RESUMO
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.
Assuntos
Ibogaína , Necrose , Oxirredução , Estresse Oxidativo , Animais , Ibogaína/análogos & derivados , Ibogaína/farmacologia , Ibogaína/efeitos adversos , Ratos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Masculino , Feminino , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Antioxidantes/farmacologia , Miocárdio/metabolismo , Miocárdio/patologia , Ratos WistarRESUMO
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.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Dopamina , Ibogaína , Ibogaína/análogos & derivados , Nicotina , Receptores Nicotínicos , Animais , Dopamina/metabolismo , Masculino , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/efeitos dos fármacos , Nicotina/farmacologia , Ibogaína/farmacologia , Camundongos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Camundongos Endogâmicos C57BL , Antagonistas Nicotínicos/farmacologia , Oócitos/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Autoadministração , Xenopus laevis , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Relação Dose-Resposta a Droga , Atividade Motora/efeitos dos fármacosRESUMO
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.
Assuntos
Ibogaína , Polissonografia , Sono REM , Vigília , Animais , Sono REM/efeitos dos fármacos , Vigília/efeitos dos fármacos , Vigília/fisiologia , Masculino , Ratos , Ibogaína/análogos & derivados , Ibogaína/farmacologia , Ibogaína/administração & dosagem , Ratos Sprague-Dawley , Sono de Ondas Lentas/efeitos dos fármacos , Sono de Ondas Lentas/fisiologia , Alucinógenos/farmacologia , Alucinógenos/administração & dosagem , Eletroencefalografia/efeitos dos fármacosRESUMO
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.
Assuntos
Citocromo P-450 CYP2D6 , Genótipo , Alucinógenos , Ibogaína , Transtornos Relacionados ao Uso de Opioides , Humanos , Ibogaína/farmacocinética , Ibogaína/efeitos adversos , Ibogaína/farmacologia , Ibogaína/análogos & derivados , Masculino , Adulto , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Feminino , Alucinógenos/farmacocinética , Alucinógenos/efeitos adversos , Alucinógenos/sangue , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/genética , Pessoa de Meia-Idade , Síndrome de Abstinência a Substâncias/genética , Adulto Jovem , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/genéticaRESUMO
Colorectal cancer (CRC), among the most aggressive and prevailing neoplasms, is primarily treated with chemotherapy. Voacamine (VOA), a novel bisindole natural product, possesses a variety of conspicuous pharmacological activities. Within the current research, we evaluated in vitro and in vivo the anticancer efficacy of VOA against CRC and its potential mechanisms. Our results illustrated that VOA concentrationdependently suppressed the proliferation and migration of CT26 and HCT116 cells as correspondingly indicated by IC50 values of 1.38 ± 0.09 µM and 4.10 ± 0.14 µM. Furthermore, treatment of VOA also suppressed tumor cell colony formation, escalated the late-stage apoptosis rate of tumor cells, and evoked cell cycle of CT26 and HCT116 cells arrest inhibition in G2-M and G0-G1 phases, respectively. Meanwhile, VOA markedly disrupted the mitochondrial membrane potential eliciting mitochondrial dysfunction, decreased ATP production, and intermediated an enhanced accumulation of intracellular reactive oxygen species with a concentration-dependent pattern, accompanied by elevated expression levels of pro-apoptotic related protein Bax, Cyt-C, cleaved caspases 3/8/9 and by diminished Bcl-2, Bid, PRAP and caspases 3/8/9 expression. Further mechanistic studies revealed VOA treatment suppressed the EGFR/PI3K/Akt pathway with the evidence of the decreased phosphorylation proteins of EGFR, PI3K, Akt, and downstream proteins of p-mTOR, p-NF-kB, and p-P70S6. Additionally, molecular dynamics simulations further displayed VOA could enter the EGFR pocket followed by multiple mutual interaction effects. Interestingly, the EGFR activator (NSC228155) could slack the inhibitory capability of VOA on the EGFR/PI3K/Akt pathway as well as VOA-induced impairment of mitochondrial function. Finally, administration of VOA (15, 30 mg/kg every 2 days, i.p., for 16 days) in CT26 syngeneic mice dose-dependently suppressed the neoplastic development without appreciable organ toxicities. Taken together, our study demonstrated that VOA may be a prospective therapeutic agent for the treatment of CRC.
