Article

Neuroprotective potential of Ayahuasca and untargeted metabolomics analyses: Applicability to Parkinson's disease

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Abstract

Ethnopharmacology relevance: Ayahuasca is a tea produced through decoction of Amazonian plants. It has been used for centuries by indigenous people of South America. The beverage is considered to be an ethnomedicine, and it is traditionally used for the treatment of a wide range of diseases, including neurological illness. Besides, some scientific evidence suggests it may be applicable to Parkinson's disease (PD) treatment. Thus, Ayahuasca deserves in depth studies to clarify its potential role in this disease. Aim of the study: This study aimed to use an untargeted metabolomics approach to evaluate the neuroprotective potential of the Ayahuasca beverage, the extracts from its matrix plants (Banisteriopsis caapi and Psychotria viridis), its fractions and its main alkaloids on the viability of SH-SY5Y neuroblastoma cells in an in vitro PD model. Material and methods: The cytotoxicity of Ayahuasca, crude extracts, and fractions of B. caapi and P. viridis, as well as neuroprotection promoted by these samples in a 6-hydroxydopamine (6-OHDA)-induced neurodegeneration model, were evaluated by the MTT assay at two time-points: 48 h (T1) and 72 h (T2). The main alkaloids from Ayahuasca matrix plants, harmine (HRE) and N,N-dimethyltryptamine (DMT), were also isolated and evaluated. An untargeted metabolomics approach was developed to explore the chemical composition of samples with neuroprotective activity. Ultra-Performance Liquid Chromatography coupled to Electrospray Ionisation and Time-of-Flight (UPLC-ESI-TOF) metabolome data was treated and further analysed using multivariate statistical analyses (MSA): principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). The metabolites were dereplicated using the Dictionary of Natural Products and an in house database. The main alkaloids were also quantified by UPLC-MS/MS. Results: The samples did not cause cytotoxicity in vitro and three of samples intensely increased cell viability at T1. The crude extracts, alkaloid fractions and HRE demonstrated remarkable neuroprotective effect at T2 while the hydroalcoholic fractions demonstrated this neuroprotective effect at T1 and T2. Several compounds from different classes, such as β-carbolines and monoterpene indole alkaloids (MIAs) were revealed correlated with this property by MSA. Additionally, a total of 2419 compounds were detected in both ionisation modes. HRE showed potent neuroprotective action at 72 h, but it was not among the metabolites positively correlated with the most efficacious neuroprotective profile at either time (T1 and T2). Furthermore, DMT was statistically important to differentiate the dataset (VIP value > 1), although it did not exhibit sufficient neuroprotective activity by in vitro assay, neither a positive correlation with T1 and T2 neuroprotective profile, which corroborated the MSA results. Conclusion: The lower doses of the active samples stimulated neuronal cell proliferation and/or displayed the most efficacious neuroprotection profile, namely by preventing neuronal damage and improving cell viability against 6-OHDA-induced toxicity. Intriguingly, the hydroalcoholic fractions exhibited enhanced neuroprotective effects when compared to other samples and isolated alkaloids. This finding corroborates the significance of a holistic approach. The results demonstrate that Ayahuasca and its base plants have potential applicability for PD treatment and the possibility to prevent its progression differently from current drugs to treat PD.

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... The other sam showed no decrease in cell viability (Table 3). These results are in agreement with t obtained by Katchborian-Neto et al. [32], which evaluated the cytotoxicity of Ayahu samples in SH-SY5Y cells. Additionally, three of the samples intensely increased cell bility within the first 48 h [32]. ...
... These results are in agreement with t obtained by Katchborian-Neto et al. [32], which evaluated the cytotoxicity of Ayahu samples in SH-SY5Y cells. Additionally, three of the samples intensely increased cell bility within the first 48 h [32]. In addition, Samoylenko et al. [33] evaluated the cyto city of B. caapi extracts in six cell lines, verifying that the extracts did not show cytotox So far, no bioaccessibility studies have been carried out on Ayahuasca or plants used in its preparation. ...
... The other samples showed no decrease in cell viability (Table 3). These results are in agreement with those obtained by Katchborian-Neto et al. [32], which evaluated the cytotoxicity of Ayahuasca samples in SH-SY5Y cells. Additionally, three of the samples intensely increased cell viability within the first 48 h [32]. ...
Article
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Ayahuasca is a psychoactive beverage that contains the psychoactive compound N,N-dimethyltryptamine and β-carboline alkaloids. This study aims at determining in vitro the bioavailability and bioaccessibility of the main compounds present in decoctions of four individual plants, in a commercial mixture and in four mixtures of two individual plants used in the preparation of Ayahuasca. The samples were subjected to an in vitro digestion process, and the Caco-2 cell line was used as an absorption model. The integrity and permeability of the cell monolayer were evaluated, as well as the cytotoxicity of the extracts. After digestion and cell incubation, the compounds absorbed by the cell monolayer were quantified by high-performance liquid chromatography coupled to a diode array detector. The results showed that compounds such as N,N-dimethyltryptamine, Harmine, Harmaline, Harmol, Harmalol and Tetrahydroharmine were released from the matrix during the in vitro digestion process, becoming bioaccessible. Similarly, some of these compounds, after being incubated with the cell monolayer, were absorbed, becoming bioavailable. The extracts did not show cytotoxicity after cell incubation, and the integrity and permeability of the cell monolayer were not compromised.
... In vitro studies using rodent cell lines include neuronal stem cells (NSCs) derived from the subgranular zone of the hippocampus of embryonic mice (41). Human cell lines include induced pluripotent stem cells (iPSCs), cerebral organoids that consist of artificially grown cells of synthesized tissues resembling the cortex, and the neuroblastoma cell line SH-SY5Y (42)(43)(44). The latter can be used to model neuronal function and differentiation, and neurodegeneration by inducing chemical damage (oxygen deprivation) via in vitro administration of the dopamine analog and neurotoxin 6-hydroxydopamine (6-OHDA) (44). ...
... Human cell lines include induced pluripotent stem cells (iPSCs), cerebral organoids that consist of artificially grown cells of synthesized tissues resembling the cortex, and the neuroblastoma cell line SH-SY5Y (42)(43)(44). The latter can be used to model neuronal function and differentiation, and neurodegeneration by inducing chemical damage (oxygen deprivation) via in vitro administration of the dopamine analog and neurotoxin 6-hydroxydopamine (6-OHDA) (44). In vivo studies in rodents use electrophysiology, the measurement of gene transcription and protein levels, and receptor knockout models to test the contribution of-for example-a specific receptor in the drug effects. ...
