RESUMEN
The coronaridine congeners catharanthine and 18-methoxycoronaridine (18-MC) display sedative, anxiolytic, and antidepressant properties by acting on mechanisms involving GABAergic and/or monoaminergic transmissions. Here, we expanded their pharmacological properties by studying their anticonvulsant activity in male and female mice using the pentylenetetrazole (PTZ)-induced seizure test. To determine potential neurochemical mechanisms, the effect of congeners on monoamine content and kainic acid (KA)-induced epileptiform discharge was studied in the hippocampus. The behavioral results showed that coronaridine congeners induce acute anticonvulsant activity in a dose-dependent but sex-independent manner. Repeated treatment with a subthreshold dose (20 mg/kg) of each congener produced anticonvulsant activity in a sex-independent manner, but was significantly higher in male mice when compared to its acute effect. Using a behaviourally relevant regimen, we found that PTZ increased dopamine metabolites and serotonin tissue content. Coronaridine congeners, which induced distinct effects on monoamines, blunted the effect of PTZ instead of potentiating it, suggesting the existence of another mechanism in their anticonvulsant activity. The electrophysiological results indicated that both congeners inhibit KA-induced epileptiform discharges in hippocampal slices. A key aspect of this study is that the activity of both congeners was observed only in the presence of GABA, supporting the notion that hippocampal GABAAR potentiation plays an important role. Our study showed that coronaridine congeners induce acute anticonvulsant activity in a sex-independent manner. However, a comparatively higher susceptibility was observed in male mice after repeated treatment. The underlying hippocampal mechanisms mainly involve GABAAR potentiation, whereas monoamines play a minor role in the anticonvulsive action.
Asunto(s)
Anticonvulsivantes , Hipocampo , Receptores de GABA-A , Convulsiones , Animales , Masculino , Anticonvulsivantes/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Femenino , Receptores de GABA-A/metabolismo , Convulsiones/tratamiento farmacológico , Convulsiones/inducido químicamente , Convulsiones/metabolismo , Convulsiones/fisiopatología , Pentilenotetrazol , Ibogaína/análogos & derivados , Ibogaína/farmacología , Relación Dosis-Respuesta a DrogaRESUMEN
Ibogaine is an organic indole alkaloid that is used in alternative medicine to combat addiction. Numerous cases of life-threatening complications and sudden deaths associated with ibogaine use have been reported, and it has been hypothesized that the adverse effects are related to ibogaine's tendency to induce cardiac arrhythmias. Considering that the bioavailability of ibogaine and its primary metabolite noribogaine is two to three times higher in female rats than in male rats, we here investigated the effect of a single oral dose (1 or 20 mg/kg) of ibogaine on cardiac histopathology and oxidative/antioxidant balance. Our results show that ibogaine induced dose-dependent cardiotoxic necrosis 6 and 24 h after treatment and that this necrosis was not a consequence of inflammation. In addition, no consistent dose- and time-dependent changes in antioxidant defense or indicators of oxidative damage were observed. The results of this study may contribute to a better understanding of ibogaine-induced cardiotoxicity, which is one of the main side effects of ibogaine use in humans and is often fatal. Nevertheless, based on this experiment, it is not possible to draw a definitive conclusion regarding the role of redox processes or oxidative stress in the occurrence of cardiotoxic necrosis after ibogaine administration.