Assuntos
Produtos Biológicos , Neoplasias Colorretais , Trifosfato de Adenosina/farmacologia , Animais , Apoptose , Produtos Biológicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Receptores ErbB/metabolismo , Ibogaína/análogos & derivados , Camundongos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Proteína X Associada a bcl-2RESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ibogaína/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias do Colo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ibogaína/química , Ibogaína/farmacologia , Estrutura MolecularRESUMO
BACKGROUND: In the present study, fatty acid synthesis is targeted to combat mammary gland carcinoma by activating prolyl hydroxylase-2 with Voacamine alone and in combination with Tamoxifen. It was hypothesized that the activation of prolyl hydroxylase-2 would inhibit the hypoxia-induced fatty acid synthesis and mammary gland carcinoma. Mammary gland carcinoma was induced with a single dose administration of N-methyl-N-nitrosourea (50 mg/kg,i.p.) and treatment with Voacamine and Tamoxifen 15 days after carcinogen administration. RESULTS: At the end of the study, hemodynamic profiling of animals was recorded to assess the cardiotoxic potential of the drug. Blood serum was separated and subjected to nuclear magnetic resonance spectroscopy. Carmine staining and histopathology of mammary gland tissue were performed to evaluate the anti-angiogenic potential of the drug. The antioxidant potential of the drug was measured with antioxidant markers. Western blotting was performed to study the effect of the drug at the molecular level. CONCLUSION: Results of the study have shown that Voacamine treatment stopped further decrease in body weight of experimental animals. The hemodynamic study evidenced that Voacamine at a low dose is safe in cardiac patients. Microscopic evaluation of mammary gland tissue documented the anti-angiogenic potential of Voacamine and Tamoxifen therapy. Perturbed serum metabolites were also restored to normal along with antioxidant markers. Immunoblotting of mammary gland tissue also depicted restoration of proteins of the hypoxic and fatty acid pathway. Conclusively, Voacamine and its combination with Tamoxifen activated prolyl hydroxylase-2 to combat mammary gland carcinoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Ibogaína/análogos & derivados , Neoplasias Mamárias Experimentais/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Peso Corporal/efeitos dos fármacos , Carcinoma/induzido quimicamente , Carcinoma/metabolismo , Carcinoma/patologia , Simulação por Computador , Eletrocardiografia , Ácidos Graxos/biossíntese , Feminino , Frequência Cardíaca/efeitos dos fármacos , Ibogaína/química , Ibogaína/farmacocinética , Ibogaína/uso terapêutico , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Metaboloma , Metilnitrosoureia , Neovascularização Patológica/tratamento farmacológico , Ratos Wistar , Tamoxifeno/uso terapêuticoRESUMO
Ibogaine is a psychotropic indole alkaloid extracted from the roots of the Tabernanthe iboga shrub from the Apocynaceae family. Depending on the taken dose, it can lead to stimulant effects, euphoria, visual and auditory hallucinations, along with auditory, olfactory, and gustatory synesthesia. In addition to its historical usage in spiritual rituals of African tribes, these days iboga extract presents a prohibited, alternative drug widely used as a part of addiction treatment. Ibogaine used in opioid withdrawal is associated with serious side effects and sudden deaths. Besides its main use as an anti-addiction medication in alternative medicine, in moderate doses (from 100mg to 1g) ibogaine most commonly causes a "trance-like state".In this paper, we report the case of a heroin addict who died suddenly 5-12 hours after oral ingestion of powder labeled Tabernanthe iboga which had been bought online and used in the process of detoxification during an addiction treatment. The man was found dead in a rented apartment, where he was undergoing the addiction treatment.External examination revealed no lesions other than nonspecific injuries on the legs. The autopsy showed congestion of internal organs and pulmonary edema. Histopathological analysis of the heart showed neither macroscopic nor microscopic abnormalities. The concentration of ibogaine was 3.26mg/L. Moreover, systematic toxicological analyses of biological samples showed the presence of morphine and codeine. These data suggest that death, which occurred unnaturally after initiation of the "treatment", was probably the result of the cardiovascular effects caused by the ibogaine powder.The presented case highlights the worldwide problem of various products being widely available over the internet and the danger associated with consumption thereof.
Assuntos
Alucinógenos/intoxicação , Ibogaína/intoxicação , Adulto , Hidrocarbonetos Aromáticos com Pontes/análise , Evolução Fatal , Alucinógenos/análise , Dependência de Heroína , Humanos , Ibogaína/análogos & derivados , Ibogaína/análise , Alcaloides Indólicos/análise , MasculinoRESUMO
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.
Assuntos
Alcaloides/biossíntese , Alcaloides/química , Alcaloides/farmacologia , Tabernaemontana/química , Alcaloides/isolamento & purificação , Animais , Humanos , Ibogaína/análogos & derivados , Ibogaína/síntese química , Ibogaína/farmacologia , Estrutura MolecularRESUMO
The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.
