Bangladesh Journal of Pharmacology Mini-Review Harmine and its derivatives: Biological activities and therapeutic potential in human diseases BJP Introduction Natural products have served humanity as a funda- mental source of medicine throughout the history of civilization. The term natural product is usually defin- ed as chemical entities that are mainly originated from the living species such as microorganisms, plants, terrestrial vertebrates, marine organisms, and inverte- brates (Rasul et al., 2013). Plants offer an extensive reservoir of natural products providing a far-reaching diversity of novel chemical entities in drug industries (Newman et al., 2003). Plants have established the basis of refined traditional medicinal systems including Chinese, Unani, Ayur- vedic, and some others. These traditional systems have a great potential regarding the discovery of many beneficial drugs (Gurib-Fakim, 2006). Since past deca- des, natural products have been an affluent source of many chemical entities for drug discovery (Harvey et al., 2015). To date, 61% anti-cancer agents and approxi- mately 49% anti-infective compounds are directly inspired from nature (Luo et al., 2014). Alkaloids have been recently described as the most significant group of natural products with basic nitro- gen atoms, playing an important role in the ecological aspects of organisms (Bouayad et al., 2012). Addi- tionally, β-carbolines are the major class of alkaloids with a tricyclic pyrido[3,4-b]indole ring (Filali et al., 2015). They have been proved as natural constituents of human body fluids and tissues. They also display a wide range of behavioral, psychopharmacological, and biochemical effects in both humans and animals (Patel et al., 2012). Harmine (7-methoxy-1-methyl-9H-pyrido[3,4-b]indole), a naturally existing β-carboline alkaloid (Filali et al., 2015) has been known to possess numerous biological and pharmacological activities prescribed as anti-cancer (Shabani et al., 2015), anti-microbial (Salman et al., 2016), anti-oxidant (Choi et al., 2004), anti-inflammatory (Hara et al., 2013), anti-depressant (Hamid et al., 2017) and neuroprotective (Herraiz, 2012). Of all β-carboline groups, harmine and its derivatives have potential pharmacological value (Zhao et al., 2011; Arora et al., 2013; Li et al., 2015). Abstract This review article aims to provide an update on the sources, pharmaco- logical and biological profile of a β-carboline alkaloid, harmine which is a major bioactive component of various plants mainly Peganum harmala. Harmine’s wide range of pharmacological properties has been well- documented as anti-cancer, anti-inflammatory, anti-oxidant, neuroprotective, anti-depressant, and antimicrobial. Although reported data suggests a multifunctional pharmacological role of harmine but farther experimentation on its molecular mechanism of action, synthetic chemistry approaches, and preclinical studies are yet obligatory to fully uncover its pharmacological efficacy. Article Info Received: 26 December 2017 Accepted: 1 June 2018 Available Online: 7 July 2018 DOI: 10.3329/bjp.v13i3.34990 Cite this article: Javeed M, Rasul A, Hussain G, Jabeen F, Rasool B, Shafiq N, Riaz A, Kaukab G, Ali M. Harmine and its derivatives: Biological activities and therapeutic potential in human diseases. Bangla- desh J Pharmacol. 2018; 13: 203-213. Harmine and its derivatives: Biological activities and therapeutic potential in human diseases Maria Javeed1, Azhar Rasul1, Ghulam Hussain2, Farhat Jabeen1, Bilal Rasool1, Nusrat Shafiq3, Ammara Riaz1, Ghazala Kaukab1 and Muhammad Ali1 1Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad, 38000 Pakistan; 2Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad, 38000 Pakistan; 3Department of Chemistry, Government College Women University, Faisalabad 38000, Pakistan. This work is licensed under a Creative Commons Attribution 4.0 License. You are free to copy, distribute and perform the work. You must attribute the work in the manner specified by the author or licensor. A Journal of the Bangladesh