... Evidence from in vitro studies (n = 5) suggests that psychedelics stimulate molecular and cellular neuroplasticity (41)(42)(43)(44)53). The acute effect of a single dose of (5-MeO-)DMT on neuroplasticity was investigated by three in vitro studies (42,43,53). ...
Article
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Clinical studies suggest the therapeutic potential of psychedelics, including ayahuasca, DMT, psilocybin, and LSD, in stress-related disorders. These substances induce cognitive, antidepressant, anxiolytic, and antiaddictive effects suggested to arise from biological changes similar to conventional antidepressants or the rapid-acting substance ketamine. The proposed route is by inducing brain neuroplasticity. This review attempts to summarize the evidence that psychedelics induce neuroplasticity by focusing on psychedelics' cellular and molecular neuroplasticity effects after single and repeated administration. When behavioral parameters are encountered in the selected studies, the biological pathways will be linked to the behavioral effects. Additionally, knowledge gaps in the underlying biology of clinical outcomes of psychedelics are highlighted. The literature searched yielded 344 results. Title and abstract screening reduced the sample to 35; eight were included from other sources, and full-text screening resulted in the final selection of 16 preclinical and four clinical studies. Studies ( n = 20) show that a single administration of a psychedelic produces rapid changes in plasticity mechanisms on a molecular, neuronal, synaptic, and dendritic level. The expression of plasticity-related genes and proteins, including Brain-Derived Neurotrophic Factor (BDNF), is changed after a single administration of psychedelics, resulting in changed neuroplasticity. The latter included more dendritic complexity, which outlasted the acute effects of the psychedelic. Repeated administration of a psychedelic directly stimulated neurogenesis and increased BDNF mRNA levels up to a month after treatment. Findings from the current review demonstrate that psychedelics induce molecular and cellular adaptations related to neuroplasticity and suggest those run parallel to the clinical effects of psychedelics, potentially underlying them. Future (pre)clinical research might focus on deciphering the specific cellular mechanism activated by different psychedelics and related to long-term clinical and biological effects to increase our understanding of the therapeutic potential of these compounds.
... JID: ACTBIO [m5G; 22:33 ] naphthoquinone-dopamine-based hybrid small molecules to improve cellular viability [160] . Katchborian-Neto et al. utilized an untargeted metabolomics approach to identify the neuroprotective capability of Ayahuasca-derived compounds towards 6-OHDA damage [161] . Finally, Getachew et al. investigated the therapeutic potential of short-chain fatty acid butyrate (produced in the gut) towards salsolinol-induced damage to SH-SY5Y cells [162]. ...
... While there is no single method to induce PD pathology, studies continue to utilize different chemical models to match their specific experimental goals. Recently ayahuasca (6-OHDA) [161] and butyrate (salsolinol) [162] have been utilized for ameliorating toxicity and validating a midbrain organoid cellular model (MPTP) [172] . Additionally, rotenone was used as a model in recent work to screen the therapeutic potential of the SCFA propionic acid and Rho-kinase inhibitor Fasudil [199] . ...
... Indian tribes from Amazonia have been using leaves from Psychotria viridis (in combination with Banisteriopsis caapi) for the preparation of Ayahuasca, a decoction applied in rituals for the treatment of various health problems, including mental diseases (Katchborian-Neto et al., 2020). Since the early 1990s, research groups have investigated the use of Ayahuasca for the treatment of anxiety, depression, alcohol addiction, and neurodegenerative diseases (NDs) (Domínguez-Clavé et al., 2016;Dos Santos and Hallak, 2021). ...
... Since the early 1990s, research groups have investigated the use of Ayahuasca for the treatment of anxiety, depression, alcohol addiction, and neurodegenerative diseases (NDs) (Domínguez-Clavé et al., 2016;Dos Santos and Hallak, 2021). The pharmacological properties of Ayahuasca are attributed to the indole alkaloids identified in the beverage: tryptamine derivatives from P. viridis and β-carboline derivatives from B. caapi (Katchborian-Neto et al., 2020). Stimulated by the research on Ayahuasca, further Psychotria species became the subject of pharmacological and pharmacobotanical studies. ...
Article
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Nemorosine A (1) and fargesine (2), the main azepine-indole alkaloids of Psychotria nemorosa, were explored for their pharmacological profile on neurodegenerative disorders (NDs) applying a combined in silico–in vitro–in vivo approach. By using 1 and 2 as queries for similarity-based searches of the ChEMBL database, structurally related compounds were identified to modulate the 5-HT2A receptor; in vitro experiments confirmed an agonistic effect for 1 and 2 (24 and 36% at 10 μM, respectively), which might be linked to cognition-enhancing properties. This and the previously reported target profile of 1 and 2, which also includes BuChE and MAO-A inhibition, prompted the evaluation of these compounds in several Caenorhabditis elegans models linked to 5-HT modulation and proteotoxicity. On C. elegans transgenic strain CL4659, which expresses amyloid beta (Aβ) in muscle cells leading to a phenotypic paralysis, 1 and 2 reduced Aβ proteotoxicity by reducing the percentage of paralyzed worms to 51%. Treatment of the NL5901 strain, in which α-synuclein is yellow fluorescent protein (YFP)-tagged, with 1 and 2 (10 μM) significantly reduced the α-synuclein expression. Both alkaloids were further able to significantly extend the time of metallothionein induction, which is associated with reduced neurodegeneration of aged brain tissue. These results add to the multitarget profiles of 1 and 2 and corroborate their potential in the treatment of NDs.
... The religious use of ayahuasca has been nationally regulated in Brazil since 2010, including plants cultivation, beverage preparation and transport, as well as a set of rules, norms, and ethical principles to be applied to the use of ayahuasca by religious groups (Labate and Feeney, 2012). The indication of ayahuasca in folk medicine relates to a vast range of medical conditions, in particular mental health (Katchborian-Neto et al., 2020). In addition, ayahuasca is considered to be an ethnomedicine with importance against mood alterations and substance abuse (Domínguez-Clavé et al., 2016;Estrella-Parra et al., 2019;Hamill et al., 2019). ...