Assuntos
Comportamento Aditivo/tratamento farmacológico , Desenho de Fármacos , Ibogaína/análogos & derivados , Ibogaína/efeitos adversos , Alcoolismo/tratamento farmacológico , Animais , Antidepressivos/farmacologia , Arritmias Cardíacas/induzido quimicamente , Técnicas de Química Sintética , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Alucinógenos/efeitos adversos , Dependência de Heroína/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Segurança do Paciente , Receptor 5-HT2A de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Natação , Tabernaemontana/químicaRESUMO
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.
Assuntos
Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Ibogaína/análogos & derivados , Neoplasias Bucais/terapia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Morte Celular , Citometria de Fluxo , Humanos , Ibogaína/farmacologia , Ibogaína/uso terapêutico , Espécies Reativas de Oxigênio , Transdução de SinaisRESUMO
The primary aim of this study was to determine the anti-neuropathic activity of (±)-18-methoxycoronaridine [(±)-18-MC] and (+)-catharanthine in mice by using the oxaliplatin-induced neuropathic pain paradigm and cold plate test. The results showed that both coronaridine congeners induce anti-neuropathic pain activity at a dose of 72 mg/kg (per os), whereas a lower dose (36 mg/kg) of (+)-catharanthine decreased the progress of oxaliplatin-induced neuropathic pain. To determine the underlying molecular mechanism, electrophysiological recordings were performed on α9α10, α3ß4, and α4ß2 nAChRs as well as voltage-gated calcium (CaV2.2) channels modulated by G protein-coupled γ-aminobutyric acid type B receptors (GABABRs). The results showed that (±)-18-MC and (+)-catharanthine competitively inhibit α9α10 nAChRs with potencies higher than that at α3ß4 and α4ß2 nAChRs and directly block CaV2.2 channels without activating GABABRs. Considering the potency of the coronaridine congeners at Cav2.2 channels and α9α10 nAChRs, and the calculated brain concentration of (+)-catharanthine, it is plausible that the observed anti-neuropathic pain effects are mediated by peripheral and central mechanisms involving the inhibition of α9α10 nAChRs and/or CaV2.2 channels.
Assuntos
Analgésicos/administração & dosagem , Caveolina 2/metabolismo , Ibogaína/análogos & derivados , Neuralgia/metabolismo , Receptores Nicotínicos/metabolismo , Alcaloides de Vinca/administração & dosagem , Animais , Células HEK293 , Humanos , Ibogaína/administração & dosagem , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Xenopus laevisRESUMO
Anecdotal reports and open-label case studies in humans indicated that the psychedelic alkaloid ibogaine exerts profound antiaddictive effects. Ample preclinical evidence demonstrated the efficacy of ibogaine, and its main metabolite, noribogaine, in substance-use-disorder rodent models. In contrast to addiction research, depression-relevant effects of ibogaine or noribogaine in rodents have not been previously examined. We have recently reported that the acute ibogaine administration induced a long-term increase of brain-derived neurotrophic factor mRNA levels in the rat prefrontal cortex, which led us to hypothesize that ibogaine may elicit antidepressant-like effects in rats. Accordingly, we characterized behavioral effects (dose- and time-dependence) induced by the acute ibogaine and noribogaine administration in rats using the forced swim test (FST, 20 and 40 mg/kg i.p., single injection for each dose). We also examined the correlation between plasma and brain concentrations of ibogaine and noribogaine and the elicited behavioral response. We found that ibogaine and noribogaine induced a dose- and time-dependent antidepressant-like effect without significant changes of animal locomotor activity. Noribogaine's FST effect was short-lived (30 min) and correlated with high brain concentrations (estimated >8 µM of free drug), while the ibogaine's antidepressant-like effect was significant at 3 h. At this time point, both ibogaine and noribogaine were present in rat brain at concentrations that cannot produce the same behavioral outcome on their own (ibogaine â¼0.5 µM, noribogaine â¼2.5 µM). Our data suggests a polypharmacological mechanism underpinning the antidepressant-like effects of ibogaine and noribogaine.
