Papers by Elaine Elisabetsky
Journal of Natural Products, 1998
Fractionation of an alkaloid extract of Psychotria colorata flowers led to the isolation of six a... more Fractionation of an alkaloid extract of Psychotria colorata flowers led to the isolation of six alkaloids, identified by UV, 1D and 2D NMR, and MS as (-)-calycanthine, isocalycanthine, (+)-chimonanthine, hodgkinsine, quadrigemine C, and a new alkaloid (1), whose structure was deduced by X-ray analysis to be (8-8a),(8'-8'a)-tetradehydroisocalycanthine 3a(R), 3'a(R).
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this study points to the validity of NAC clinical evaluation in the context of alcohol detoxifica... more this study points to the validity of NAC clinical evaluation in the context of alcohol detoxification and withdrawal.
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Linalool is a monoterpene compound reported to be a major component of essential oils of several ... more Linalool is a monoterpene compound reported to be a major component of essential oils of several aromatic species. Several linalool-producing species are used in traditional medical systems for sedative purposes , including the interruption and prevention of seizures. Previous studies in mice revealed that linalool modulates glutamatergic (competitive antagonism of L-[ 3 H]glutamate binding, delayed intraper-itoneal NMDA-induced convulsions and blockade of intracerebroventricular Quin-induced convulsions) and GABAergic transmission (protection against pentylenetetrazol and picrotoxin-induced convulsions). To further clarify the anticonvulsive mechanisms of linalool, we studied the effects of linalool on binding of [ 3 H]MK801 (NMDA antagonist) and [ 3 H]muscimol (GABA A agonist) to mouse cortical membranes. Linalool showed a dose dependent non-competitive inhibition of [ 3 H]MK801 binding (IC 50 = 2.97 mM) but no effect on [ 3 H]muscimol binding. The data suggest that the anticonvulsant mode of action of lina-lool includes a direct interaction with the NMDA receptor complex. The data do not, however, support a direct interaction of linalool with GABA A receptors, although changes in GABA-mediated neuronal inhibition or effects on GABA release and uptake cannot be ruled out.
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Linalool, a monoterpene compound prevalent in essential oil of plant species traditionally used a... more Linalool, a monoterpene compound prevalent in essential oil of plant species traditionally used as sedatives, has been characterized as anticonvulsant in several experimental models. Linalool inhibits the binding of [ 3 H]glutamate and [ 3 H]dizocilpine to brain cortical membranes, indicating a participation of the glutamatergic transmission its mechanism of action. In this study, we investigated the effects of linalool on [ 3 H]glutamate release (basal and potassium-stimulated) and [ 3 H]glutamate uptake in mice cortical synaptosomes. Linalool significantly reduced potassium stimulated glutamate release as well as glutamate uptake, not interfering with basal gluta-mate release. The data indicates that linalool may interfere with several relevant elements of the glutamatergic transmission, including detriment of the K-stimulated glutamate release.
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Brachycerine (1), an unusual alkaloid from the leaves of Psychotria brachyceras, was characterize... more Brachycerine (1), an unusual alkaloid from the leaves of Psychotria brachyceras, was characterized through spectroscopic data interpretation and its stereochemistry established by NOE difference techniques. Brachycerine (1) was found to be restricted to shoots in rooted cuttings of P. brachyceras (0.018 (0.004% dry weight), and accumulation was unaffected by root induction treatment with auxin.
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this study points to the validity of NAC clinical evaluation in the context of alcohol detoxifica... more this study points to the validity of NAC clinical evaluation in the context of alcohol detoxification and withdrawal.
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It is well known that adenine-based purines exert multiple effects on pain transmission. Recently... more It is well known that adenine-based purines exert multiple effects on pain transmission. Recently, we have demonstrated that guanine-based purines may produce some antinociceptive effects against chemical and thermal pain in mice. The present study was designed to investigate the antinociceptive effects of intrathecal (i.t.) administration of inosine or guanine in mice. Additionally, investigation into the mechanisms of action of these purines, their general toxicity and measurements of CSF purine levels were performed. Animals received an i.t. injection of vehicle (30 mN NaOH), inosine or guanine (up to 600 nmol) and submitted to several pain models and behavioural paradigms. Guanine and inosine produced dose-dependent antinociceptive effects in the tail-flick, hot-plate, intraplantar (i.pl.) glutamate, i.pl. capsaicin and acetic acid pain models. Additionally, i.t. inosine inhibited the biting behaviour induced by spinal injection of capsaicin and i.t. guanine reduced the biting behaviour induced by spinal injection of glutamate or AMPA. Intrathecal administration of inosine (200 nmol) induced an approximately 115-fold increase on CSF inosine levels. This study provides new evidence on the mechanism of action of extracellular guanine and inosine presenting antinociceptive effects following spinal administration. These effects seem to be related, at least partially, to the modulation of A 1 adenosine receptors.