Pharmacological Society (BDPS) Bangladesh J Pharmacol 2018; 13: 203-213 Journal homepage: www.banglajol.info Abstracted/indexed in Academic Search Complete, Agroforestry Abstracts, Asia Journals Online, Bangladesh Journals Online, Biological Abstracts, BIOSIS Previews, CAB Abstracts, Current Abstracts, Directory of Open Access Journals, EMBASE/Excerpta Medica, Google Scholar, HINARI (WHO), International Pharmaceutical Abstracts, Open J-gate, Science Citation Index Expanded, SCOPUS and Social Sciences Citation Index ISSN: 1991-0088 M in i-r ev ie w This review will emphasize the most recent researches on harmine focusing on its pharmacological and bio- logical properties. Structure Activity Relationship Harmine (C13H12ON2) is commonly distributed among the animals, marine creatures, plants, and insects (Zhang et al., 2015). Harmine derivatives are gifted with pharmacological profiles (Zhang et al., 2016). Chemical structures of biologically active harmine and its derivatives are represented in Figure 1. Structure-activity relationship of harmine derivatives has been established by TD-DFT study (Lamchouri et al., 2013) and this study showed that position-3 and 9 played a crucial role in antitumor as well as neurotoxicity of harmine derivatives. Structure activity relationship analysis indicated that replacement of proton presents at position-9 with short alkyl or aryl group increased the cytotoxicity while replacement of proton presents at position-3 with long alkyl or aryl group reduced the antitumor activity. Without any substitution of the proton at position-3 in harmine derivatives led to enhanced antitumor activity. SAR analysis demonstrated that by introducing alkoxy substituents into position-7 of harmine led to enhanced cytotoxic activities, the length of alkoxy chain affected both cytotoxicity and cell line specificity, N9-alkylated harmine derivatives displayed specific cytotoxic effects, N2-alkylated. Furthermore, SARs studies suggested that substitution of proton of position-9 of harmine enhanced the antitumor activity, 7-methoxy of harmine very important in determining the neurotoxic effects, replacement of methoxy at position-7 with a bulky alkoxy group led to eliminating neurotoxic effects and enhanced antitumor activity (Cao et al., 2013). In comparison to harmine, the derivatives showed more antitumor potential e.g. 2DG-Har-01 and MET-Har-02 showed more antitumor activity and cell safety as compared to harmine due to the modification of methoxy at position-7 with oxime derivatives. Similar- ly, JKA97 (methoxy-1-styryl-9H-pyrid-[3,4-b]-indole) showed greater antitumor activity against MCF7, MDA- MB-468 and MCF7p53kD cell lines than harmine (Luo et al., 2008). Similarly, 17A and 21A, two harmine derivatives acting as anti-malarial agents. These were found more active as compared to chloroquine and artemisinin due to the substitution of halogens (Bayih et al., 2016). Structure–activity relationship of N-9 substituted har- mine analog 11d demonstrated that by the introduction of a haloalkyl or benzene-sulfonyl group in the N9- position of harmine could significantly increase the anticancer activity (Du et al., 2016). Harmine derivative 2 and HRMS (harmine derive isoxazole) acting as anti- Alzheimer, anti-cancer, and anti-inflammatory agent showed good activity due to N9-substitution (Filali et al., 2015). 204 Bangladesh J Pharmacol 2018; 13: 203-213 Harmine derivative 17A 3c . B en zy lid en e su bs tit ut ed (h ar m in e) N-(9)-substituted Harmine derivative 2D G -H ar -0 1 Figure 1: Hermine and its derivatives MET-Har-02 Harmine derivative 11d (1-(4-nitrostyryle)-7- methoxy-β-carboline Harmine derivative CM16Harmine derivative 21A Harmine derivative 2 JK A 97 Harmine N H N CH3H3CO 1 2 34 56 7 8 9 H Moreover, in vivo and in vitro results demonstrated that substitutions at the position-2, 7 and 9 of harmine led to excellent enhancement in antitumor activity and remarkable reduction in the adverse effects of the drugs because the structural modification at the said positions results in reduced uptake of