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Subchronic exposure to mitragynine, the principal alkaloid of Mitragyna speciosa, in rats

Sabetghadam A, Ramanathan S, Sasidharan S, Mansor SM

J Ethnopharmacol, 2013 Apr 19;146(3):815-23.
PMID: 23422336 DOI: 10.1016/j.jep.2013.02.008

ETHNOPHARMACOLOGICAL RELEVANCE: Mitragyna speciosa is a popular medicinal plant in Southeast Asia which is commonly used for its morphine-like effects. Although the analgesic properties of Mitragyna speciosa and its ability to ameliorate withdrawal signs after abrupt cessation of opioid abuse are well known, information about the long-term safety of the plant's active compounds is lacking. In this work, we evaluated the effects of sub-chronic exposure to mitragynine, the principal alkaloid of Mitragyna speciosa leaves in rats.
MATERIALS AND METHODS: Male and female Sprague-Dawley rats received three doses of mitragynine (1, 10, 100mg/kg, p.o) for 28 days respectively. Food intake and relative body weight were measured during the experiment. After completion of drug treatment biochemical, hematological, and histological analyses were performed.
RESULTS: No mortality was observed in any of the treatment groups. The groups of rats treated with the lower and intermediate doses showed no toxic effects during the study. However, the relative body weight of the group of female rats treated with the 100mg/kg dose was decreased significantly. Food intake also tended to decrease in the same group. Only relative liver weight increased after treatment with the high dose of mitragynine (100mg/ kg) in both the male and female treatment groups of rats. Biochemical and hematological parameters were also altered especially in high dose treatment group which corresponds to the histopathological changes.
CONCLUSIONS: The study demonstrated that mitragynine is relatively safe at lower sub-chronic doses (1-10mg/kg) but exhibited toxicity at a highest dose (sub-chronic 28 days: 100mg/kg). This was confirmed by liver, kidney, and brain histopathological changes, as well as hematological and biochemical changes.

Matched MeSH terms: Secologanin Tryptamine Alkaloids/administration & dosage; Secologanin Tryptamine Alkaloids/isolation & purification; Secologanin Tryptamine Alkaloids/toxicity*
Biologically active aspidofractinine alkaloids from Kopsia singapurensis

Subramaniam G, Hiraku O, Hayashi M, Koyano T, Komiyama K, Kam TS

J Nat Prod, 2008 Jan;71(1):53-7.
PMID: 18078327

Ten new indole alkaloids of the aspidofractinine type, in addition to several recently reported indole alkaloids and 20 other known alkaloids, were obtained from the leaf and stem-bark extract of the Malayan Kopsia singapurensis, viz., kopsimalines A-E (1-5), kopsinicine (6), kopsofinone (7), and kopsiloscines H-J (8-10). The structures of these alkaloids were determined using NMR and MS analysis. Kopsimalines A (1), B (2), C (3), D (4), and E (5) and kopsiloscine J (10) were found to reverse multidrug-resistance in vincristine-resistant KB cells, with 1 showing the highest potency.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/pharmacology*; Indole Alkaloids/chemistry
Annonaceae: bio-resource for tomorrow's drug discovery

Aminimoghadamfarouj N, Nematollahi A, Wiart C

J Asian Nat Prod Res, 2011 May;13(5):465-76.
PMID: 21534046 DOI: 10.1080/10286020.2011.570265

One of the rich sources of lead compounds is the Angiosperms. Many of these lead compounds are useful medicines naturally, whereas others have been used as the basis for synthetic agents. These are potent and effective compounds, which have been obtained from plants, including anti-cancer (cytotoxic) agents, anti-malaria (anti-protozoal) agents, and anti-bacterial agents. Today, the number of plant families that have been extensively studied is relatively very few and the vast majorities have not been studied at all. The Annonaceae is the largest family in the order Magnoliales. It includes tropical trees, bushes, and climbers, which are often used as traditional remedies in Southeast Asia. Members of the Annonaceae have the particularity to elaborate a broad spectrum of natural products that have displayed anti-bacterial, anti-fungal, and anti-protozoal effects and have been used for the treatment of medical conditions, such as skin diseases, intestinal worms, inflammation of the eyes, HIV, and cancer. These special effects and the vast range of variation in potent compounds make the Annonaceae unique from other similar families in the Magnoliales and the Angiosperms in general. This paper attempts to summarize some important information and discusses a series of hypotheses about the effects of Annonaceae compounds.