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Background and purpose: Allopurinol is a potent inhibitor of the enzyme xanthine oxidase, used pr... more Background and purpose: Allopurinol is a potent inhibitor of the enzyme xanthine oxidase, used primarily in the treatment of hyperuricemia and gout. It is well known that purines exert multiple effects on pain transmission. We hypothesized that the inhibition of xanthine oxidase by allopurinol, thereby reducing purine degradation, could be a valid strategy to enhance purinergic activity. The aim of this study was to investigate the anti-nociceptive profile of allopurinol on chemical and thermal pain models in mice. Experimental approach: Mice received an intraperitoneal (i.p.) injection of vehicle (Tween 10%) or allopurinol (10– 400 mg kg-1). Anti-nociceptive effects were measured with intraplantar capsaicin, intraplantar glutamate, tail-flick or hot-plate tests. Key results: Allopurinol presented dose-dependent anti-nociceptive effects in all models. The opioid antagonist naloxone did not affect these anti-nociceptive effects. The non-selective adenosine-receptor antagonist caffeine and the selective A1 adenosine-receptor antagonist, DPCPX, but not the selective A2A adenosine-receptor antagonist, SCH58261, completely prevented allopurinol-induced anti-nociception. No obvious motor deficits were produced by allopurinol, at doses up to 200 mg kg-1. Allopurinol also caused an increase in cerebrospinal fluid levels of purines, including the nucleosides adenosine and guanosine, and decreased cerebrospinal fluid concentration of uric acid. Conclusions and implications: Allopurinol-induced anti-nociception may be related to adenosine accumulation. Allopurinol is an old and extensively used compound and seems to be well tolerated with no obvious central nervous system toxic effects at high doses. This drug may be useful to treat pain syndromes in humans.
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Alstonine is the major component of plant based remedies that traditional psychiatrists use in Ni... more Alstonine is the major component of plant based remedies that traditional psychiatrists use in Nigeria. Alsto-nine is an indole alkaloid that has an antipsychotic experimental profile comparable with that of clozapine and is compatible with the alleged effects in mental patients. Representing a desirable innovation in the pharma-codynamics of antipsychotic medications, the evidence indicates that alstonine does not bind to D 2 dopamine receptors (D2R) and differentially regulates dopamine in the cortical and limbic areas. The purpose of this study was to further investigate the effects of alstonine on D2R binding in specific brain regions using quantitative autoradiography (QAR) and its effects on dopamine (DA) uptake in mouse striatal synaptosomes. The effects of alstonine on D2R binding were determined in the nucleus accumbens and caudate-putamen using QAR in mice treated with alstonine doses that have antipsychotic effects. The effects of alstonine [3H]DA uptake were assessed in synaptosomes prepared from striatal tissue obtained from mice treated acutely or for 7 days with alstonine. Alstonine did not change the D2R binding densities in the studied regions. DA uptake was increased after acute (but not after 7 days) treatment with alstonine. Consistent with the alstonine behavioral profile, these results indicate that alstonine indirectly modulates DA receptors, specifically by modulating DA uptake. This unique mechanism for DA transmission modulation contributes to the antipsychotic-like effects of alstonine and is compatible with its behavioral profile in mice and alleged effects in patients. These results may represent an innovation in the antipsychotic development field.
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N-acetylcysteine (NAC), a glutamate-modulating agent with antioxidant and anti-inflammatory prope... more N-acetylcysteine (NAC), a glutamate-modulating agent with antioxidant and anti-inflammatory properties , has been considered as a potential anti-addictive drug. Beneficial effects were reported for cocaine, cannabis, and tobacco addicts, but the effect of NAC in alcoholics or in alcohol animal models is unknown. The aggravation of alcohol withdrawal symptoms, such as anxiety, has been associated with increased levels of serum corticosterone and leptin. Thus, the aim of this study was to assess the effects of NAC on anxiety, as well as corticosterone and leptin serum levels, after cessation of chronic alcohol treatment in rats. Male Wistar rats were treated with 2 g/kg ethanol, twice daily, by gavage for 30 days; control animals received an appropriate dose of glucose to balance caloric intake. Rats were treated for 4 days with NAC (60 and 90 mg/kg, intra-peritoneally [i.p.]) or saline after alcohol cessation. Twenty-four hours after the last treatment, rats were exposed to a 5-min session in the open-field test (OF). Corti-costerone and leptin serum levels were determined by ELISA in samples collected within 30 min after the OF. Results showed that rats were hypoactive (decreased rearing, peripheral, and total crossings), and that corticosterone and leptin levels were increased 5 days after alcohol cessation. Four days of NAC prevented the behavioral and biochemical changes brought about by alcohol cessation. We suggest that, in addition to the anti-addictive properties reported for other drugs of abuse, NAC is potentially useful in the management of alcohol withdrawal.