drug by normal cells and increase the cancer cell specificity (Li et al., 2015). Plant Sources Harmine was first discovered and isolated from the Peganum harmala which is generally utilized as potent herbal medicine due to its abortifacient, emmenagogue, hallucinogenic, lactagogue, and hypothermic properties (Filali et al., 2015). The seed extracts of P. harmala have been traditionally used in Northwest China to cure malaria and alimentary tract cancers for hundreds of years (Cao et al., 2013). P. harmala is a perennial herbaceous plant originally of family Zygophyllaceae but has been recently updated as a member of family Nitrariaceae (Filali et al., 2015). Besides P. harmala, harmine was identified in P. nigellastrum (Ma et al., 2000), and P. multisectum (Liu, 2011). Harmine was also isolated from the roots and leaves of A. paniculata. It is useful in Chinese Traditional Medi- cine as an anti-code for snakebite, and to treat dysen- tery, dyspepsia, malaria, influenza, and respiratory dis- eases (Kurzawa et al., 2015). Moreover, the stalks of B. caapi vine (Dos Santos and Hallak, 2017), and the roots of O. tuberosa (Bais et al., 2003) are found to be a rich source of harmine. Quantitative analysis on harmine showed that it is present in major quantity in P. caerulea while in minor quantity in P. incarnata (Fyre and Haustein, 2007). Extraction and Method of Estimation Harmine has been extracted by chromatography on silica gel (Ma et al., 2000; Liu, 2011; Filali et al., 2015). It is detected by UPLC/HPLC (Zhao et al., 2011; Bensa- lem et al., 2014; Li et al., 2017), HPLC–DAD, GC–MS and LC–MS/MS (Kurzawa et al., 2015). Shoots, untrans- formed roots and leaves of Oxalis tuberosa were extrac- ted in methanol to measure harmine. The experiment proved that quantity of harmine was higher in shoots when compared with leaves and roots (Bais et al., 2003). JKA97 (methoxy-1-styryl-9H-pyrido-[3,4-b]-indole), a derivative of harmine was identified by HPLC and MS analysis (Yang et al., 2012). Biological Activities The biologically active compound harmine has been demonstrated for its broad spectrum of pharmacological and biological traits such as anti- cancer, anti-microbial, anti-oxidant, neuroprotective, anti-inflammatory, and anti-depressant (Figure 2). Several in vitro and in vivo investigations have elucidated its medicinal characteristics and mechanism of actions. Anti-cancer activity Programmed cell death or apoptosis is a natural process of eliminating old cells from our body. Approximately all the anti-cancer agents stimulate apoptosis to remove malignant cells. Nevertheless, in cancer, de-regulation of signaling pathways provide gateway towards cellu- lar proliferation which is uncontrolled resulting in the survival of tumor, cancer recurrence and therapeutic resistance (Mohammad et al., 2015). Previous investiga- Table I Plants containing harmine with their biological functions Botanical name English name Parts used Disease/function References Andrographis paniculata Green chirayta Root, leaf Anti-oxidant Kurzawa et al., 2015 Banisteriopsis caapi Ayahuasca vine Stalk Neuroprotective, cognitive enhanc- ing property Dos Santos and Hallak, 2017 Kochia scoparia Mexican fireweed - Reduction in survival and weight Westcott et al., 1992 Oxalis tuberosa Wood sorrel Root Anti-microbial Bais et al., 2003 Passiflora incarnata Purple passion flower - Anti-leishmanial, anti-HIV, vasorelaxant Fyre and Haustein, 2007 Passiflora caerulea Blue passion flower - - Fyre and Haustein, 2007 Peganum harmala Wild rue Seed Anti-proliferative Cao et al., 2013; Filali et al., 2015; Li et al., 2017 Peganum multisectum African rue - - Liu, 2011 Peganum nigellastrum Bunge Aerial part - Ma et al., 2000 Bangladesh J Pharmacol 2018; 13: 203-213 205 tions have reported that AMPK (adenosine-5’-mono- phosphate-activated protein kinase) and MAPK (mito- gen activated protein kinase) signaling pathways are noteworthy to activate apoptosis and autophagy (Li et al., 2017). Cumulative data by the researchers strongly commend that various chemopreventive