The Effects of Ibogaine on Uterine Smooth Muscle Contractions: Relation to the Activity of Antioxidant Enzymes

Abstract

Ibogaine is an indole alkaloid originally extracted from the root bark of the African rainforest shrub Tabernanthe iboga. It has been explored as a treatment for substance abuse because it interrupts drug addiction and relieves withdrawal symptoms. However, it has been shown that ibogaine treatment leads to a sharp and transient fall in cellular ATP level followed by an increase of cellular respiration and ROS production. Since contractile tissues are sensitive to changes in the levels of ATP and ROS, here we investigated an ibogaine-mediated link between altered redox homeostasis and uterine contractile activity. We found that low concentrations of ibogaine stimulated contractile activity in spontaneously active uteri, but incremental increase of doses inhibited it. Inhibitory concentrations of ibogaine led to decreased SOD1 and elevated GSH-Px activity, but doses that completely inhibited contractions increased CAT activity. Western blot analyses showed that changes in enzyme activities were not due to elevated enzyme protein concentrations but posttranslational modifications. Changes in antioxidant enzyme activities point to a vast concentration-dependent increase in H2O2 level. Knowing that extracellular ATP stimulates isolated uterus contractility, while H2O2 has an inhibitory effect, this concentration-dependent stimulation/inhibition could be linked to ibogaine-related alterations in ATP level and redox homeostasis.

Ibogaine-Mediated ROS/Antioxidant Elevation in Isolated Rat Uterus Is β-Adrenergic Receptors and KATP Channels Mediated

“…Its effects depend on applied dose and tissue distribution, with the most prominent effects involving the most sensitive receptor and effector(s). Sigmoid response of uterine contractility to an increasing dose of ibogaine in a hormetic manner found in our previous work [14] was in concordance with observed effects at traditional use of iboga, where small doses were used for its stimulant properties while higher doses used in ritual context were praised for their inhibitory influence on brain cortex causing shifts in perception with emergence of subconscious contents. However, increasing the addition of ibogaine led to cessation of uterine contractility ex vivo which could possibly be attributed to different receptors and eventually a reversible ATP and/or Ca 2+ depletion.…”

Effects of ibogaine per os application on redox homeostasis in rat liver and erythrocytes

“…At the doses used in our study, it seems that ibogaine did not provoke a significant antioxidative response either in the liver or at the systemic level. However, since ibogaine effects are rapid, it is possible that compensatory antioxidative activities by antioxidative enzymes were carried out soon after ibogaine administration, much earlier than at 6 or 24 h. Previous results from in vitro studies on yeast [11,12], ex vivo data obtained in human erythrocytes [13] and isolated rat uterus [15] showed that antioxidant enzymes responded to an ibogaine challenge by changing their activities. Furthermore, previous results on yeast showed that 5 h is the time period necessary for ROS production to return to the normal cellular level after application of ibogaine at doses ranging from 1 to 20 mg/L [11].…”

“…It was also shown that ibogaine caused rapid depletion of ATP that was accompanied by increased production of reactive oxygen species (ROS) [13] and activation of antioxidant defense enzymes in yeast [11]. While ibogaine in vitro did not show any significant antioxidant properties per se [12], the observed ibogaineassociated increase in activities of antioxidant enzymes (cytosolic copper-zinc superoxide dismutase (SOD1), glutathione reductase (GR) [13] and catalase (CAT) [15]) in different in vitro [12] and ex vivo [13] model systems supported ibogaine as a pro/antioxidative agent. In previous work on yeast [11], elevated expression of metabolic enzymes involved in glycolysis and of SOD protein were detected after 5 h at a dose of 1 mg/L ibogaine (equivalent to ibogaine levels found in brains of rats that received 20 mg/kg b.w., i.p.).…”

“…Having in mind ibogaine pharmacokinetics, as well as its influence on both energy metabolism and the activity of antioxidant enzymes explored ex vivo [11,12,15] and in vitro [13] using different doses and experimental models, herein we examined the effects of ibogaine in vivo after application of a single dose (1 or 20 mg/kg b.w., p.o.) on rat liver and erythrocytes after 6 and 24 h. Histological examination of the liver was performed in order to (i) visualize the potential changes in the amount of glycogen (as representation of energy metabolism), and (ii) to examine the possible morphological effects on hepatocytes.…”

Effects of ibogaine per os treatment on redox homeostasis in rat kidney

“…In addition, thiobarbituric acid reactive substances (TBARS) were elevated 6 h after application of 1 mg/kg b.w., suggesting a mild prooxidant effect, but the increase was insufficient to promote a systemic change in hepatic antioxidant enzyme activities [6]. Previous in vitro findings showed that ibogaine affected cellular energy metabolism as it leads to the rapid discharge of ATP pools in yeast [7] and erythrocytes [8], which is associated with an increase in the amount of certain metabolic enzymes involved in glycolysis and Krebs cycle [9], reactive oxygen species (ROS) production and increased activities of antioxidative enzymes [10]. Therefore, ibogaine is considered a pro-antioxidant, although it does not possess antioxidant properties [11].…”