Asunto(s)
Ibogaína , Necrosis , Oxidación-Reducción , Estrés Oxidativo , Animales , Ibogaína/análogos & derivados , Ibogaína/farmacología , Ibogaína/efectos adversos , Ratas , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Masculino , Femenino , Cardiotoxicidad/etiología , Cardiotoxicidad/patología , Antioxidantes/farmacología , Miocardio/metabolismo , Miocardio/patología , Ratas WistarRESUMEN
Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective of this study was to evaluate the effects of catharanthine and 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission and cholinergic interneurons in the mesolimbic DA system, nicotine-induced locomotor activity, and nicotine-taking behavior. Utilizing ex vivo fast-scan cyclic voltammetry (FSCV) in the nucleus accumbens core of male mice, we found that catharanthine or 18-MC differentially inhibited evoked DA release. Catharanthine inhibition of evoked DA release was significantly reduced by both α4 and α6 nicotinic acetylcholine receptors (nAChRs) antagonists. Additionally, catharanthine substantially increased DA release more than vehicle during high-frequency stimulation, although less potently than an α4 nAChR antagonist, which confirms previous work with nAChR antagonists. Interestingly, while catharanthine slowed DA reuptake measured via FSCV ex vivo, it also increased extracellular DA in striatal dialysate from anesthetized mice in vivo in a dose-dependent manner. Superfusion of catharanthine or 18-MC inhibited the firing rate of striatal cholinergic interneurons in a concentration dependent manner, which are known to potently modulate presynaptic DA release. Catharanthine or 18-MC suppressed acetylcholine currents in oocytes expressing recombinant rat α6/α3ß2ß3 or α6/α3ß4 nAChRs. In behavioral experiments using male Sprague-Dawley rats, systemic administration of catharanthine or 18-MC blocked nicotine enhancement of locomotor activity. Importantly, catharanthine attenuated nicotine self-administration in a dose-dependent manner while having no effect on food reinforcement. Lastly, administration of catharanthine and nicotine together greatly increased head twitch responses, indicating a potential synergistic hallucinogenic effect. These findings demonstrate that catharanthine and 18-MC have similar, but not identical effects on striatal DA dynamics, striatal cholinergic interneuron activity and nicotine psychomotor effects.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Dopamina , Ibogaína , Ibogaína/análogos & derivados , Nicotina , Receptores Nicotínicos , Animales , Dopamina/metabolismo , Masculino , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/efectos de los fármacos , Nicotina/farmacología , Ibogaína/farmacología , Ratones , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Ratones Endogámicos C57BL , Antagonistas Nicotínicos/farmacología , Oocitos/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Autoadministración , Xenopus laevis , Interneuronas/efectos de los fármacos , Interneuronas/metabolismo , Relación Dosis-Respuesta a Droga , Actividad Motora/efectos de los fármacosRESUMEN
OBJECTIVE: Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine. METHODS: The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity. RESULTS: The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype (p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid Emax model. Spearman correlations were significant (p < 0.03) for ibogaine but not noribogaine with QTc (p = 0.109) and cerebellar effects (p = 0.668); neither correlated with the severity of opioid withdrawal symptoms. CONCLUSIONS: The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype.
Asunto(s)
Citocromo P-450 CYP2D6 , Genotipo , Alucinógenos , Ibogaína , Trastornos Relacionados con Opioides , Humanos , Ibogaína/farmacocinética , Ibogaína/efectos adversos , Ibogaína/farmacología , Ibogaína/análogos & derivados , Masculino , Adulto , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Femenino , Alucinógenos/farmacocinética , Alucinógenos/efectos adversos , Alucinógenos/sangre , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/genética , Persona de Mediana Edad , Síndrome de Abstinencia a Sustancias/genética , Adulto Joven , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/genéticaRESUMEN
Ibogaine is a potent atypical psychedelic that has gained considerable attention due to its antiaddictive and antidepressant properties in preclinical and clinical studies. Previous research from our group showed that ibogaine suppresses sleep and produces an altered wakefulness state, which resembles natural REM sleep. However, after systemic administration, ibogaine is rapidly metabolized to noribogaine, which also shows antiaddictive effects but with a distinct pharmacological profile, making this drug a promising therapeutic candidate. Therefore, we still ignore whether the sleep/wake alterations depend on ibogaine or its principal metabolite noribogaine. To answer this question, we conducted polysomnographic recordings in rats following the administration of pure noribogaine. Our results show that noribogaine promotes wakefulness while reducing slow-wave sleep and blocking REM sleep, similar to our previous results reported for ibogaine administration. Thus, we shed new evidence on the mechanisms by which iboga alkaloids work in the brain.