agents prompt apoptosis in cancerous cells (Rasul et al., 2012; Rasul et al., 2014). About 9 derivatives of harmine are reported to have anti-cancer effects in lung and liver cancers (Chen et al., 2005). Overexpression of dual specificity tyrosine- phosphorylated and regulated kinase 1A (DYRK1A) has been implicated in an uncontrolled cell proliferation and tumorigenesis. Harmine is an effective inhibitor of protein kinase DYRK1A. Harmine-associated prohibi- tion of DYRK1A triggered apoptosis in human oligodendroglioma (Hs683) cancer cells along with caspase-9 activation (Frederick et al., 2012; Atteya et al., 2017). A harmine derivative, harmine hydrochloride (Har-hc) has been well-known for its anti-cancer potential against glioblastoma C6, U87, and U373 cells with different inhibitory concentrations. Enhanced levels of p21, and Bax while reduced levels of Bcl-2, and Bcl-xl were examined after Har-hc treatment (Liu et al., 2013). Harmine also showed anti-proliferative activity towards thyroid TPC-1 cells via down-regulation of Bcl- 2 dose-dependently (Ruan et al., 2017). Harmine, a potent inducer of autophagy and apoptosis displayed multiple anti-proliferative effects on gastric SGC-7901 and MGC-803 cancer cell lines. Attempts were made to investigate apoptosis (mitochondrial- mediated, and Akt/mTOR/p70S6K pathway) and autophagy (adenosine 5’-monophosphate-activated protein kinase pathway) affiliated pathways in harmine -treated stomach cancerous cells. Harmine treatment has been linked with the modulation of microtubule protein light chain 3 (LC3-II), Beclin-1, and P62. PI3K/ Akt signaling performs an imperative function in autophagy, DNA repair, apoptosis, cell growth, and translation. A specific combination of 40 µM harmine with 10 µM LY294002 (inhibitor of PI3K/Akt) enhanced Figure 2: Biological activities of harmine Figure 3: Diagram representing organ-based anti-cancer activity of harmine and its derivatives 206 Bangladesh J Pharmacol 2018; 13: 203-213 000 cytotoxicity in gastric cells by up-regulating apoptosis- related proteins (Li et al., 2017). Harmine together with paclitaxel have been reported as the novel drug candi- date in numerous cancer types. Harmine and paclitaxel leads to cellular growth inhibition dose-dependently and apoptosis induction in SGC-7901 cells. The cell death mechanism involves activation of Bax while reduced expression of Bcl-2, COX-2, MMP-2, and PCNA expressions (Yu et al., 2016). In BGC-823 gastric cells, harmine 3c compound (benzylidene substituted β- carboline) exhibited strong apoptotic effect via intra- cellular ROS production, and suppression of PI3K/Akt pathway (Zhang et al., 2016). In a study, an optimized harmine derivative, CM16’s anti-cancer activity was assessed against oligodendro- glioma (Hs683), breast adenocarcinoma (MDA-MB- 231), and melanoma (SKMEL-28) cell lines. CM16 mainly reduced the translation of neosynthesized pro- teins in a dose- and concentration-dependent way with- out affecting mRNA transcription. Moreover, CM16 significantly induced phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) (Carvalho et al., 2017). A benzylidene analog of harmine JKA97 has been documented to be a novel drug candidate for breast cancerous cells both in vivo and in vitro. JKA97 dose- dependently inhibited proliferation of MDA-MB-468 (p53 mutant), MCF-7 (wild-type), and MCF-7 (p53 knockdown) cells. JKA97 also triggered cellular apoptosis and cell cycle arrest at G1 phase (Yang et al., 2012). In breast MDA-MB-231 cell line, harmine enhan- ced the expression of BH3 interacting-domain death agonist (Bid), Bax, TRAIL, caspase-8, and modulator of apoptosis (puma) while Bcl-2 expression was reduced (Bruel et al., 2014; Shabani et al., 2015; Carvalho et al., 2017). Aggregated data indicated that harmine demonstrates pronounced anti-proliferative effects in MCF-7 cells which are associated with the prohibition of telomerase activity. Furthermore, N(9)-acyl deriva- tives of harmine 11c, and 11d with IC50 of <1 µM had displayed remarkable cytotoxic effects against MCF-7 