Matched MeSH terms: Alkaloids
Fulltext (+)-Kunstlerone, a new antioxidant neolignan from the Leaves of Beilschmiedia kunstleri gamble

Mollataghi A, Hadi AH, Awang K, Mohamad J, Litaudon M, Mukhtar MR

Molecules, 2011 Aug 04;16(8):6582-90.
PMID: 21818061 DOI: 10.3390/molecules16086582

A new neolignan, 3,4-dimethoxy-3',4'-methylenedioxy-2,9-epoxy-6,7-cyclo-1,8-neolign-11-en-5(5H)-one, which has been named (+)-kunstlerone (1), together with six known alkaloids: (+)-norboldine (2), (+)-N-methylisococlaurine (3), (+)-cassythicine (4), (+)-laurotetanine (5), (+)-boldine (6) and (-)-pallidine (7), were isolated from the leaves of Beilschmiedia kunstleri. The structures were established through various spectroscopic methods notably 1D- and 2D-NMR, UV, IR and LCMS-IT-TOF. (+)- Kunstlerone (1) showed a strong antioxidant activity, with an SC(50) of 20.0 µg/mL.

Matched MeSH terms: Alkaloids/isolation & purification*; Alkaloids/pharmacology; Alkaloids/chemistry
Ancistrobenomine a, the first naphthylisoquinoline oxygenated at Me-3, and related 5,1'-coupled alkaloids, from the "new" plant species ancistrocladusbenomensis

Bringmann G, Dreyer M, Rischer H, Wolf K, Hadi HA, Brun R, et al.

J Nat Prod, 2004 Dec;67(12):2058-62.
PMID: 15620251

Three new 5,1'-coupled naphthylisoquinoline alkaloids, ancistrobenomine A (1), 6-O-demethylancistrobenomine A (2), and 5'-O-demethylancistrocline (3), have been isolated from the stem bark of a botanically as yet undescribed highland liana Ancistrocladus sp., proposed to be named "A. benomensis" according to the region in Peninsular Malaysia where it has been discovered on the mountain of Gunung Benom. Two of the compounds possess an unprecedented structure with a novel hydroxymethylene group at C-3 of the fully dehydrogenated isoquinoline moiety. The structural elucidation was achieved by chemical, spectroscopic, and chiroptical methods. As typical of the so-called Ancistrocladaceae type, all of the compounds isolated bear an oxygen at C-6. Biological activities of these alkaloids against different protozoic pathogens are described.

Matched MeSH terms: Alkaloids/isolation & purification*; Alkaloids/pharmacology; Alkaloids/chemistry
Cytotoxic vobasine, tacaman, and corynanthe-tryptamine bisindole alkaloids from Tabernaemontana and structure revision of tronoharine

Sim DS, Chong KW, Nge CE, Low YY, Sim KS, Kam TS

J Nat Prod, 2014 Nov 26;77(11):2504-12.
PMID: 25333996 DOI: 10.1021/np500589u

Seven new indole alkaloids (1-7) comprising four vobasine, two tacaman, and one corynanthe-tryptamine bisindole alkaloid were isolated from the stem-bark extract of a Malayan Tabernaemontana. Two of the new vobasine alkaloids (1, 3), as well as 16-epivobasine (15) and 16-epivobasenal (17), showed appreciable cytotoxicity toward KB cells (IC50 ca. 5 μg/mL). The structure of the known Tabernaemontana alkaloid tronoharine (8) was revised based on newly acquired NMR data, as well as X-ray diffraction analysis.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/pharmacology*; Indole Alkaloids/chemistry
Fulltext Evaluation of the cardiotoxicity of mitragynine and its analogues using human induced pluripotent stem cell-derived cardiomyocytes

Lu J, Wei H, Wu J, Jamil MF, Tan ML, Adenan MI, et al.

