Abstract
IntroductionMitragynine 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 ResultsThe rapid delayed rectifier potassium current (I Kr), L-type Ca2+ current (I Ca,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 I Kr 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 I Kr 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.ConclusionsOur study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of I Kr in human cardiomyocytes.
Highlights
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
After significant IKr. Suppression of hERG/Kv11.1 (IKr) suppression by Mitragynine (10 mM) was confirmed in human Ether-a-go-go-Related Gene (hERG)-human embryonic kidney (HEK) cells, we systematically examined the effects of Mitragynine and other chemical constituents in human induced pluripotent stem cells (hiPSCs)-CMs
Recent progress in generating human induced pluripotent stem cells from somatic cells by reprogramming helps to create a unique source of functional human cardiomyocytes named hiPSC-derived cardiomyocytes generated via cardiomyogenic differentiation of hiPSCs. [19] hiPSC-CMs have ionic currents characteristics resembling those reported for adult human cardiomyocytes. [20, 21] They have been successfully adopted in disease modeling of long QT syndrome (LQTS) and drug testing [22]
Summary
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. We determined the cardiotoxicity of Mitragynine and other chemical constituents isolated using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). [18] Cardiotoxicity assessment using hERG-overexpressing human embryonic kidney (HEK) cells has been commonly utilized though human cardiomyocytes may be a more pertinent model as both IKr and the action potential duration (APD) could be determined. Our data show that Mitragynine and its analogues, at concentrations close to the plasma levels reported in lethal cases, [16, 23] exert a significant cardiotoxicity by inhibiting hERG current, prolonging APD and inducing arrhythmia
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