carcinoma cells. The most active derivative of harmine 11d induced apoptosis dose-dependently and caused cell cycle arrest at G2/M phase (Yang et al., 2012; Zhao and Wink 2013; Filali et al., 2015; Du et al., 2016; Filali et al., 2016). Harmine showed potent anti-metastatic activity against melanoma B16F-10 cells. It also prevented tumor invasion, proliferation and migration in vitro. Further, harmine stimulated apoptosis by activating Bax, caspase-3/-8/-9, and Bid along with decreasing Bcl-2 expression in B16F-10 cells. It also blocked the expression of IL-1β, IL-6, and TNF-α which are pro- inflammatory cytokines (Hamsa and Kuttan, 2011). Harmine derivative B-9-3 is an angiogenesis inhibitor. It has been reported to possess strong antitumor and angiogenic effects against Lewis lung cancerous cells (LLC). B-9-3 significantly inhibited the growth of vascular fibroblasts, and endothelial cells, and stimu- lated regression of LLC, human ovary (SKOV-3), prostate (22RV1), and mouse fore-stomach tumor cells. Additionally, B-9-3 elevated apoptotic rate by disrupting VEGF-A/VEGFR2 pathway (Ma et al., 2016). A hybrid of hydroxamic acid and β-carboline alkaloid harmine exhibited cytotoxicity against lung carcinoma (H460) cells through apoptosis induction associated with the activation of Bax, and down-regulating the Bcl- 2 expression (Xu et al., 2016), and also known to have protective effects against A549 cancer cells (Filali et al., 2015; Du et al., 2016). Harmine has the competency to prevent cancer progression in liver Hep3B and Huh-7 cells by inhibiting DYRK1A activity with effective inhibitory concentrations of 10 and 0.25 µM, respectively (Bruel et al., 2014; Zhang et al., 2015). Harmine has also been proved to be effective against liver HepG2, SMMC- 7221, and Bel-7402 cells as it can stimulate cellular apoptosis with the activation of Bax, Fas, and caspase- 3/-9 along with the down-regulating the expression of Bcl-2, and Mcl-1 (Cao et al., 2011). Harmine and its derivatives have been investigated for their anti-cancer activities against colon HCT-116 cells (Filali et al., 2015; Filali et al., 2016; Xu et al., 2016; Zhang et al., 2016)(Figure 3). In another study, harmine exhibited anti-proliferative effect against colon (Caco2) cancer cells through inhibition of protein kinase DYRK1A (Bruel et al., 2014). Increased expression of Bax, caspase-3 along with PARP cleavage while the decreased activity of Bcl-2, CDK5/p25 and GSK3ᵅ/ᵝ were observed against colorectal RKO, and DLDI cells by harmine treatment (Zhang et al., 2016). Harmine prevented the growth of human SW620 cells in a dose- related manner. The percentage of apoptotic cells was enhanced from 12.0 to 26.4% when treated with harmine. Results have shown that harmine has the capability to cause cell cycle arrest at G2/M and S phases associated with the increased expression of cyclin A/B1/E2, CDK1/cdc2, p-cdc2 (Tyr15), and Myt- 1 while decreased expression of cyclin D1. Apoptotic cellular death is accompanied by activation of Bax, PARP, and caspase-3/-9 along with down-regulation of Bcl-2 and Mcl-1 levels. Harmine also inhibited ERK, and Akt pathways in SW620 cells (Liu et al., 2016). Harmine exerted antitumor effects against bladder EJ cells via up-regulating the expression of Bax and down- regulating the expression of Bcl-2 levels (Xu et al., 2016). Harmine derivatives carrying several substituents at position-2, 7 with other β-carboline rings have played effectual roles in modulating cytotoxic activity against mouth KB cells (Zhang et al., 2016). Harmine together with G-CSF and ATRA inhibited proliferation of leuke- mia HL-60 cells in the time- and dose-related concentra- Bangladesh J Pharmacol 2018; 13: 203-213 207 tions (Zhang et al., 2015). It can be concluded that harmine derivative 11d arrest cell cycle at G2/M phase but whether in G2 or M phase should be investigated. Moreover, it would be interesting to interrogate the mechanism by which harmine derivative JKA97 arrest cell cycle at G0/G1 phase in breast adenocarcinoma cells as in case of other cancer