... As example, ayahuasca prevents the re-establishment of drug-induced conditioned place preference (CPP) and reverts changes in Fos activation in brain regions associated with long-term drug-seeking behavior (Reis et al., 2020). Therefore, due to the restricted number of clinical reports, and indication from preliminary investigations towards the potential beneficial effects of ayahuasca on substance abuse, there has been increased interest of the scientific community at elucidating its pharmacological actions underlying the effects on ethanol consumption (Katchborian-Neto et al., 2020;McKenna, 2004). ...
Article
Ethnopharmacological relevance Ayahuasca, a psychoactive beverage prepared from Banisteriopsis caapi and Psychotria viridis, is originally used by Amazon-based indigenous and mestizo groups for medicinal and ritualistic purposes. Nowadays, ayahuasca is used in religious and shamanic contexts worldwide, and preliminary evidence from preclinical and observational studies suggests therapeutic effects of ayahuasca for the treatment of substance (including alcohol) use disorders. Aim of the study To investigate the initial pharmacological profile of ayahuasca and its effects on ethanol rewarding effect using the conditioned place preference (CPP) paradigm in mice. Materials and methods Ayahuasca beverage was prepared using extracts of B. caapi and P. viridis, and the concentration of active compounds was assessed through high performance liquid chromatography (HPLC). The following behavioral tests were performed after ayahuasca administration: general pharmacological screening (13, 130, or 1300 mg/kg – intraperitoneally – i.p., and 65, 130, 1300, or 2600 mg/kg – via oral – v.o.); acute toxicity test with elevated doses (2600 mg/kg – i.p., and 5000 mg/kg – v.o.); motor activity, motor coordination, and hexobarbital-induced sleeping time potentiation (250, 500, or 750 mg/kg ayahuasca or vehicle – v.o.). For the CPP test, the animals received ayahuasca (500 mg/kg – v.o.) prior to ethanol (1.8 g/kg – i.p.) or vehicle (control group – i.p.) during conditioning sessions. Results Ayahuasca treatment presented no significant effect on motor activity, motor coordination, hexobarbital-induced sleeping latency or total sleeping time, and did not evoke signs of severe acute toxicity at elevated oral doses. Ayahuasca pre-treatment successfully inhibited the ethanol-induced CPP and induced CPP when administered alone. Conclusions Our results indicate that ayahuasca presents a low-risk acute toxicological profile when administered orally, and presents potential pharmacological properties that could contribute to the treatment of alcohol use disorders.
... In this context, Palicourea and Psychotria species have already been considered as "hot genera" due to the diversity of their alkaloidal types (Cragg et al., 2006), such as monoterpene indole alkaloids (MIA), among other classes such as pyrrolidinoindoline and β-carboline alkaloids (Berger et al., 2017;Calixto et al., 2016;Jannic et al., 1999;Klein-Júnior et al., 2017;Verotta et al., 1998;Yang et al., 2016). Currently, these genera remain phytochemically and biologically scarcely investigated (Berger et al., 2015(Berger et al., , 2017Bertelli et al., 2017;Carvalho Jr. et al. 2019;Formagio et al., 2019;Katchborian-Neto et al., 2020;Klein-Júnior et al., 2017, 2020Kornpointner et al., 2018Kornpointner et al., , 2020Moura et al., 2020;Pinto et al., 2021;Porto et al., 2020). Therefore, considering that these genera are sources of bioactive metabolites, highlighting different classes of alkaloids, besides the urgent need of new antimalarial drugs, the evaluation of different species of Palicourea and Psychotria represent a promising route to new antimalarial leads. ...
Article
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IntroductionA great variety of bioactive natural products has been reported for different Palicourea and Psychotria species (Rubiaceae). However, few of them as well as few of species of these botanical genera have been evaluated for antiplasmodial activity.Objective To assess the antiplasmodial activity of 24 extracts from Palicourea and Psychotria genera, along with the targeted LC–MS metabolite profiling, as well as identification of the main metabolites in the bioactive extracts.Methods Twenty four ethanol and acid–base extracts from Palicourea and Psychotria genera collected in the Amazonia and Atlantic Forest, Brazil, were evaluated against chloroquine-resistant Plasmodium falciparum W2 strain by PfLDH. The metabolite profiling and putative identification of metabolites from bioactive extracts were determined by LC-DAD-ESI–MS and LC-HRMS, respectively.ResultsThe ethanol extracts disclosed low antiplasmodial activity (% GI < 50%). High antiplasmodial effect was observed for the acid–base extracts from Psychotria apoda and Psychotria colorata with 100% inhibition of parasite growth inhibition. Fragment ions related to pyrrolidinoindoline alkaloids were observed by LC-DAD-ESI–MS mainly in the most bioactive extracts. The results of the in vitro screening associated with the LC-DAD-ESI–MS and LC-HRMSn data allowed to predict, for the first time, the pyrrolidinoindoline alkaloids as possible antiplasmodial representing, then, new potential natural antimalarial hits. In addition, other metabolite classes such as flavanones, lignans and chalcones were also putatively identified in the bioactive extracts of Psychotria apoda, Psychotria capitata, and Psychotria poeppigiana.Conclusion The present results point to Palicourea and Psychotria species as sources of new antimalarial hits.
... Remarkably, those effects were less significant with isolated compounds. 5 This suggests that using ayahuasca as a brew may be more beneficial in some cases. However, these hypotheses need to be tested in future studies. ...
Article
Research with psychedelic drugs has mainly focused on isolated compounds. However, this approach is challenged by the "polypharmacology" paradigm. In this Viewpoint, we suggest that we may be missing something if we do not use the whole product in the case of ayahuasca or Psilocybe mushrooms. After describing how research on psychedelic drugs can be effectively combined with the polypharmacol-ogy paradigm, ethical issues are also briefly discussed.
... DMT has also been shown to produce neurogenesis and neuroprotection in cell cultures (Berthoux et al., 2018). Using metabolomics, a recent study found that ayahuasca contains compounds with highly neuroprotective properties (Katchborian-Neto et al., 2020). Psilocybin also induces neurogenesis, and it has been suggested that it is geroprotective (Catlow et al., 2013;Germann, 2020). ...