Asunto(s)
Ibogaína , Polisomnografía , Sueño REM , Vigilia , Animales , Sueño REM/efectos de los fármacos , Vigilia/efectos de los fármacos , Vigilia/fisiología , Masculino , Ratas , Ibogaína/análogos & derivados , Ibogaína/farmacología , Ibogaína/administración & dosificación , Ratas Sprague-Dawley , Sueño de Onda Lenta/efectos de los fármacos , Sueño de Onda Lenta/fisiología , Alucinógenos/farmacología , Alucinógenos/administración & dosificación , Electroencefalografía/efectos de los fármacosRESUMEN
Ibogaine (IBO) is an atypical psychedelic with a complex mechanism of action. To date, the mechanisms that may underlie its anti-addictive effects are still not defined. This study aims to identify changes in gene expression induced by a single oral dose of IBO in the cortex of mice by means of a transcriptomic analysis for the first time. Our results showed significant alterations in gene expression in mouse frontal cortex samples 4 h after a single oral dose of IBO. Specifically, genes involved in hormonal pathways and synaptogenesis exhibited upregulation, while genes associated with apoptotic processes and endosomal transports showed downregulation. The findings were further corroborated through quantitative polymerase chain reaction (qPCR) analysis. However, the validation of gene expression related to hormonal pathways did not entirely align with the transcriptomic analysis results, possibly due to the brain region from which tissue was collected. Sex differences were observed, with female mice displaying more pronounced alterations in gene expression after IBO treatment. High variability was observed across individual animals. However, this study represents a significant advancement in comprehending IBO's molecular actions. The findings highlight the influence of IBO on gene expression, particularly on hormonal pathways, synaptogenesis, apoptotic processes, and endosomal transports. The identification of sex differences underscores the importance of considering sex as a potential factor influencing IBO's effects. Further research to assess different time points after IBO exposure is warranted.
Asunto(s)
Alucinógenos , Ibogaína , Ratones , Femenino , Animales , Masculino , Ibogaína/metabolismo , Ibogaína/farmacología , Alucinógenos/farmacología , Corteza Cerebral/metabolismo , Encéfalo/metabolismoRESUMEN
Noribogaine (noribo) is the primary metabolite from ibogaine, an atypical psychedelic alkaloid isolated from the root bark of the African shrub Tabernanthe iboga. The main objective of this study was to test the hypothesis that molecular, electrophysiological, and behavioral responses of noribo are mediated by the 5-HT2A receptor (5-HT2AR) in mice. In that regard, we used male and female, 5-HT2AR knockout (KO) and wild type (WT) mice injected with a single noribo dose (10 or 40 mg/kg; i.p.). After 30 min., locomotor activity was recorded followed by mRNA measurements by qPCR (immediate early genes; IEG, glutamate receptors, and 5-HT2AR levels) and electrophysiology recordings of layer V pyramidal neurons from the medial prefrontal cortex. Noribo 40 decreased locomotion in male, but not female WT. Sex and genotype differences were observed for IEG and glutamate receptor expression. Expression of 5-HT2AR mRNA increased in the mPFC of WT mice following Noribo 10 (males) or Noribo 40 (females). Patch-clamp recordings showed that Noribo 40 reduced the NMDA-mediated postsynaptic current density in mPFC pyramidal neurons only in male WT mice, but no effects were found for either KO males or females. Our results highlight that noribo produces sexually dimorphic effects while the genetic removal of 5HT2AR blunted noribo-mediated responses to NMDA synaptic transmission.