cell lines it is generally arresting cells at G2/M or S phase. So, extensive studies are still obligatory to fully understand the molecular mechanism by which harmine and its derivatives regulate the cell cycle. Furthermore, the exact mechanism of action of harmine in colon (HCT-116), ovary (OVCAR-3), prostate (22RV1), and leukemia (HL-60) cancers has not been fully investigated. Anti-inflammatory activity Various studies have determined that anti-inflamma- tory activity of natural products are linked with the prohibition of pro-inflammatory mediators and cyto- kines (TNF-α, iNOS, COX-2), ROS, and transcription factors (NF-κB) (Debnath et al., 2013). Harmine possesses anti-inflammatory potential as it can inhibit the LPS- and TNF-α-stimulated NF-κB trans- activity in mouse macrophages. It also reduced IL-6, IL- 1β, and TNF-α level respectively (Liu et al., 2017). P. harmala alkaloids including harmine have the competency to block myeloperoxidase activity (MPO), and MPO-mediated LDL-oxidation with IC50 of 0.26 µM. Molecular docking analysis indicated that all P. harmala alkaloids have great selectivity for the active site of MPO (Bensalem et al., 2014). Harmine has also been reported to suppress TNF-α, IL-6, and NO production in LPS-induced RAW264 macrophages and THP-1 cells of humans in a dose-dependent manner (Yamazaki and Kawano, 2011; Liu et al., 2017) (Table II). There are only preliminary studies regarding anti- inflammatory efficacy of harmine. Anti-oxidant activity Harmine from P. harmala has the capacity to inhibit CuSO4-mediated LDL oxidation and free radical formation. The anti-oxidant effect of harmine was determined by an increased lag phase time of conjugated dienes, and MDA production. It showed free radical scavenging activity at 10 µM concentration (Berrougui et al., 2006). In another study, harmine was found to prohibit lipid peroxidation in enzymatic Fe3+ADP-NADPH and non-enzymatic Fe3+ADP-DHF oxygen radical generating systems in a concentration- dependent way (Tse et al., 1991). Furthermore, harmine along with other β-carbolines possess protective activity against H2O2-stimulated oxidative injury in both yeast and mammalian cells (Moura et al., 2007). 1-Methylated β-carboline (harmine) also has a potential to block SlN-1-induced mitochondrial injury in PC12 cells. The molecular mechanism involves inhibition of apoptotic cell death, and caspase-3/-9 activity via decreasing ROS, and GSH levels (Choi et al., 2004) (Table III). To date, there have been a limited number of studies regarding anti-oxidant, and free radical scaven- ging activities of harmine. Also, no studies have been done on the anti-oxidant effect of harmine derivatives. Neuroprotective activity The multifarious array of bioactive compounds abundantly found in nature plays an important role in the treatment and prevention of neurodegenerative diseases such as Alzheimer’s, Huntington's and other neuronal dysfunctions (Essa et al., 2012). Alkaloids that are isolated from the seeds of TAPH such as harmine exerts the cerebroprotective effect on ethanol-stimula- ted neurodegeneration and sodium nitrite-stimulated hypoxia in young mice. TAPH eloquently protects the brain from sodium nitrite-induced memory deteriora- tion and retention by reducing the transverse latency time (TLT), and enhancing step down latency (SDL) in a dose-related manner. It also inhibits acetylcholines- terase activity, protects DNA fragmentation, up- regulates GSH level, and down-regulates TBARS expression in brain (Biradar et al., 2013). Preclinical studies on harmine have suggested that it exhibits the neuroprotective effect in a rat model of Table II Molecular targets of anti-inflammatory activities of harmine Assay Organism tested Dose/conc. Molecular targets References Evaluation of anti-inflammatory effect of isoxazoline derivatives from harmine Mouse macrophages (RAW264 cells) 29.2, 55.5 µM - Filali et al., 2015 Anti-inflammatory effects of harmine on myeloperoxidase activity - 0.26 µM - Bensalem et al., 2014 Anti-inflammatory effects of harmine in RAW264 