Assuntos
Alucinógenos , Ibogaína , Animais , Antidepressivos/farmacologia , Alucinógenos/farmacologia , Ibogaína/análogos & derivados , Ibogaína/farmacologia , Ratos , RoedoresRESUMO
Although natural products are an important source of drugs and drug leads, identification and validation of their target proteins have proven difficult. Here, we report the development of a systematic strategy for target identification and validation employing drug affinity responsive target stability (DARTS) and mass spectrometry imaging (MSI) without modifying or labeling natural compounds. Through a validation step using curcumin, which targets aminopeptidase N (APN), we successfully standardized the systematic strategy. Using label-free voacangine, an antiangiogenic alkaloid molecule as the model natural compound, DARTS analysis revealed vascular endothelial growth factor receptor 2 (VEGFR2) as a target protein. Voacangine inhibits VEGFR2 kinase activity and its downstream signaling by binding to the kinase domain of VEGFR2, as was revealed by docking simulation. Through cell culture assays, voacangine was found to inhibit the growth of glioblastoma cells expressing high levels of VEGFR2. Specific localization of voacangine to tumor compartments in a glioblastoma xenograft mouse was revealed by MSI analysis. The overlap of histological images with the MSI signals for voacangine was intense in the tumor regions and showed colocalization of voacangine and VEGFR2 in the tumor tissues by immunofluorescence analysis of VEGFR2. The strategy employing DARTS and MSI to identify and validate the targets of a natural compound as demonstrated for voacangine in this study is expected to streamline the general approach of drug discovery and validation using other biomolecules including natural products.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Ibogaína/análogos & derivados , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Antígenos CD13/metabolismo , Curcumina/farmacologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Ibogaína/química , Ibogaína/farmacocinética , Ibogaína/farmacologia , Espectrometria de Massas , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Distribuição Tecidual , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In continuation of our efforts to provide quantitative information on antiaddictive ibogan type alkaloid-producing Tabernaemontana species, we used gas chromatography-mass spectrometry (GC/MS) to compare the alkaloid profiles of the barks and/or leaves of one Mexican and one African species - T. arborea and T. crassa, respectively, with the primary sources of commercially available semisynthetic ibogaine, Voacanga africana root and stem bark. The qualitative and quantitative similarities between T. arborea and V. africana barks consolidate previous reports regarding the potential of the former as a promising alternative source of voacangine and ibogaine. The results also suggest that T. crassa could be used to produce conopharyngine and ibogaline, two compounds with the same basic skeletal structure and possibly similar antiaddictive properties as ibogaine.
Assuntos
Ibogaína/química , Tabernaemontana/química , Voacanga/química , Gana , Ibogaína/análogos & derivados , México , Conformação Molecular , Especificidade da EspécieRESUMO
To determine whether (+)-catharanthine induces sedative- or anxiolytic/anxiogenic-like activity in male mice, proper animal paradigms were used. The results showed that (+)-catharanthine induces sedative-like activity in the 63-72 mg/Kg dose range in a flumazenil-insensitive manner, but neither this effect nor anxiolytic/anxiogenic-like activity was observed at lower doses. To determine the underlying molecular mechanism of the sedative-like activity, electrophysiological and radioligand binding experiments were performed with (+)-catharanthine and (±)-18-methoxycoronaridine [(±)-18-MC] on GABAA (GABAARs) and glycine receptors (GlyRs). Coronaridine congeners both activated and potentiated a variety of human (h) GABAARs, except hρ1. (+)-Catharanthine-induced potentiation followed this receptor selectivity (EC50's in µM): hα1ß2 (4.6 ± 0.8) > hα2ß2γ2 (12.6 ± 3.8) ~ hα1ß2γ2 (14.4 ± 4.6) indicating that both α1 and α2 are equally important, whereas γ2 is not necessary. (+)-Catharanthine was >2-fold more potent and efficient than (±)-18-MC at hα1ß2γ2. (+)-Catharanthine also potentiated, whereas (±)-18-MC inhibited, hα1 GlyRs with very low potency. Additional [3H]-flunitrazepam competition binding experiments using rat cerebellum membranes clearly demonstrated that these ligands do not bind to the benzodiazepine site. This is supported by the observed activity at hα1ß2 (lacking the BDZ site) and similar effects between α1- and α2-containing GABAARs. Our study shows, for the first time, that (+)-catharanthine induced sedative-like effects in mice, and coronaridine congeners potentiated human α1ß2γ2, α1ß2, and hα2ß2γ2, but not ρ1, GABAARs, both in a benzodiazepine-insensitive fashion, whereas only (+)-catharanthine slightly potentiated GlyRs.