PLoS One, 2014;9(12):e115648.
PMID: 25535742 DOI: 10.1371/journal.pone.0115648

INTRODUCTION: Mitragynine is a major bioactive compound of Kratom, which is derived from the leave extracts of Mitragyna speciosa Korth or Mitragyna speciosa (M. speciosa), a medicinal plant from South East Asia used legally in many countries as stimulant with opioid-like effects for the treatment of chronic pain and opioid-withdrawal symptoms. Fatal incidents with Mitragynine have been associated with cardiac arrest. In this study, we determined the cardiotoxicity of Mitragynine and other chemical constituents isolated using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
METHODS AND RESULTS: The rapid delayed rectifier potassium current (IKr), L-type Ca2+ current (ICa,L) and action potential duration (APD) were measured by whole cell patch-clamp. The expression of KCNH2 and cytotoxicity was determined by real-time PCR and Caspase activity measurements. After significant IKr suppression by Mitragynine (10 µM) was confirmed in hERG-HEK cells, we systematically examined the effects of Mitragynine and other chemical constituents in hiPSC-CMs. Mitragynine, Paynantheine, Speciogynine and Speciociliatine, dosage-dependently (0.1∼100 µM) suppressed IKr in hiPSC-CMs by 67%∼84% with IC50 ranged from 0.91 to 2.47 µM. Moreover, Mitragynine (10 µM) significantly prolonged APD at 50 and 90% repolarization (APD50 and APD90) (439.0±11.6 vs. 585.2±45.5 ms and 536.0±22.6 vs. 705.9±46.1 ms, respectively) and induced arrhythmia, without altering the L-type Ca2+ current. Neither the expression, and intracellular distribution of KCNH2/Kv11.1, nor the Caspase 3 activity were significantly affected by Mitragynine.
CONCLUSIONS: Our study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of IKr in human cardiomyocytes.

Matched MeSH terms: Secologanin Tryptamine Alkaloids/isolation & purification; Secologanin Tryptamine Alkaloids/toxicity*; Secologanin Tryptamine Alkaloids/chemistry
Corynanthean, eburnan, secoleuconoxine, and pauciflorine alkaloids from Kopsia pauciflora

Gan CY, Yoganathan K, Sim KS, Low YY, Lim SH, Kam TS

Phytochemistry, 2014 Dec;108:234-42.
PMID: 25442910 DOI: 10.1016/j.phytochem.2014.09.014

Eleven indole alkaloids, comprising four corynanthean, two eburnane, one aspidofractinine, one secoleuconoxine, one andranginine, and two pauciflorine type alkaloids were isolated from the stem-bark and leaf extracts of Kopsia pauciflora. Their structures were determined using NMR and MS analyses. The catharinensine type alkaloid kopsirensine B and the secoleuconoxine alkaloid arboloscine A showed moderate to weak activity in reversing MDR in vincristine-resistant KB cells. The alkaloid content was markedly different compared to that of a sample from Malaysian Borneo.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/pharmacology; Indole Alkaloids/chemistry
Ibogan, tacaman, and cytotoxic bisindole alkaloids from tabernaemontana. Cononusine, an iboga alkaloid with unusual incorporation of a pyrrolidone moiety

Lim KH, Raja VJ, Bradshaw TD, Lim SH, Low YY, Kam TS

J Nat Prod, 2015 May 22;78(5):1129-38.
PMID: 25919190 DOI: 10.1021/acs.jnatprod.5b00117

Six new indole alkaloids, viz., cononusine (1, a rare example of an iboga-pyrrolidone conjugate), ervaluteine (2), vincamajicine (3), tacamonidine (4), 6-oxoibogaine (5), and N(4)-chloromethylnorfluorocurarine chloride (6), and two new vobasinyl-iboga bisindole alkaloids, ervatensines A (7) and B (8), in addition to other known alkaloids, were isolated from the stem-bark extract of the Malayan Tabernaemontana corymbosa. The structures of these alkaloids were established on the basis of NMR and MS analyses and, in one instance (7), confirmed by X-ray diffraction analysis. Vincamajicine (3) showed appreciable activity in reversing multidrug resistance in vincristine-resistant KB cells (IC50 2.62 μM), while ervatensines A (7) and B (8) and two other known bisindoles displayed pronounced in vitro growth inhibitory activity against human KB cells (IC50 < 2 μM). Compounds 7 and 8 also showed good growth inhibitory activity against A549, MCF-7, MDA-468, HCT-116, and HT-29 cells (IC50 0.70-4.19 μM). Cell cycle and annexin V-FITC apoptosis assays indicated that compounds 7 and 8 inhibited proliferation of HCT-116 and MDA-468 cells, evoking apoptotic and necrotic cell death.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/pharmacology*; Indole Alkaloids/chemistry
Macroline, akuammiline, sarpagine, and ajmaline alkaloids from Alstonia macrophylla

