennenga SE, Gerson JE, Dunckley T, Bimonte-Nelson HA. Harmine treatment improves short-term memory in older rats: Dissociation of cognition and the ability to meet the procedural requirements of maze testing. Physiol Behav. 2015;138:260-5. https://doi.org/10.1016/j.physbeh.2014.09.001 PMid:25250831 DOI: https://doi.org/10.1016/j.physbeh.2014.09.001

Becker V, Sipple V. Activation, regulation, and inhibition DYRK1A. FEBS J. 2011;278:246-56. https://doi.org/10.1111/j.1742-4658.2010.07956.x PMid:21126318 DOI: https://doi.org/10.1111/j.1742-4658.2010.07956.x

Fortunato JJ, Réus GZ, Kirsch TR,Stringari RB, Stertz L, Kapczinski F, et al. Acute harmine administration induces antidepressive-like effects and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(8):1425-30. https://doi.org/10.1016/j.pnpbp.2009.07.021 PMid:19632287 DOI: https://doi.org/10.1016/j.pnpbp.2009.07.021

Fortunato JJ, Réus GZ, Kirsch TR,Stringari RB, Fries GR, Kapczinski F, et al. Chronic administration of harmine elicits antidepressant-like effects and increases BDNF levels in rat hippocampus.J Neural Transm. 2010;117:1131-7. https://doi.org/10.1007/s00702-010-0451-2 PMid:20686906 DOI: https://doi.org/10.1007/s00702-010-0451-2

Voronina TA, Ostrovskaya TA. In: Khabriev RN, editor. Guidelines for Experimental (Preclinical) Study of New Pharmacological Substances. Moscow: Food and Drug Administration; 2005. p. 308-20.