Assuntos
Benzodiazepinas/metabolismo , Hipnóticos e Sedativos/metabolismo , Ibogaína/análogos & derivados , Ibogaína/metabolismo , Receptores de GABA-A/metabolismo , Animais , Benzodiazepinas/farmacologia , Relação Dose-Resposta a Droga , Agonistas de Receptores de GABA-A/metabolismo , Agonistas de Receptores de GABA-A/farmacologia , Células HEK293 , Humanos , Hipnóticos e Sedativos/farmacologia , Ibogaína/farmacologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , CamundongosRESUMO
Search for natural substances in association with conventional chemotherapeutic drugs with a chemiosensitizing action easily accessible to the tumor mass has encouraged our studies on voacamine (VOA) and its monomeric units, voacangine and vobasine. Our previous results showed that VOA sensitized multidrug resistant (MDR) osteosarcoma cells (U-2 OS/DX) to doxorubicin (DOX) cytotoxicity. VOA, extracted by Peschiera fuchsiaefolia plant, is a bisindole alkaloid consisting of an Iboga skeleton (voacangine) directly linked to a 2-acyl indole unit (vobasine). High-performance thin-layer chromatography densitometry demonstrated the purity of VOA, voacangine and vobasine samples. Flow cytometry analysis showed that VOA, voacangine and vobasine enhanced DOX accumulation of U-2 OS/DX cells, in equally way, whereas VOA reduced more efficiently DOX efflux. Optical microscopy and clonogenic assay confirmed that VOA was more effective than voacangine and vobasine in enhancing DOX cytotoxic effect. These results showed that monomers linked together are necessary to modulate resistant phenotype of osteosarcoma cells. To complete the study, we evaluated the effect of three compounds on microtubules by confocal microscopy, suggesting that only the whole molecule depolymerizes the microtubules blocking so DOX efflux-mediated by vesicles.
Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ibogaína/análogos & derivados , Linhagem Celular Tumoral , Dimerização , Humanos , Ibogaína/farmacologia , Microscopia Confocal , Microtúbulos/efeitos dos fármacosRESUMO
Coronaridine (1) was isolated from the CH2Cl2 root extract of Tabernaemontana ternifolia. The structure of 1 was established from 1D- and 2D-NMR and HR-ESIMS experiments, and by comparison with reported spectroscopic data. To date, this is the first report of compound 1 from T. ternifolia, introduced as new Tabernaemontana species from Philippines in 2005 on the basis of morphological characters. Coronaridine, an iboga-type indole alkaloid, has been isolated from over 50 Tabernaemontana species and can thus be inferred as a chemotaxonomic marker of the genus. T. ternifolia has a distinct arrangement of leaves not known in the genus, but is variable in other genera. Its isolation from endemic T. ternifolia establishes its position in the genus and supports the claim that coronaridine is a chemical marker of the genus Tabernaemontana. Interestingly, coronaridine exhibited relatively weak activity against Mycobacterium tuberculosis H37Rv (MIC 82.64 µg/mL) (Rifampicin MIC 0.05 µg/mL).
Assuntos
Antituberculosos/farmacologia , Alcaloides Indólicos/isolamento & purificação , Tabernaemontana/química , Antituberculosos/isolamento & purificação , Classificação , Ibogaína/análogos & derivados , Ibogaína/isolamento & purificação , Alcaloides Indólicos/química , Mycobacterium tuberculosis/efeitos dos fármacos , Folhas de Planta/anatomia & histologiaRESUMO
(-)-Ibogaine and (-)-voacangine are plant derived psychoactives that show promise as treatments for opioid addiction. However, these compounds are produced by hard to source plants, making these chemicals difficult for broad-scale use. Here we report the complete biosynthesis of (-)-voacangine, and de-esterified voacangine, which is converted to (-)-ibogaine by heating, enabling biocatalytic production of these compounds. Notably, (-)-ibogaine and (-)-voacangine are of the opposite enantiomeric configuration compared to the other major alkaloids found in this natural product class. Therefore, this discovery provides insight into enantioselective enzymatic formal Diels-Alder reactions.
Assuntos
Ibogaína/análogos & derivados , Ibogaína/metabolismo , Psicotrópicos/metabolismo , Tabernaemontana/metabolismo , Vias Biossintéticas , Humanos , Ibogaína/análise , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Psicotrópicos/análise , Estereoisomerismo , Tabernaemontana/química , Tabernaemontana/enzimologiaRESUMO
The plant alkaloid voacamine (VOA) displays many interesting pharmacological activities thus, considering its scarce solubility in water, its encapsulation into liposome formulations for its delivery is an important goal. Different cationic liposome formulations containing a phospholipid, cholesterol and one of two diasteromeric cationic surfactants resulted able to maintain a stable transmembrane difference in ammonium sulfate concentration and/or pH gradient and to accumulate VOA in their internal aqueous bulk. The fluidity of the lipid bilayer affects both the ability to maintain a stable imbalance of protons and/or ammonium ions across the membrane and the entrapment efficiency. It was shown that VOA loaded into liposomes is more efficient than the free alkaloid to revert resistance of osteosarcoma cells resistant to doxorubicin to an extent depending on their composition.