Lim SH, Low YY, Sinniah SK, Yong KT, Sim KS, Kam TS

Phytochemistry, 2014 Feb;98:204-15.
PMID: 24342109 DOI: 10.1016/j.phytochem.2013.11.014

A total of seventeen alkaloids, comprising six macroline (including alstofolinine A, a macroline indole incorporating a butyrolactone ring-E), two ajmaline, one sarpagine, and eight akuammiline alkaloids, were isolated from the stem-bark and leaf extracts of the Malayan Alstonia macrophylla. The structure and relative configurations of these alkaloids were established using NMR, MS and in several instances, confirmed by X-ray diffraction analysis. Six of these alkaloids were effective in reversing multidrug-resistance (MDR) in vincristine-resistant KB cells.

Matched MeSH terms: Indole Alkaloids/isolation & purification; Indole Alkaloids/pharmacology*; Indole Alkaloids/chemistry
Fulltext Antiplasmodial alkaloids from the bark of Cryptocarya nigra (Lauraceae)

Nasrullah AA, Zahari A, Mohamad J, Awang K

Molecules, 2013 Jul 08;18(7):8009-17.
PMID: 23884132 DOI: 10.3390/molecules18078009

A dichloromethane extract of the stem bark of Cryptocarya nigra showed strong in vitro inhibition of Plasmodium falciparum growth, with an IC50 value of 2.82 μg/mL. The phytochemical study of this extract has led to the isolation and characterization of four known alkaloids: (+)-N-methylisococlaurine (1), atherosperminine (2), 2-hydroxyathersperminine (3), and noratherosperminine (4). Structural elucidation of all alkaloids was accomplished by means of high field 1D- and 2D-NMR, IR, UV and LCMS spectral data. The isolated extract constituents (+)-N-methylisococlaurine (1), atherosperminine (2) and 2-hydroxy-atherosperminine (3) showed strong antiplasmodial activity, with IC50 values of 5.40, 5.80 and 0.75 μM, respectively. In addition, (+)-N-methylisocolaurine (1) and atherosperminine (2) showed high antioxidant activity in a DPPH assay with IC50 values of 29.56 ug/mL and 54.53 ug/mL respectively. Compounds 1 and 2 also both showed high antioxidant activity in the FRAP assay, with percentages of 78.54 and 70.66 respectively and in the metal chelating assay, with IC50 values of 50.08 ug/mL and 42.87 ug/mL, respectively.

Matched MeSH terms: Alkaloids/isolation & purification; Alkaloids/pharmacology*; Alkaloids/chemistry
Fulltext Aporphine alkaloids from the leaves of Phoebe grandis (Nees) Mer. (Lauraceae) and their cytotoxic and antibacterial activities

Omar H, Hashim NM, Zajmi A, Nordin N, Abdelwahab SI, Azizan AH, et al.

Molecules, 2013 Jul 29;18(8):8994-9009.
PMID: 23899833 DOI: 10.3390/molecules18088994

The oxoaporphine alkaloid lysicamine (1), and three proaporphine alkaloids, litsericinone (2), 8,9,11,12-tetrahydromecambrine (3) and hexahydromecambrine A (4) were isolated from the leaves of Phoebe grandis (Nees) Merr. (Lauraceae). Compounds 2 and 3 were first time isolated as new naturally occurring compounds from plants. The NMR data for the compounds 2-4 have never been reported so far. Compounds 1 and 2 showed significant cytotoxic activity against a MCF7 (human estrogen receptor (ER+) positive breast cancer) cell line with IC₅₀ values of 26 and 60 µg/mL, respectively. Furthermore, in vitro cytotoxic activity against HepG2 (human liver cancer) cell line was evaluated for compounds 1-4 with IC₅₀ values of 27, 14, 81 and 20 µg/mL, respectively. Lysicamine (1) displayed strong antibacterial activity against Bacillus subtilis (B145), Staphylococcus aureus (S1434) and Staphylococus epidermidis (a clinically isolated strain) with inhibition zones of 15.50 ± 0.57, 13.33 ± 0.57 and 12.00 ± 0.00 mm, respectively. However, none of the tested pathogenic bacteria were susceptible towards compounds 2 and 3.