Asunto(s)
Ibogaína , Femenino , Masculino , Animales , Ratones , Ratones Noqueados , Ibogaína/farmacología , Receptor de Serotonina 5-HT2A/genética , N-Metilaspartato , Serotonina , Ácido Glutámico , ARN MensajeroRESUMEN
El trastorno por uso de sustancias es una enfermedad crónica de graves consecuencias. Actualmente, los tratamientos farmacológicos no apuntan a corregir los cambios neurobiológicos generados en el cerebro por el uso crónico de sustancias de abuso, sino que se enfocan principalmente en la atenuación de algunos de los síntomas que padece el consumidor. La ibogaína es un psicodélico atípico que, tanto en estudios observacionales como en ensayos clínicos abiertos, ha mostrado una propiedad antiadictiva que perdura en el tiempo. Sin embargo, su delicado perfil de toxicidad cardíaca, así como su uso en entornos sin adecuadas medidas de seguridad, han limitado su progresión en las investigaciones clínicas. Los efectos antiadictivos de ibogaína han disparado diversas líneas de investigación básica, preclínica y clínica, que buscan confirmar su efectividad, entender sus mecanismos de acción y delimitar su perfil de seguridad. Dada la poca información disponible para los profesionales de salud sobre esta sustancia, esta revisión busca aportar información acerca de su potencial terapéutico, posibles mecanismos de acción y riesgos asociados a su administración.
Substance use disorder is a chronic disease with severe consequences. Currently, pharmacological treatments do not aim to correct the neurobiological changes generated in the brain by the chronic use of substances of abuse, but rather focus mainly on attenuating some of the user's symptoms. Ibogaine is an atypical psychedelic that has shown long-lasting and interesting antiaddictive properties in both observational studies and open-label clinical trials. However, its delicate profile of cardiac toxicity, as well as its use in settings without adequate safety measures, have limited its progression in clinical research. The anti-addictive effects of ibogaine have triggered diverse scientific research in basic, preclinical, and clinical areas, which seek efficacy confirmation and to fully understand ibogaine´s underlying mechanisms of action and its safety profile. Given that there is little information available to health professionals about ibogaine and its antiaddictive properties, this review aims to provide published data about its therapeutic potential in drug addiction, its mechanisms of action, and risks associated with its administration.
Asunto(s)
Humanos , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Alucinógenos/uso terapéutico , Ibogaína/uso terapéutico , Alucinógenos/efectos adversos , Alucinógenos/farmacología , Ibogaína/efectos adversos , Ibogaína/farmacologíaRESUMEN
The iboga alkaloids scaffold shows great potential as a pharmacophore in drug candidates for the treatment of neuropsychiatric disorders. Thus, the study of the reactivity of this type of motif is particularly useful for the generation of new analogs suitable for medicinal chemistry goals. In this article, we analyzed the oxidation pattern of ibogaine and voacangine using dioxygen, peroxo compounds, and iodine as oxidizing agents. Special focus was placed on the study of the regio- and stereochemistry of the oxidation processes according to the oxidative agent and starting material. We found that the C16-carboxymethyl ester present in voacangine stabilizes the whole molecule toward oxidation in comparison to ibogaine, especially in the indole ring, where 7-hydroxy- or 7-peroxy-indolenines can be obtained as oxidation products. Nevertheless, the ester moiety enhances the reactivity of the isoquinuclidinic nitrogen to afford C3-oxidized products through a regioselective iminium formation. This differential reactivity between ibogaine and voacangine was rationalized using computational DFT calculations. In addition, using qualitative and quantitative NMR experiments combined with theoretical calculations, the absolute stereochemistry at C7 in the 7-hydroxyindolenine of voacangine was revised to be S, which corrects previous reports proposing an R configuration.