Article
Microdosing psychedelic drugs -that is, taking sub-behavioral doses of lysergic acid diethylamide (LSD) or psilocybin- is a growing practice in Western societies. Taken mainly for creative or mood-enhancing purposes, thousands of users are increasingly being exposed to (micro)doses of psychedelic drugs. In this systematic review, we searched the available evidence from human studies, focusing our results in terms of three main axes: efficacy, safety, and the influence of the placebo effect in microdosing practices. While the available evidence has some strengths (e.g. large sample sizes, robust methodologies) there are also remarkable limitations (e.g. gender bias, heterogeneity of dosing schedules and drugs used). Highly contradictory results have been found, showing both the benefits and detriments of microdosing in terms of mood, creative processes, and energy, among other regards. This review provides a general overview of the methods and approaches used, which could be useful for improving future studies.
... Metabolomic studies on ayahuasca are extremely scarce. Very recently, the neuroprotective role of ayahuasca was investigated in human neuroblastoma cells (SH-SY5Y) challenged with 6-hydroxydopamine (6-OHDA), this being a suitable model to study the neuroprotective effect of substances on Parkinson's disease (PD) [209]. SH-SY5Y cells were treated with samples of ayahuasca, fractions of its source plants (B. ...
Article
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Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N‐dimethyltryptamine (DMT)‐containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids. Herein, the toxicokinetics and toxicodynamics of the psychoactive DMT and harmala alkaloids harmine, harmaline and tetrahydroharmine, are comprehensively covered, particularly emphasizing the psychological, physiological, and toxic effects deriving from their concomitant intake. Potential therapeutic utility, particularly in mental and psychiatric disorders, and forensic aspects of DMT and ayahuasca are also reviewed and discussed. Following administration of ayahuasca, DMT is rapidly absorbed and distributed. Harmala alkaloids act as potent inhibitors of monoamine oxidase A (MAO‐A), preventing extensive first‐pass degradation of DMT into 3‐indole‐ acetic acid (3‐IAA), and enabling sufficient amounts of DMT to reach the brain. DMT has affinity for a variety of serotonergic and non‐serotonergic receptors, though its psychotropic effects are mainly related with the activation of serotonin receptors type 2A (5‐HT2A). Mildly to rarely severe psychedelic adverse effects are reported for ayahuasca or its alkaloids individually, but abuse does not lead to dependence or tolerance. For a long time, the evidence has pointed to potential psychotherapeutic benefits in the treatment of depression, anxiety, and substance abuse disorders; and although misuse of ayahuasca has been diverting attention away from such clinical potential, research onto its therapeutic effects has now strongly resurged.
... Moreover, assessments of biochemical parameters related to liver damage in serum in 22 volunteers who consumed Ayahuasca twice a month or more for at least one year indicate that chronic consumption of Ayahuasca in a religious context apparently does not affect liver function [56]. Furthermore, both DMT and HRM demonstrated a cyto-protective effect in vitro on different cell lines of human neurons submitted to hypoxia [57] or by exposure to 6-hydroxydopamine [58]. ...
Article
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Introduction: Ayahuasca is a traditional psychoactive tea of Amazonian indigenous, used medicinal and spiritual purposes. Wide variation in the concentration of N,N-dimethyltryptamine (DMT), Harmaline (HRL), Harmine (HRM) and Tetrahydroharmine (THH) alkaloids in Ayahuasca has been reported worldwide. Objective: To evaluate the causes of variations in alkaloids concentrations of Ayahuasca prepared with fresh and dehydrated plants from different environments and determine the best drying method to plants according to alkaloids content and cytotoxicity of Ayahuasca tea. Material and methods: The environment interference on the alkaloids of the two species was evaluated in samples of Ayahuasca tea prepared with fresh plants. The most suitable drying process to the two species was evaluated in sample Ayahuasca tea prepared with plants submitted to drying under the sun conditions and five different temperatures in forced circulation oven. The concentration of the alkaloids determined by high performance liquid chromatography with UV-vis detector with diode array detection (HPLC-DAD). The in vitro cytotoxicity of Ayahuasca was evaluated in human keratinocytes cells (HaCaT) by colorimetric assay. Results: Environmental characteristics, preparation process and temperature of plants drying interfered on DMT, HRL, HRM and THH concentrations of Ayahuasca. No effect cytotoxicity was detected with relationship to psychoactive alkaloids in samples of Ayahuasca tea prepared with fresh or dried plants. Conclusion: Concentration of DMT, HRL, HRM and THH alkaloids in Ayahuasca are influenced by plants environmental. The most suitable drying process was obtained in forced circulation oven at 43 and 45°C to P. viridis leaves and B. caapi stems respectively. The Ayahuasca prepared with fresh or dry plants no showed cytotoxicity in human keratinocytes cells.
... The reasons why the regular use of psychedelic drugs might be protective during a period of confinement can only be speculative. First, they are 5-HT 2A agonists and have interesting anti-inflammatory, plasticity-promoting, and neuroprotective properties that could be associated with mood enhancement (34,(64)(65)(66). Also, the feelings of awe produced by the psychedelic experience (67) and the enhancement of certain traits or psychological processes, such as decentering (68), can be especially beneficial during a prolonged lockdown. ...
Article
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Background: One of the main public health strategies adopted at the beginning of the COVID-19 pandemic consisted of implementing strict lockdowns to stop the transmission of the virus. Despite being an effective measure, the confinement and the associated social isolation create a stressful, potentially lengthy situations that has been proven to have several psychological consequences. Given the potential benefits that certain psychedelic drugs have shown for the treatment of psychological disorders, this study aimed to assess the impact of lifetime psychedelic drug use on mental health in relation to the first strict lockdown adopted by various countries (April-July 2020). Methods: Subjects completed an online survey that inquired about sociodemographic factors, activities, and lifestyle factors during confinement, as well as health and mental health related factors. Subjects were asked about their lifetime use of psychedelic drugs (MDMA, ayahuasca, psilocybin-containing mushrooms, LSD, peyote, San Pedro, Bufo alvarius or 5-MeO-DMT, and others), being classified as regular users (more than once per 6 months), occasional users, or non-users. The survey included psychometric tests used to assess psychological distress, peritraumatic stress, social support, psychopathological symptoms, and personality. Linear regressions were performed with psychedelic drug users as the independent variable and psychometric factors as the outcomes, while correcting for age, gender, language, religion, spirituality, and use of non-psychedelic drugs. Results: The study included 2,974 English, Portuguese, and Spanish speakers (497 regular users of psychedelic drugs, 606 occasional users, and 1,968 non-users). On average, respondents were 36 years old and 70% were female. Psychedelic drug users, especially regular ones, reported less psychological distress, less peritraumatic stress, and more social support. Regarding personality measures, psychedelic drug users scored higher on the novelty-seeking and self-transcendence scales, and lower on cooperativeness. Conclusion: Our findings showed that regular users of psychedelic drugs had less psychological stress and some personality differences when compared to occasional users and non-users. This suggests that either the use of psychedelics might be a protective factor itself or people with certain previous traits are more prone to frequently using psychedelic drugs. Future prospective longitudinal research should investigate the underlying processes observed in this study to develop consistent hypotheses.