Matched MeSH terms: Alkaloids/administration & dosage*; Alkaloids/isolation & purification; Alkaloids/chemistry
Aspidofractinine and Eburnane Alkaloids from a North Borneo Kopsia. Ring-Contracted, Additional Ring-Fused, and Paucidactine-Type Aspidofractinine Alkaloids from K. pauciflora

Yap WS, Gan CY, Sim KS, Lim SH, Low YY, Kam TS

J Nat Prod, 2016 Jan 22;79(1):230-9.
PMID: 26717050 DOI: 10.1021/acs.jnatprod.5b00992

Eleven new indole alkaloids (1-11) comprising seven aspidofractinine and four eburnane alkaloids, were isolated from the stem-bark extract of Kopsia pauciflora occurring in Malaysian Borneo. The aspidofractinine alkaloids include a ring-contracted, an additional ring-fused, a paucidactine regioisomer, two paucidactine, and one kopsine alkaloid. The structures of several of these alkaloids were also confirmed by X-ray diffraction analyses. The bisindole alkaloids isolated, norpleiomutine and kopsoffinol, showed in vitro growth inhibitory activity against human PC-3, HCT-116, MCF-7, and A549 cells and moderate effects in reversing multidrug-resistance in vincristine-resistant human KB cells.

Matched MeSH terms: Indole Alkaloids/isolation & purification*; Indole Alkaloids/pharmacology*; Indole Alkaloids/chemistry
Bisleuconothine A Induces Autophagosome Formation by Interfering with AKT-mTOR Signaling Pathway

Wong CP, Seki A, Horiguchi K, Shoji T, Arai T, Nugroho AE, et al.

J Nat Prod, 2015 Jul 24;78(7):1656-62.
PMID: 26176165 DOI: 10.1021/acs.jnatprod.5b00258

We have previously reported that bisleuconothine A (Bis-A), a novel bisindole alkaloid isolated from Leuconotis griffithii, showed cytostatic activity in several cell lines. In this report, the mechanism of Bis-A-induced cytostatic activity was investigated in detail using A549 cells. Bis-A did not cause apoptosis, as indicated by analysis of annexin V and propidium iodide staining. Expression of all tested apoptosis-related proteins was also unaffected by Bis-A treatment. Bis-A was found to increase LC3 lipidation in MCF7 cells as well as A549 cells, suggesting that Bis-A cytostatic activity may be due to induction of autophagy. Subsequent investigation via Western blotting and immunofluorescence staining indicated that Bis-A induced formation but prevented degradation of autophagosomes. Mechanistic studies showed that Bis-A down-regulated phosphorylation of protein kinase B (AKT) and its downstream kinase, PRAS40, which is an mTOR repressor. Moreover, phosphorylation of p70S6K, an mTOR-dependent kinase, was also down-regulated. Down-regulation of these kinases suggests that the increase in LC3 lipidation may be due to mTOR deactivation. Thus, the cytostatic activity shown by Bis-A may be attributed to its induction of autophagosome formation. The Bis-A-induced autophagosome formation was suggested to be caused by its interference with the AKT-mTOR signaling pathway.

Matched MeSH terms: Indole Alkaloids/isolation & purification; Indole Alkaloids/pharmacology*; Indole Alkaloids/chemistry
Intestinal permeability of mitragynine in rats using in situ absorption model

Jagabalan JDY, Murugaiyah V, Zainal H, Mansor SM, Ramanathan S

J Asian Nat Prod Res, 2019 Apr;21(4):351-363.
PMID: 29667422 DOI: 10.1080/10286020.2018.1461088

The intestinal permeability of mitragynine was investigated in situ using a single pass intestinal perfusion (SPIP) absorption model, in small intestine of rat using mitragynine in the absence/presence of the permeability markers, P-gp and/or CYP3A4 inhibitors. Mitragynine demonstrated high intestinal permeability (Peff of 1.11 × 10-4 cm/s) that is in the range of highly permeable drugs such as propranolol (Peff of 1.27 × 10-4 cm/s) indicating that it readily crosses the intestine. The addition of azithromycin (P-glycoprotein inhibitor) and ciprofloxacin (CYP3A4 inhibitor) or combination of both has no effect on intestinal permeability of mitragynine across the rat small intestine.

Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacokinetics*
The inhibitory effects of mitragynine on P-glycoprotein in vitro

Rusli N, Amanah A, Kaur G, Adenan MI, Sulaiman SF, Wahab HA, et al.

Naunyn Schmiedebergs Arch Pharmacol, 2019 04;392(4):481-496.
PMID: 30604191 DOI: 10.1007/s00210-018-01605-y

Mitragynine is a major component isolated from Mitragyna speciosa Korth or kratom, a medicinal plant known for its opiate-like and euphoric properties. Multiple toxicity and fatal cases involving mitragynine or kratom have been reported but the underlying causes remain unclear. P-glycoprotein (P-gp) is a multidrug transporter which modulates the pharmacokinetics of xenobiotics and plays a key role in mediating drug-drug interactions. This study investigated the effects of mitragynine on P-gp transport activity, mRNA, and protein expression in Caco-2 cells using molecular docking, bidirectional assay, RT-qPCR, Western blot analysis, and immunocytochemistry techniques, respectively. Molecular docking simulation revealed that mitragynine interacts with important residues at the nucleotide binding domain (NBD) site of the P-gp structure but not with the residues from the substrate binding site. This was consistent with subsequent experimental work as mitragynine exhibited low permeability across the cell monolayer but inhibited digoxin transport at 10 μM, similar to quinidine. The reduction of P-gp activity in vitro was further contributed by the downregulation of mRNA and protein expression of P-gp. In summary, mitragynine is likely a P-gp inhibitor in vitro but not a substrate. Hence, concurrent administration of mitragynine-containing kratom products with psychoactive drugs which are P-gp substrates may lead to clinically significant toxicity. Further clinical study to prove this point is needed.

Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
Tissue-specific and maturity-dependent distribution of pyridine alkaloids in Areca triandra

Wu J, Zhang H, Wang S, Yuan L, Grünhofer P, Schreiber L, et al.

J Plant Res, 2019 Jul;132(4):531-540.
PMID: 31127431 DOI: 10.1007/s10265-019-01115-9

Areca nuts (seeds of Areca catechu L.) are a traditional and popular masticatory in India, Bangladesh, Malaysia, certain parts of China, and some other countries. Four related pyridine alkaloids (arecoline, arecaidine, guvacoline, and guvacine) are considered being the main functional ingredients in areca nut. Until now, A. catechu is the only known species producing these alkaloids in the Arecaceae family. In the present study, we investigated alkaloid contents in 12 Arecaceae species and found that only Areca triandra Roxb. contained these pyridine alkaloids. We further analyzed in more detail tissue-specific and development-related distribution of these alkaloids in leaves, male and female flowers and fruits in different stages of maturity in A. triandra by ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry. Results revealed that the alkaloids were most abundant in young leaves, the pericarp of ripe fruits and the endosperm of unripe fruits in developmental stage 2. Abundance of the 4 different alkaloids in A. triandra fruits varied during maturation. Pericarps of ripe fruits had the highest arecaidine concentration (4.45 mg g-1) and the lowest guvacoline concentration (0.0175 mg g-1), whereas the endosperm of unripe fruits of developmental stage 2 contained the highest guvacoline concentration (3.39 mg g-1) and the lowest guvacine concentration (0.245 mg g-1). We conclude that A. triandra is useful in future as a further valuable source of Areca alkaloids.

Matched MeSH terms: Alkaloids/metabolism*
Fulltext Simultaneous quantification of ten key Kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra-performance liquid chromatography-tandem mass spectrometry

Sharma A, Kamble SH, León F, Chear NJ, King TI, Berthold EC, et al.