Asunto(s)
Ibogaína , Tabernaemontana , Ibogaína/farmacología , Ibogaína/química , Tabernaemontana/química , Oxidación-Reducción , EsqueletoRESUMEN
The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has unusual anti-depressant and substance-withdrawal effects, and stabilizes the inward-open conformation. Unfortunately, ibogaine's promiscuity and cardiotoxicity limit the understanding of inward-open state ligands. We docked over 200 million small molecules against the inward-open state of the SERT. Thirty-six top-ranking compounds were synthesized, and thirteen inhibited; further structure-based optimization led to the selection of two potent (low nanomolar) inhibitors. These stabilized an outward-closed state of the SERT with little activity against common off-targets. A cryo-EM structure of one of these bound to the SERT confirmed the predicted geometry. In mouse behavioral assays, both compounds had anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold better than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects.
Asunto(s)
Ibogaína , Inhibidores Selectivos de la Recaptación de Serotonina , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Bibliotecas de Moléculas Pequeñas , Animales , Ratones , Fluoxetina/farmacología , Ibogaína/química , Ibogaína/farmacología , Conformación Molecular , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/ultraestructura , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
Ibogaine is a powerful psychoactive substance that not only alters perception, mood and affect, but also stops addictive behaviors. Ibogaine has a very long history of ethnobotanical use in low doses to combat fatigue, hunger and thirst and, in high doses as a sacrament in African ritual contexts. In the 1960's, American and European self-help groups provided public testimonials that a single dose of ibogaine alleviated drug craving, opioid withdrawal symptoms, and prevented relapse for weeks, months and sometimes years. Ibogaine is rapidly demethylated by first-pass metabolism to a long-acting metabolite noribogaine. Ibogaine and its metabolite interact with two or more CNS targets simultaneously and both drugs have demonstrated predictive validity in animal models of addiction. Online forums endorse the benefits of ibogaine as an "addiction interrupter" and present-day estimates suggest that more than ten thousand people have sought treatment in countries where the drug is unregulated. Open label pilot studies of ibogaine-assisted drug detoxification have shown positive benefit in treating addiction. Ibogaine, granted regulatory approval for human testing in a Phase 1/2a clinical trial, joins the current landscape of psychedelic medicines in clinical development.
Asunto(s)
Alucinógenos , Ibogaína , Síndrome de Abstinencia a Sustancias , Trastornos Relacionados con Sustancias , Animales , Humanos , Ibogaína/farmacología , Ibogaína/uso terapéutico , Alucinógenos/uso terapéutico , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Analgésicos Opioides/uso terapéuticoRESUMEN
Plants of Tabernaemontana species have several pharmacological activities including antimicrobial effects. Amoebiasis continues to be a public health problem, with increasing evidence of resistance to metronidazole. In this study, we assessed the effect of the alkaloid fraction of T. arborea root bark and the alkaloids ibogaine and voacangine on the viability and infectivity of Entamoeba histolytica trophozoites. Cultures were exposed to 0.1â-â10 µg/mL for 24, 48 and 72 h, and viability was then determined using a tetrazolium dye reduction assay and type of cellular death analyzed by flow cytometry. Results showed that the alkaloid fraction, but mainly ibogaine and voacangine alkaloids, exhibited potent dose-dependent anti-amoebic activity at 24 h post-exposure (IC50 4.5 and 8.1 µM, respectively), comparable to metronidazole (IC50 6.8 µM). However, the effect decreased after 48 and 72 h of exposure to concentrations below 10 µg/mL, suggesting that the alkaloids probably were catabolized to less active derivatives by the trophozoites. The treatment of trophozoites with the IC50 s for 24 h induced significant morphological changes in the trophozoites, slight increase in granularity, and death by apoptonecrosis. The capacity of T. arborea alkaloids to inhibit the development of amoebic liver abscesses in hamsters was evaluated. Results showed that even when the treatments reduced the number of amoebic trophozoites in tissue sections of livers, they were unable to limit the formation of abscesses, suggesting their rapid processing to inactive metabolites. This work leaves open the possibility of using Tabernaemontana alkaloids as a new alternative for amoebiasis control.