... For example, extract from Ayahuasca, a tea produced by the decoction of Amazonian plants, was analyzed by ESI using the non-target metabolomics strategy aiming to explore its chemical composition and neuroprotective activity. In the end, 1447 and 972 peaks were respectively detected in the positive and negative mode of analysis, with the major alkaloids with isolated and quantified and their neuroprotective activity evaluated [55] . Nine cycloartane were also identified by LC-MS-APCI, which proved that the methodology was completely adequate to describe putative annotations in metabolomics [56] . ...
Article
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Drug discovery and development is a multi and interdisciplinary process that includes chemistry and biology understanding. Though, drug discovery is an expensive and time-consuming process, promoting the lack of new drugs approval in recent years. In general, most of the drugs are established based on a macromolecular target, which is vital to disease progression. However, in many cases, the mechanism of drug-macromolecular target interaction is complex and not understood. All this missed information is strongly dependent on the physicalal-chemical stability and behavior of the molecule inside the cell, which is correlated to its metabolism resistance and entrance into the cell through the cellular membrane, respectively. Thus, bioanalysis often provides enough data about these molecular characteristics and helps to figure out new information about these subjects. In this context, the study of the metabolism of parental compound plays a key role in bioanalysis and, consequently in drug discovery. For a long time, the study of metabolism represented a huge challenge in medicinal chemistry, but with the technological advancements, many powerful techniques were developed and, currently, the metabolomics fields are essential steps in the process of discovering a new drug. Herein, we briefly discuss the biological aspects of the drug metabolism, focusing on the most used analytical tools to better understand the metabolite generation, and consequently, their chemical and biological characteristics.
... The harmane derivatives β-carboline-1-propanoic acid and 2-methyl-β-carbolinium-1propanoate (10 and 11, Figure 2), the latter as a new compound, were also isolated from B. curtisii [25]. Compound 10 was also found in Cortinarius infractus [88] and in the plant kingdom [89][90][91], including its tentative identification in extracts from the matrix plants of the Ayahuasca tea beverage [92]. ...
Article
Full-text available
Alkaloids are a wide family of basic N-containing natural products, whose research has revealed bioactive compounds of pharmacological interest. Studies on these compounds have focused more attention on those produced by plants, although other types of organisms have also been proven to synthesize bioactive alkaloids, such as animals, marine organisms, bacteria, and fungi. This review covers the findings of the last 20 years (2002–2022) related to the isolation, structures, and biological activities of the alkaloids produced by mushrooms, a fungal subgroup, and their potential to develop drugs and agrochemicals. In some cases, the synthesis of the reviewed compounds and structure−activity relationship studies have been described.
... However, it should be noted that this limitation is widely found with regards to natural products, since efforts to describe the complete metabolome of such products only began recently [190]. Through untargeted metabolomics, more than 2,000 compounds were found in the ayahuasca brew, and a potent neuroprotective effect was found to result from synergy or additive interactions, since it was not found after administering the main active principles in isolation [191]. Thus, if the main active principles of ayahuasca (DMT + β-carbolines) are isolated for their clinical use, this interesting effect (and maybe others still undescribed) would be lost. ...
Chapter
Interest in psychoactive ethnobotanicals such as ayahuasca or Psilocybe mushrooms for clinical uses has increased over the last two decades. While clinical and experimental approaches have focused on using isolated compounds of interest (such as psilocybin), an emerging trend in drug discovery involves a more comprehensive approach. The polypharmacology paradigm, as it has been named, suggests that promiscuous drugs could be safer and more effective than highly selective ones. This is especially relevant with regards to complex diseases, like most mental health problems and neurodegenerative diseases, and for natural products, including psychoactive ethnobotanicals. Natural products not only show a multi-target profile, but they also contain several compounds capable of interacting with one another and producing synergistic effects. In this chapter, the use of whole natural products instead of isolated compounds is suggested in support of combining two recent paradigms: psychedelic-assisted therapy on the one side and polypharmacology on the other.
... [13,19] Among the metabolomics strategies, the use of liquid chromatography techniques coupled with mass spectrometry to provide an overview of the chemical composition and multivariate statistical analysis (MSA) to correlate active compounds that are common in active and absent in inactive samples is one of the main strategies for markers discovery. [20,21] In this work, we have applied the ultra-performance liquid chromatography coupled to an electrospray ionisation quadrupole time of flight mass spectrometer (UPLC-ESI-qTOF) to explore metabolites produced by different hop cultivars of the United States of America and Brazil. Employing MSA we aimed to indicate the potential candidate markers responsible for the anti-inflammatory activity profiles. ...
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Hops ( Humulus lupulus L.) are edible flowers commonly used to add flavour and aroma to beer, besides they have rich chemical diversity and medicinal potential. In this work, an ex‐vivo anti‐inflammatory assay via the LPS‐induced signalling pathway and metabolomics approaches were performed to evaluate the ability of hops to cause inhibition of prostaglandin E2 (PGE2) inflammatory mediator and analyze which metabolites produced by the different hop cultivars are potential anti‐inflammatory markers. Columbus, Chinook and Hallertau Mittelfrüh hop cultivars yielded extracts with PGE2 release inhibition rates of 92.5, 86.7 and 73.5%, respectively. According to the multivariate statistical analysis, the majority of the metabolites correlated with the activity were prenylated phloroglucinol and phenolic homologs. These results suggest promissory anti‐inflammatory hop metabolites.