macrophages and THP-1 cells Mouse RAW264 cells, Human THP-1 cells 4, 10, 2.1, 0.02, 8 µM IL-6↓, TNF-α↓, NO↓, Yamazaki and Kawano, 2011 In vitro anti-inflammatory effects of harmine Mouse (RAW264 cells) - TNF-α↓, IL-1β↓, IL-6↓, NF- κB┴ Liu et al., 2017 208 Bangladesh J Pharmacol 2018; 13: 203-213 sclerosis via increasing the activity of glutamate trans- porter-1 (GLT-1), and decreasing TNF-α, IL-1β levels in the hippocampus. Further, post-GCl harmine adminis- tration has the ability to debilitate cerebral infarct volume, and to reduce neuronal cell death in vivo (Li et al., 2011; Sun et al., 2014). Some recent experimentation showed that continuous usage of ayahuasca (harmine- rich hallucinogen) is linked with improved neuro- psychological functioning. Moreover, harmine treat- ment reduced inflammation, excitotoxicity and, oxida- tive stress along with enhanced levels of neurotrophic factors (BDNF), and glutamate transporters in the hippocampus (Dos Santos and Hallak, 2017). Antidepressant activity Various studies in animals have shown that ayahuasca and harmine possess antidepressant-like effects in the behavioral animal model of depression. Harmine and tetrahydroharmine encouraged adult neurogenesis and stimulated neural stem cell growth, migration, and differentiation in vitro (Morales-Garcia et al., 2017). Furthermore, acute and chronic administration of harmine at high dosage (5, 10, 15 mg/kg) demonstrated behavioral and physiological effects by elevating SOD, CAT, BDNF and ACTH circulation levels in a rat model of hippocampus and prefrontal cortex (Fortunato et al., 2009; Fortunato et al., 2010a; Fortunato et al., 2010b; Reus et al., 2010). In another investigation, harmine significantly increased the proliferation in human neural progenitor cells and blocked DYRK1A activity, respectively (Dakic et al., 2016). Harmine has also been known as a modulator of astro- cytic glutamate transporters on CUS-stimulated astro- cytic dysfunctions and depressive behaviors. Harmine treatment (20 mg/kg) improved BDNF expression on hippocampal neurogenesis and up-regulated GLT-1 activity (Liu et al., 2017). Accumulated data by the researchers acclaim that inhibition of monoamine- oxidase A (MAO-A) is associated with antidepressant efficacy of harmine (Chiuccariello et al., 2015; Sacher et al., 2015; Balint et al., 2017; Hamid et al., 2017; Li et al., 2017; Meyer, 2017). Harmine (300 nM) was also repor- ted to augment dopamine efflux by an innovative and 5 -HT(2A) receptor-dependent mechanism (Brierley and Davidson, 2013). Anti-microbial activity Harmine its various synthetic derivatives are known to possess anti-microbial effects against different fungal species such as Fusarium oxysporum, Colletotrichum gloeosporioides (Salman et al., 2016). Harmine exerted a noticeable prohibitory effect on germination of conidia at the concentration between 0.5 to 1 mM. In another study, harmine showed fungicidal activity (>60%) against Physalospora piricola at 50 mg/kg concentration (Olmedo et al., 2017). Furthermore, harmine and its derivatives have anti- viral activities against tobacco mosaic virus as well as anti-fungal effects against Puccinia sorghi (Lu et al., 2015). Harmine has been found to prohibit HSV infection at CC50 value around 337.1 µM and, EC50 value of 1.5 µM in a dose-dependent way. Harmine signifi- cantly down-regulated HSV-2-mediated activation of NF-κB along with p65 nuclear translocation, and IκB-α degeneration. It also blocked HSV-2-induced JNK phosphorylation and p38 MAPK kinase activity, respectively (Chen et al., 2016). Moreover, a synthetic derivative of harmine, 9N-methylharmine demonstrates a strong inhibitory effect on DENV-2 generation. The quantification of extracellular and intracellular viral genomes designated that 9N-methylharmine has capa- bility to debilitate maturation time and discharge of viral entities to the extracellular medium influencing the transmission of the disease (Quintana et al., 2016). The study of harmine’s anti-viral mode of action indicated that it eloquently prohibits