Asunto(s)
Alcaloides , Amebiasis , Ibogaína , Tabernaemontana , Ibogaína/metabolismo , Ibogaína/farmacología , Metronidazol/farmacología , Metronidazol/metabolismo , Corteza de la Planta , Alcaloides/farmacología , Alcaloides/metabolismoRESUMEN
For decades, ibogaineâthe main psychoactive alkaloid found in Tabernanthe ibogaâhas been investigated as a possible treatment for substance use disorders (SUDs) due to its purported ability to interrupt the addictive properties of multiple drugs of abuse. Of the numerous pharmacological actions of ibogaine and its derivatives, the inhibition of α3ß4 nicotinic acetylcholine receptors (nAChRs), represents a probable mechanism of action for their apparent anti-addictive activity. In this Perspective, we examine several classes of compounds that have been discovered and developed to target α3ß4 nAChRs. Specifically, by focusing on compounds that have proven efficacious in pre-clinical models of drug abuse and have been evaluated clinically, we highlight the promising potential of the α3ß4 nAChRs as viable targets to treat a wide array of SUDs. Additionally, we discuss the challenges faced by the existing classes of α3ß4 nAChR ligands that must be overcome to develop them into therapeutic treatments.
Asunto(s)
Ibogaína , Receptores Nicotínicos , Trastornos Relacionados con Sustancias , Humanos , Ibogaína/farmacología , Ibogaína/uso terapéutico , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Relación Dosis-Respuesta a DrogaRESUMEN
INTRODUCTION: Ibogaine is one of the alkaloids naturally found in plants such as Tabernanthe iboga, which has been traditionally used by members of the Bwiti culture. Since the discovery of its anti-addictive properties by Howard S. Lotsof in 1962, ibogaine has been used experimentally to treat substance use disorders (SUD), especially those involving opioids. We aim to provide a detailed understanding of the underlying psychological aspects of underground ibogaine use for the treatment of SUD. METHODS: Semi-structured interviews were carried out with 13 participants with SUD, which motivated their self-treatment with ibogaine. The data were analysed using the grounded theory approach and considered the context of the treatment, and the nature of the occurring hallucinogenic and cognitive phenomena during the treatment experience. RESULTS: We identified several psychological effects that the study respondents experienced, which seem to play a substantial role in the therapeutic process concerning SUD. The evoking of interpersonal and transpersonal experiences, autobiographical memories, and preparation, integration and motivation for a lifestyle change are important components that participants reported during and after ibogaine intake. DISCUSSION AND CONCLUSION: Ibogaine is increasingly being used for the treatment of SUD, due in part to the limited treatment options currently available. Its beneficial effects seem to be related not only to its complex pharmacology but also to the subjective experience that ibogaine induces. The main aspects of this experience are related to autobiographical memories and valuable personal insights, which together appear to help individuals cope with their SUD.