Drug Test Anal, 2019 Aug;11(8):1162-1171.
PMID: 30997725 DOI: 10.1002/dta.2604

Kratom (Mitragyna speciosa) is a psychoactive plant popular in the United States for the self-treatment of pain and opioid addiction. For standardization and quality control of raw and commercial kratom products, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of ten key alkaloids, namely: corynantheidine, corynoxine, corynoxine B, 7-hydroxymitragynine, isocorynantheidine, mitragynine, mitraphylline, paynantheine, speciociliatine, and speciogynine. Chromatographic separation of diastereomers, or alkaloids sharing same ion transitions, was achieved on an Acquity BEH C18 column with a gradient elution using a mobile phase containing acetonitrile and aqueous ammonium acetate buffer (10mM, pH 3.5). The developed method was linear over a concentration range of 1-200 ng/mL for each alkaloid. The total analysis time per sample was 22.5 minutes. The analytical method was validated for accuracy, precision, robustness, and stability. After successful validation, the method was applied for the quantification of kratom alkaloids in alkaloid-rich fractions, ethanolic extracts, lyophilized teas, and commercial products. Mitragynine (0.7%-38.7% w/w), paynantheine (0.3%-12.8% w/w), speciociliatine (0.4%-12.3% w/w), and speciogynine (0.1%-5.3% w/w) were the major alkaloids in the analyzed kratom products/extracts. Minor kratom alkaloids (corynantheidine, corynoxine, corynoxine B, 7-hydroxymitragynine, isocorynantheidine) were also quantified (0.01%-2.8% w/w) in the analyzed products; however mitraphylline was below the lower limit of quantification in all analyses.

Matched MeSH terms: Alkaloids/analysis*
Fulltext Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells

Tay YL, Amanah A, Adenan MI, Wahab HA, Tan ML

Sci Rep, 2019 12 24;9(1):19757.
PMID: 31874991 DOI: 10.1038/s41598-019-56106-6

Mitragyna speciosa Korth (M. speciosa) has been widely used as a recreational product, however, there are growing concerns on the abuse potentials and toxicity of the plant. Several poisoning and fatal cases involving kratom and mitragynine have been reported but the underlying causes remain unclear. The human ether-a-go-go-related gene 1 (hERG1) encodes the pore-forming subunit underlying cardiac rapidly delayed rectifier potassium current (IKr). Pharmacological blockade of the IKr can cause acquired long QT syndrome, leading to lethal cardiac arrhythmias. This study aims to elucidate the mechanisms of mitragynine-induced inhibition on hERG1a/1b current. Electrophysiology experiments were carried out using Port-a-Patch system. Quantitative RT-PCR, Western blot analysis, immunofluorescence and co-immunoprecipitation methods were used to determine the effects of mitragynine on hERG1a/1b expression and hERG1-cytosolic chaperones interaction. Mitragynine was found to inhibit the IKr current with an IC50 value of 332.70 nM. It causes a significant reduction of the fully-glycosylated (fg) hERG1a protein expression but upregulates both core-glycosylated (cg) expression and hERG1a-Hsp90 complexes, suggesting possible impaired hERG1a trafficking. In conclusion, mitragynine inhibits hERG1a/1b current through direct channel blockade at lower concentration, but at higher concentration, it upregulates the complexation of hERG1a-Hsp90 which may be inhibitory towards channel trafficking.

Matched MeSH terms: Secologanin Tryptamine Alkaloids/pharmacology*
Neuropharmacological potentials of β-carboline alkaloids for neuropsychiatric disorders

Ayipo YO, Mordi MN, Mustapha M, Damodaran T

Eur J Pharmacol, 2021 Feb 15;893:173837.
PMID: 33359647 DOI: 10.1016/j.ejphar.2020.173837

Neuropsychiatric disorders are diseases of the central nervous system (CNS) which are characterised by complex pathomechanisms that including homeostatic failure, malfunction, atrophy, pathology remodelling and reactivity anomaly of the neuronal system where treatment options remain challenging. β-Carboline (βC) alkaloids are scaffolds of structurally diverse tricyclic pyrido[3,4-b]indole alkaloid with vast occurrence in nature. Their unique structural features which favour interactions with enzymes and protein receptor targets account for their potent neuropharmacological properties. However, our current understanding of their biological mechanisms for these beneficial effects, especially for neuropsychiatric disorders is sparse. Therefore, we present a comprehensive review of the scientific progress in the last two decades on the prospective pharmacology and physiology of the βC alkaloids in the treatment of some neuropsychiatric conditions such as depression, anxiety, Alzheimer's disease, Parkinson's disease, brain tumour, essential tremor, epilepsy and seizure, licking behaviour, dystonia, agnosia, spasm, positive ingestive response as demonstrated in non-clinical models. The current evidence supports that βC alkaloids offer potential therapeutic agents against most of these disorders and amenable for further drug design.

Matched MeSH terms: Alkaloids; Indole Alkaloids

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