enterovirus (EV71) via targeting NF-κB signaling pathway with CC50 value of 500 µM and, EC50 value of 20 µM in vitro. The associated mechanism involves decreased ROS produc- Table III Molecular targets of anti-oxidant function of harmine Assay Organism tested Dose/conc. Mechanisms References Anti-oxidant effect of harmine on CuSO4- stimulated LDL oxidation - 10 µM Decrease in α- tocopherol level Berrougui et al., 2006 Anti-oxidant effect of harmine on lipid peroxidation Sprague Dawley rats 0.5-150 µg/mL - Tse et al., 1991 Defensive effects of harmine against H2O2- induced oxidative damage WT cells, isogenic mutant strains of S. cerevisiae 10, 25, 50 µg/ mL - Moura et al., 2007 Defensive potential of 1-methylated β- carboline (harmine) against 3-morpholino- sydnonimine-mediated mitochondrial damage PC12 cells - Reduction in ROS and GSH levels, inhibition of caspa- se-3/-9 Choi et al., 2004 Bangladesh J Pharmacol 2018; 13: 203-213 209 tion, and suppressed EV71-prompted NF-κB activation. Additionally, harmine treatment has a potential to defend AG129 mice against EV71 replication in vivo (Quintana et al., 2016; Chen et al., 2018). Other biological activities of harmine Harmine has also been known to possess several other biological activities. Primitive studies have declared that harmine is an auspicious anti-malarial agent selectively targeting P. falciparum PfHsp90. The unique and non-toxic harmine analogues 17A and 21A have the affinity to bind with heat shock protein-90, inhibits P. falciparum at concentration of 4.2 ± 1.3 µM and 5.7 ± 1.7 µM during in vitro investigation, decreases parasitaemia and extends survival of P. berghei-affected BALB/c mice (100 mg/kg) in vivo (Bayih et al., 2016). Harmine has the competency to block multinucleated bone resorption and osteoclast differentiation both in vivo and in vitro. In MC3T3-E1 cells, harmine actively induced alkaline phosphatase activity without affecting their growth. Harmine significantly up-regulates mRNA levels of Bmp-2/-4/-6/-7, Runx2, Osterix, as well as its target genes ld1 and ld2. In another investi- gation, harmine treatment (10 mg/kg/day) prevented osteoclast production by RANKL-stimulated bone resorption via reducing the expression of NFATc1 (a key regulator of osteoclastogenesis), c-Fos respectively (Egusa et al., 2011; Yonezawa et al., 2011). Further, the chondroprotective effect of harmine was examined under inflammatory situation by induction with TNF-α. Results showed that in human HCS-2/8 cells, harmine is capable to attenuate TNF-α-stimulated reduction in the expression and activity of cartilage markers (COL2α1, aggrecan) and CCN2 (Egusa et al., 2011). Harmine is efficiently utilized in biotechnological fields (Rasse-Suriani et al., 2018) with some more bioactivities including anti-mutagenic, and anti-genotoxic (Patel et al., 2012). Harmine along with other alkaloids have shown anti- leishmanial activity against Leishmania infantum (with both forms of parasites e.g. amastigote and promasti- gote) in vivo in hamster models (Dai et al., 2012). Har- mine acts as an anti-toxoplasmic agent against Toxoplas- ma gondii (Alomar et al., 2013), as a photosensitizer (Vignoni et al., 2013) and also as an anti-trichomonal agent against T. gallinae (Tabari et al., 2017). Conclusion Harmine is a potent drug candidate and its synthetic derivatives exhibit pharmacological and biological effects in various ailments through diversified mecha- nisms of action. Pharmacodynamically and pharmaco- kinetically up-graded harmine and its derivatives may also boost up further advances. This review has emphasized on recent researches from various in vivo and in vitro investigations on the ability of harmine and its derivatives to cure different pathological conditions. Conflict of Interest Authors declare that no conflicts of interest exist. Acknowledgement This study was supported by the research grants from the TWAS-COMSTECH (no.17-180 RG/PHA/AS_C) and The Nagai Foundation Tokyo, Japan (NFT-R4-2017 and NFT-R- 2018). 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