Asunto(s)
Alcaloides , Ibogaína , Trastornos Relacionados con Sustancias , Tabernaemontana , Humanos , Ibogaína/uso terapéutico , Ibogaína/farmacología , Alcaloides/uso terapéutico , Trastornos Relacionados con Sustancias/tratamiento farmacológicoRESUMEN
Several Apocynaceae species, most notably Tabernanthe iboga, Voacanga africana and many Tabernaemontana species, produce ibogan-type alkaloids. Although a large amount of information exists about the Tabernaemontana genus, knowledge concerning chemistry and biological activity remains lacking for several species, especially related to their effects on the central nervous system (CNS). The aim of this study was to evaluate the effect of Tabernaemontana arborea Rose ex J.D.Sm. (T. arborea) hydroalcoholic extract (30, 56.2 and 100 mg/kg, i.p.) and two of its main alkaloids (ibogaine and voacangine, 30 mg/kg, i.p.) on electroencephalographic (EEG) activity alone and in the presence of the chemical convulsant agent pentylenetetrazole (PTZ, 85 mg/kg, i.p.) in mice. EEG spectral power analysis showed that T. arborea extract (56.2 and 100 mg/kg) and ibogaine (30 mg/kg, i.p.) promoted a significant increase in the relative power of the delta band and a significant reduction in alpha band values, denoting a CNS depressant effect. Voacangine (30 mg/kg, i.p.) provoked an EEG flattening pattern. The PTZ-induced seizures were not modified in the presence of T. arborea, ibogaine, or voacangine. However, sudden death was observed in mice treated with T. arborea extract at 100 mg/kg, i.p., combined with PTZ. Because T. arborea extract (100 mg/kg, i.p.) and ibogaine (30 mg/kg, i.p.), but not voacangine (30 mg/kg, i.p.), induced paroxysmal activity in the EEG, both were explored in the presence of a serotonin 5-HT1A receptor antagonist (WAY100635, 1 mg/kg, i.p.). The antagonist abolished the paroxysmal activity provoked by T. arborea (100 mg/kg, i.p.) but not that observed with ibogaine, corroborating the participation of serotonin neurotransmission in the T. arborea effects. In conclusion, high doses of the T. arborea extract induced abnormal EEG activity due in part to the presence of ibogaine and involving serotonin 5-HT1A receptor participation. Nevertheless, other possible constituents and mechanisms might participate in this complex excitatory activity that would be interesting to explore in future studies.
Asunto(s)
Ibogaína , Tabernaemontana , Animales , Electroencefalografía , Ibogaína/análisis , Ibogaína/farmacología , Ratones , Receptor de Serotonina 5-HT1A , SerotoninaRESUMEN
Two iboga-vobasine bisindoles, 16'-decarbomethoxyvoacamine (1: ) and its 19,20-dihydro derivative, 16'-decarbomethoxydihydrovoacamine (2: ) from Tabernaemontana corymbosa exhibited potent cytotoxicity against the human colorectal adenocarcinoma HT-29 cells in our previous studies. Bisindoles 1: and 2: selectively inhibited the growth of HT-29 cells without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with bisindoles 1: and 2: suppressed the formation of HT-29 colonies via G0/G1 cell cycle arrest and induction of mitochondrial apoptosis. Owing to its higher antiproliferative activity, bisindole 2: was chosen for the subsequent studies. Bisindole 2: inhibited the formation of HT-29 spheroids (tumor-like cell aggregates) in 3D experiments in a dose-dependent manner, while an in vitro tubulin polymerization assay and molecular docking analysis showed that bisindole 2: is a microtubule-stabilizing agent which is predicted to bind at the ß-tubulin subunit at the taxol-binding site. The binding resulted in the generation of ROS, which consequently activated the oxidative stress-related cell cycle arrest and apoptotic pathways, viz., JNK/p38, p21Cip1/Chk1, and p21Cip1/Rb/E2F, as shown by microarray profiling.