... There are also reports of other benefits such as anxiolytic effects, enhanced well-being and lower prevalence of mental disorders in long-term ayahuasca consumers compared with the general population, among other positive effects [19,30]. Moreover, pre-clinical trials have demonstrated ayahuasca's alkaloids' neuroprotective [31,32] and neuroplastic properties [33], which probably underlie at least in part its therapeutic effects. There are other possible medicinal uses for ayahuasca. ...
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Introduction: Ayahuasca is a psychedelic brew originally used by indigenous tribes from the Amazon Rainforest and in religious rituals. Pre-clinical and observational studies have demonstrated its possible potential as an antidepressant, and open and placebo-controlled clinical trials corroborated these results. For it to become an approved treatment for depression, its safety and tolerability need to be assessed and documented. Areas covered: We have gathered data regarding occurrence of adverse events (AEs) in all reported randomized, placebo-controlled trials with healthy and clinical populations involving ayahuasca administration (n = 108 ayahuasca administrations). We systematically categorized these results, recorded their prevalence and discussed the possible mechanisms related to their emergence. Expert opinion: : There were no reports of serious AEs, indicating a relative safety of ayahuasca administration in controlled settings. Most common AEs related to ayahuasca administration included nausea, vomiting, headaches and transient increases in cardiovascular measurements. Ayahuasca research is still in its infancy, especially concerning the absence of large and robust clinical trials to verify its antidepressant effects. Dose standardization, legal prohibition of the possession of its alkaloids and how traditional communities will be compensated if ayahuasca becomes an approved medicine are the biggest obstacles to overcome for its future use in the therapeutic context.
... While several metabolomic studies have been carried out on the ayahuasca beverage [22,31,66], to date, scarce metabolomics investigations have been conducted in humans [75]. Previous studies in other drugs with psychedelic effects using animal models provided support on alteration of amino acids [79], lipids (M. ...
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... In this way, using metabolomics specifically, all metabolites contained in a NP can be qualitatively and quantitatively analyzed (Harvey et al. 2015). Only ayahuasca has been tested using these techniques so far (Katchborian-Neto et al. 2020), showing unexpected neuroprotective effects due to synergies among some of its compounds. Other issues that have been highlighted in regards to the limitations of NP research include the difficulty of determining their precise mechanism of action, since complex interactions often occur both within the compounds of the NP and with their biological targets (Bernardini et al. 2018). ...
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span style="font-family: Helvetica; font-size: xx-small;"> A Ayahuasca, chá produzido pela decocção do caule do cipó Jagube (Banisteriopsis caapi) e das folhas da Chacrona (Psychotria viridis), é um alucinógeno ritualístico que alcançou a atualidade através de várias doutrinas religiosas. No Brasil, entre as tradições religiosas que fazem uso da bebida estão o Santo Daime, a Barquinha e a União do Vegetal. A bebida contém a substância N,N-dimetiltriptamina, psicotrópico de uso proscrito pela Portaria SVS/MS 344/1998 e considerado droga pela Lei 11.343/2006. Apesar disto, o uso religioso do chá foi reconhecido pelo CONAD em 2004 (Resolução 4/2004) e ratificado pela Resolução 1/2010. A partir daí, posicionamentos repletos de preconceitos e desprovidos de fundamentação científica têm sido gerados. A fim de contribuir com a discussão, o presente trabalho sistematiza o conhecimento antropológico, farmacológico e legal sobre o chá. </span
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Chapter
This chapter provides an overview of the group of plant-derived, nitrogen-containing, secondary metabolites—alkaloids—and of the plant species in which they are distributed. The chapter focuses on a variety of biological and pharmaceutical applications of this diverse group of compounds, paying particular attention to their pharmacological properties, indications of administration, side effects caused, and interactions with other medicines. Although these are naturally occurring compounds applied in modern pharmacotherapeutical strategies, their numerous contraindications and narrow therapeutic indices indicate that care is needed with respect to their administration.
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Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive and selective death of dopaminergic neurons. Multifunctional neuropeptide orexin-A is involved in many biological events of the body. It has been shown that orexin-A has protective effects in neurodegenerative disease such as PD. However, its cellular mechanisms have not yet been fully clarified. Here, we investigated the intracellular signaling pathway of orexin-A neuroprotection in 6-OHDA-induced SH-SY5H cells damage as an in vitro model of PD. The cells were incubated with 150 µM 6-OHDA and the viability was examined by MTT assay. Mitochondrial membrane potential and intracellular calcium were measured by fluorescent probes. Western blotting was also used to determine COX-2, Nrf2 and HSP70 proteins levels. The data showed that 6-OHDA has decreasing effects on cell viability, Nrf2, and HSP70 proteins expression and increases the level of mitochondrial membrane potential, intracellular calcium and COX-2 protein. Orexin-A (500 pM) significantly attenuated the 6-OHDA-induced cell damage. Furthermore, Orexin-A significantly prevented the mentioned effects of 6-OHDA on SH-SY5Y cells. Orexin 1 receptor antagonist (SB3344867), PKC and PI3K inhibitors (chelerythrin and LY294002, respectively) could suppress the orexin-A neuroprotective effect. In contrast, blockage of PKA by a selective inhibitor (KT5720) had no effects on the orexin protection. The results suggest that orexin-A protective effects against 6-OHDA-induced neurotoxicity are performed via its receptors, PKC and PI3K signaling pathways.