Asunto(s)
Adenocarcinoma , Antineoplásicos Fitogénicos , Neoplasias Colorrectales , Ibogaína , Tabernaemontana , Humanos , Tabernaemontana/química , Células HT29 , Simulación del Acoplamiento Molecular , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos Fitogénicos/farmacología , Estructura Molecular , Alcaloides Indólicos/farmacología , Alcaloides Indólicos/química , Ibogaína/farmacología , Apoptosis , Neoplasias Colorrectales/tratamiento farmacológico , Microtúbulos , Línea Celular TumoralRESUMEN
Most women with ovarian cancer are treated with chemotherapy before or after surgery. Unfortunately, chemotherapy treatment can cause negative side effects and the onset of multidrug resistance (MDR). The aim of this study is to evaluate the chemosensitizing effect of a natural compound, voacamine (VOA), in ovarian (A2780 DX) and colon (LoVo DX) cancer drug-resistant cell lines which overexpress P-glycoprotein (P-gp), in combination with paclitaxel (PTX), or doxorubicin (DOX) or 5-fluorouracil (5-FU). VOA, a bisindole alkaloid extracted from Peschiera fuchsiaefolia, has already been shown to be effective in enhancing the effect of doxorubicin, because it interferes with the P-gp function. Ovarian cancer cytotoxicity test shows that single treatments with VOA, DOX and PTX do not modify cell viability, while pretreatment with VOA, and then PTX or DOX for 72 h, induces a decrease. In colon cancer, since 5-FU is not a-substrate for P-gp, VOA has no sensitizing effect while in VOA + DOX there is a decrease in viability. Annexin V/PI test, cell cycle analysis, activation of cleaved PARP1 confirm that VOA plus PTX induce apoptotic cell death. Confocal microscopy observations show the different localization of NF-kB after treatment with VOA + PTX, confirming the inhibition of nuclear translocation induced by VOA pretreatment. Our data show the specific effect of VOA which only works on drugs known to be substrates of P-gp.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Resistencia a Antineoplásicos , Ibogaína/análogos & derivados , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular , Neoplasias del Colon , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ibogaína/química , Ibogaína/farmacología , Estructura MolecularRESUMEN
Covering: 2000 up to 2020 Few classes of natural products have inspired as many chemists and biologists as have the iboga alkaloids. This family of monoterpenoid indole alkaloids includes the anti-addictive compound ibogaine as well as catharanthine, a precursor to the chemotherapeutic vinblastine. Despite being known for over 120 years, these small molecules continue to challenge our assumptions about biosynthetic pathways, catalyze our creativity for constructing complex architectures, and embolden new approaches for treating mental illness. This review will cover recent advances in both the biosynthesis and chemical synthesis of iboga alkaloids as well as their use as next-generation neurotherapeutics. Whenever appropriate, we provide historical context for the discoveries of the past decade and indicate areas that have yet to be resolved. While significant progress regarding their chemistry and pharmacology has been made since the 1960s, it is clear that the iboga alkaloids will continue to stoke scientific innovation for years to come.
Asunto(s)
Alcaloides/biosíntesis , Alcaloides/química , Alcaloides/farmacología , Tabernaemontana/química , Alcaloides/aislamiento & purificación , Animales , Humanos , Ibogaína/análogos & derivados , Ibogaína/síntesis química , Ibogaína/farmacología , Estructura MolecularRESUMEN
PURPOSE: Oral cancer is the 6th most prevalent type of cancer and is responsible for high human morbidity and mortality. The present study was designed to investigate the anticancer effects of Voacangine against human oral cancer and to decipher the underlying molecular mechanisms responsible for its anticancer properties. METHODS: CCC-1 oral cancer cell line and normal hTRET-OME cell line were used in this study. Cell viability was determined by MTT assay. Acridine orange (AO)/ ethidium bromide (EB) and annexin V/propidium iodide (PI) assay were used for assessment of apoptosis. Cell cycle analysis and reactive oxygen species (ROS) determination was done by flow cytometry. The protein expression was determined by western blot analysis. RESULTS: The results showed that Voacangine caused a remarkable decline in proliferation of SCC-1 human oral cancer cells with negligible toxic effects on the normal human hTRET-OME cells. The IC50 of Voacangine was 9 µM against SCC-1 cells relative to IC50 of 100 µM against normal hTRET-OME cells. The reduction of the proliferative rates was attributed to the induction of ROS triggered apoptosis which was associated with activation of Caspase-3, upregulation of Bax and suppression of Bcl-2. Voacangine induced G2/M cell cycle arrest in a dose-dependent manner. Additionally, the anticancer effects of Voacangine on oral cancer cells were exerted through the inhibition of PI3K/AKT signaling cascade. CONCLUSION: Taken all together, we conclude that Voacangine is a potent anticancer molecule and may be utilized for the development of systemic therapy for oral cancer.