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Post mortem studies on familial and sporadic Parkinson's disease patient striatal tissue have shown that nearly 90% of α-synuclein deposited in Lewy-bodies is phosphorylated at serine-129 (pSyn-129) as opposed to only 4% in normal human brain. We aimed to find the influence of endogenous neurotoxin 6-hydroxydopamine (6-OHDA) on α-synuclein phosphorylation, resting vesicles and vesicular dopamine release. The relative distribution of pSyn-129+ cells in apoptotic and non-apoptotic populations at different 6-OHDA concentrations was assessed along with changes in oxidant-antioxidant system, mitochondrial membrane-potential and intracellular-Ca(2+) . Exposing SH-SY5Y cells to different concentrations of 6-OHDA for 48 hours showed cell-death and apoptosis. Immunocytochemical analysis indicated an increase in pSyn-129 with increasing 6-OHDA concentration, and ELISA-estimation showed a significant increase in the pSyn-129 to α-synuclein ratio. FACS analysis also showed a significant increase in pSyn-129; and at sub-lethal 6-OHDA concentrations, pSyn-129+ cells were primarily distributed in the non-apoptotic population, suggesting that phosphorylation of α-synuclein precedes apoptosis. At higher 6-OHDA concentrations, the pSyn-129+ cell count significantly increased in the apoptotic population and decreased in the non-apoptotic population. Cytosolic co-localization of α-synuclein and ubiquitin was noticed at higher doses of 6-OHDA. FACS analysis showed decrease in vesicular monoamine transporter-2 (VMAT2) expression in 6-OHDA-treated cells, confirmed by reduction in functional dopamine-release on KCl and ATP stimulation. Significant decrease in VMAT2 expression and vesicular dopamine-release were observed with the lower 6-OHDA concentration, together with mild occurrence of apoptosis and significant increase in phosphorylated α-synuclein. This suggests that at sub-lethal 6-OHDA concentrations, the decrease in resting vesicles (VMAT2) and vesicular dopamine release are not attributable to apoptotic cell death and occur concomitantly with the phosphorylation of α-synuclein. This article is protected by copyright. All rights reserved.
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Ayahuasca is the Quechua name for a tea obtained from the vine Banisteriopsis caapi, and used for ritual purposes by the indigenous populations of the Amazon. The use of a variation of the tea that combines B. caapi with the leaves of the shrub Psychotria viridis has experienced unprecedented expansion worldwide for its psychotropic properties. This preparation contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT) from P. viridis, plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties from B. caapi. Acute administration induces a transient modified state of consciousness characterized by introspection, visions, enhanced emotions and recollection of personal memories. A growing body of evidence suggests that ayahuasca may be useful to treat substance use disorders, anxiety and depression. Here we review the pharmacology and neuroscience of ayahuasca, and the potential psychological mechanisms underlying its therapeutic potential. We discuss recent findings indicating that ayahuasca intake increases certain mindfulness facets related to acceptance and to the ability to take a detached view of one’s own thoughts and emotions. Based on the available evidence, we conclude that ayahuasca shows promise as a therapeutic tool by enhancing self-acceptance and allowing safe exposure to emotional events. We postulate that ayahuasca could be of use in the treatment of impulse-related, personality and substance use disorders and also in the handling of trauma. More research is needed to assess the full potential of ayahuasca in the treatment of these disorders.
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This review focuses on recent and potential advances in chemometric methods in relation to data processing in metabolomics, especially for data generated from mass spectrometric techniques. Metabolomics is gradually being regarded a valuable and promising biotechnology rather than an ambitious advancement. Herein, we outline significant developments in metabolomics, especially in the combination with modern chemical analysis techniques, and dedicated statistical, and chemometric data analytical strategies. Advanced skills in the preprocessing of raw data, identification of metabolites, variable selection, and modeling are illustrated. We believe that insights from these developments will help narrow the gap between the original dataset and current biological knowledge. We also discuss the limitations and perspectives of extracting information from high-throughput datasets.
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Ayahuasca (or caapi in Brazil) is a psychoactive plant beverage initially used by shamans in religious rituals practiced by indigenous peoples in the Amazon region. It is prepared by infusing the pounded stems of Banisteriopsis caapi Morton, a liana which contains beta-carbolines, alkaloids that are potent monoamine oxidase (MAO) inhibitors, together with the leaves of Psychotria viridis Ruiz & Pavón, which contains the psychedelic agent N,N-dimethyltryptamine (DMT). The enzyme MAO normally degrades DMT in the liver and gut. In Brazil, the use of ayahuasca within religious ceremonies is protected by law and it has been incorporated into rituals of syncretic religious groups. Some of these groups have established themselves in the United States and European countries, attracting international research interest in the effects of ayahuasca. Studies suggest that it may have therapeutic applications, such as in the treatment of drug addiction, and that it can be used safely by healthy adults. However, too few studies have been performed for a good assessment of its properties to be made. The aim of this article is to present a review of the history of ayahuasca, up to the recent discoveries concerning its pharmacology and toxicology.
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Medicinal Natural Products: A Biosynthetic Approach, Third Edition, provides a comprehensive and balanced introduction to natural products from a biosynthetic perspective, focussing on the metabolic sequences leading to various classes of natural products. The book builds upon fundamental chemical principles and guides the reader through a wealth of diverse natural metabolites with particular emphasis on those used in medicine. There have been rapid advances in biosynthetic understanding over the past decade through enzymology, gene isolation and genetic engineering. Medicinal Natural Products has been extended and fully updated in this new edition to reflect and explain these developments and other advances in the field. It retains the user-friendly style and highly acclaimed features of previous editions: A comprehensive treatment of plant, microbial, and animal natural products in one volume. Extensive use of chemical schemes with annotated mechanistic explanations. Cross-referencing to emphasize links and similarities. boxed topics giving further details of medicinal materials, covering sources, production methods, use as drugs, semi-synthetic derivatives and synthetic analogues, and modes of action. Medicinal Natural Products: A Biosynthetic Approach, Third Edition, is an invaluable textbook for students of pharmacy, pharmacognosy, medicinal chemistry, biochemistry and natural products chemistry.
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Parkinson's disease (PD) is an increasingly prevalent and progressively disabling neurodegenerative disease. The impact of PD on patients and their families as well as its burden on health care systems could be substantially reduced by disease-modifying therapies that slow the rate of neurodegeneration or stop the disease process. Multiple agents have been studied in clinical trials designed to assess disease modification in PD, but all have failed. Over the last 3 years, clinical trials investigating the potential of adeno-associated virus serotype 2 (AAV)-neuturin, coenzyme Q10, creatine, pramipexole, and pioglitazone reported negative findings or futility. Despite these disappointments, progress has been made by expanding our understanding of molecular pathways involved in PD to reveal new targets, and by developing novel animal models of PD for preclinical studies. Currently, at least eight ongoing clinical trials are testing the promise of isradipine, caffeine, nicotine, glutathione, AAV2-glial cell-line derived neurotrophic factor (GDNF), as well as active and passive immunization against α-synuclein (α-Syn). In this review, we summarize the clinical trials of disease-modifying therapies for PD that were published since 2013 as well as clinical trials currently in progress. We also discuss promising approaches and ongoing challenges in this area of PD research. © 2015 International Parkinson and Movement Disorder Society. © 2015 Movement Disorder Society.
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Thermal electrocyclisation of the azahexatriene system has been used as a key step for the synthesis of anti-HIV and anti-tumour compounds, harman, derivatives of harman and 1-aryl-β-carbolines. A one-pot reaction sequence was used to furnish these compounds in good yield.
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Six β-carboline alkaloids were isolated from a Chinese medicinal plant, Arenaria kansuensis. The structures of four new alkaloids named arenarines A, B, C, and D were identified based on spectral and chemical evidence.
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Multivariate statistical techniques are used extensively in metabolomics studies, ranging from biomarker selection to model building and validation. Two model independent variable selection techniques, principal component analysis and two sample t-tests are discussed in this chapter, as well as classification and regression models and model related variable selection techniques, including partial least squares, logistic regression, support vector machine, and random forest. Model evaluation and validation methods, such as leave-one-out cross-validation, Monte Carlo cross-validation, and receiver operating characteristic analysis, are introduced with an emphasis to avoid over-fitting the data. The advantages and the limitations of the statistical techniques are also discussed in this chapter.
Chapter
Alkaloids constitute a huge group of natural products, and some of them have been extensively studied for their activity on targets related to the central nervous system (CNS), especially neurodegenerative diseases and depression. In this context, the inhibition of monoamine oxidases (MAOs) was considered in the search for natural products with promising scaffolds for drug development. Among various classes, indole alkaloids possess biological and pharmacological properties in the CNS, mainly related to the serotonergic and glutamatergic transmission. Those containing a β-carboline moiety, such as harmane, are especially known for their inhibition of MAOs. Another class of alkaloids with a number of studies on the inhibition of MAOs is that of the isoquinoline alkaloids. Chelidonine, a representative of this group, shows specific and irreversible inhibition of MAO-A. The studies conducted so far on the selectivity between MAO-A and -B inhibitors contributed to a better understanding of structure –activity relationship (SAR) for the various classes of alkaloids. One example is desoxypeganine, a quinazoline alkaloid that presents selective inhibition on MAO-A. Due to its specific inhibition, this naturally occurring alkaloid has been clinically investigated for its potential application as an alcohol and smoking cessation aid. On the other hand, quinolone alkaloids presented specific in vitro MAO-B inhibition and are mainly considered for age-related neurodegenerative diseases. Several other examples are given in this chapter that consider selectivity on MAO isoforms and SAR issues of various classes of alkaloids.
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Eucommia ulmoides Oliv. Bark. (EUE) has commonly been used to fortify the muscles and lungs, lower blood pressure, prevent miscarriage, improve liver and kidney tone, and promote longevity as a traditional tonic medicine in Korea, China, and Japan. In this study, we investigated the mechanisms by which EUE protects neuronal cells from apoptosis induced by the Parkinson's disease (PD)-related neurotoxin, 6-hydroxydopamine (6-OHDA). We determined the neuroprotective effects of EUE on 6-OHDA-induced neuronal cell death, cytotoxicity, reactive oxygen species (ROS) production, and mitochondrial membrane dysfunction. Moreover, we examined whether EUE suppressed phosphorylation of c-Jun N-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3K)/Akt, and glycogen synthase kinase-3 beta (GSK-3β). Furthermore, the neuroprotective effects of EUE on 6-OHDA-induced activation of nuclear factor-kappa B (NF-κB) was studied in SH-SY5Y cells. Pretreatment of SH-SY5Y cells with EUE significantly reduced 6-OHDA-induced cell death and cytotoxicity. EUE inhibited 6-OHDA-induced generation of ROS, which conferred cytoprotection against 6-OHDA-induced oxidative injury. EUE treatment also strikingly inhibited 6-OHDA-induced mitochondrial dysfunction. In addition, EUE suppressed phosphorylation of JNK, PI3K/Akt, and GSK-3β. Furthermore, EUE blocked 6-OHDA-induced NF-κB nuclear translocation, an event downstream from JNK, PI3K/Akt, and GSK-3β phosphorylation. Moreover, chlorogenic acid (CGA), one of the active constituents of EUE, was also able to reduce 6-OHDA-induced toxicity in SH-SY5Y cells. Taken together, these results suggest that EUE attenuates oxidative stress through activation of JNK, PI3K/Akt, GSK-3β, and NF-κB pathways, thereby protecting cells from neuronal cell death.
Article
Dopaminergic therapies such as levodopa have provided benefit for millions of patients with Parkinson's disease (PD) and revolutionized the treatment of this disorder. However patients continue to experience disability despite the best of modern treatment. Dopaminergic and surgical therapies are associated with potentially serious side effects. Non-motor and non-dopaminergic features such as freezing, falling, and dementia are not adequately controlled with available medications and represent the major source of disability for advanced patients. And, the disease continues to relentlessly progress. Major therapeutic unmet needs include a dopaminergic therapy that is not associated with serious side effects, a therapy that addresses the non-motor and non-dopaminergic features of the disease, and a disease-modifying therapy that slows or stops disease progression. This review will consider current attempts to address these issues and the obstacles that must be overcome in order to develop more effective therapies for PD. Ann Neurol 2013;74:337-347
Article
Thermal electrocyclisation of the azahexatriene system has been used as a key step for the synthesis of anti-HIV and anti-tumour compounds, harman, derivatives of harman and 1-aryl-β-carbolines. A one-pot reaction sequence was used to furnish these compounds in good yield.
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It is of historical interest that 63 years ago Louis Lewin reported the use of a hallucinogenic compound prepared from the South American vine, Banisteria Caapi, to treat Parkinson's disease (PD). This psychoactive compound, named banisterine, proved to be identical to harmine, but 30 years were to pass before it was shown to be a reversible monoamine oxidase (MAO) inhibitor. The first reports of the use of banisterine to treat postencephalitic parkinsonism in 1929 created a stir in the popular press and banisterine was hailed as a "magic drug." Despite continued studies of the harmala alkaloids by other researchers, interest in the therapeutic value of these compounds vanished during the 1930's. The story of banisterine is reviewed because it was the first MAO inhibitor to be used in parkinsonism, and illustrates the historical role of psychoactive durgs in the development of effective therapies, and in elucidating the pathophysiology of PD.