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Objectives: To evaluate how personality traits are associated with occasional use, abuse, and dep... more Objectives: To evaluate how personality traits are associated with occasional use, abuse, and dependence of alcohol, cannabis, cocaine, benzodiazepines, and hallucinogens in a large availability sample of adults via online questionnaires. Methods: The sample consisted of 8,646 individuals (24.7% men and 75.3% women) who completed an anonymous web survey. Involvement with drugs and temperament/character traits were assessed through the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and the Temperament and Character Inventory-Revised (TCI-R), respectively. Interactions among variables were analyzed using MANOVA with Bonferroni adjustment. Results: Novelty seeking was the trait most associated with increased involvement with alcohol, cannabis, and cocaine. There was a significant association between harm avoidance and benzodiazepine use. Persistence was lower in cannabis-, benzodiazepine-, and cocaine-dependent subjects, as well as in hallucinogen abusers. Self-directedness was reduced in dependents of all drug classes. No strong relationships were found between other temperament or character dimensions and the severity of drug use. Conclusions: Novelty seeking was associated with increased involvement with all drugs studied in this sample, although to a lesser extent with benzodiazepines and hallucinogens. The temperament and character profile for benzodiazepine use was different from that of other drugs due to the relationship with higher harm avoidance and self-transcendence and lower self-directedness.
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Treating individuals at risk to develop schizophrenia may be strategic to delay or prevent transi... more Treating individuals at risk to develop schizophrenia may be strategic to delay or prevent transition to psychosis. We verified the effects of N-acetylcysteine (NAC) in a neurodevelopmental model of schizophrenia. C57 mice were reared in isolation or social groups and treated with NAC from postnatal day 42–70; the locomotor response to amphetamine was assessed at postnatal day 81. NAC treatment in isolated mice prevented the hypersensitivity to amphetamine, suggesting neuroprotection relevant to striatal dopamine. Considering its safety and tolerability profile, complementary studies are warranted to further evaluate the usefulness of NAC to prevent conversion to schizophrenia in at-risk individuals.
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A dysfunctional glutamatergic system is thought to be central to the negative symptoms and cognit... more A dysfunctional glutamatergic system is thought to be central to the negative symptoms and cognitive deficits recognized as determinant to the poor quality of life of people with schizophrenia. Modulating glutamate uptake has, thus, been suggested as a novel target for antipsychotics. Alstonine is an indole alkaloid sharing with atypical antipsychotics the profile in animal models relevant to schizophrenia, though divergent in its mechanism of action. The aim of this study was to evaluate the effects of alstonine on glutamate uptake. Additionally, the effects on glutathione content and extracellular S100B levels were assessed. Acute hippocampal slices were incubated with haloperidol (10 lM), clozapine (10 and 100 lM) or alstonine (1–100 lM), alone or in combination with apomorphine (100 lM), and 5-HT 2 receptor antagonists (0.01 lM altanserin and 0.1 lM SB 242084). A reduction in glutamate uptake was observed with alstonine and clozapine, but not haloperidol. Apomorphine abolished the effect of clozapine, whereas 5-HT 2A and 5-HT 2C antagonists abolished the effects of alstonine. Increased levels of glutathione were observed only with alstonine, also the only compound that failed to decrease the release of S100B. This study shows that alstonine decreases glutamate uptake, which may be beneficial to the glutamatergic deficit observed in schizophrenia. Noteworthily, the decrease in glutamate uptake is compatible with the reversal of MK-801-induced social interaction and working memory deficits. An additional potential benefit of alstonine as an antipsychotic is its ability to increase glutathione, a key cellular antioxidant reported to be decreased in the brain of patients with schizophrenia. Adding to the characterization of the novel mechanism of action of alstonine, the lack of effect of apomorphine in alstonine-induced changes in glutamate uptake reinforces that D 2 receptors are not primarily implicated. Though clearly mediated by 5-HT 2A and 5-HT 2C serotonin receptors, the precise mechanisms that result in the effects of alstonine on glutamate uptake warrant elucidation.
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Clinical studies with human subjects represent the only assessment of effectiveness and safety th... more Clinical studies with human subjects represent the only assessment of effectiveness and safety that can translate into medical practice, and national or local health policy. There are several reasons why traditional medicines (in fact medicinal plants and other alternative or complementary medicines) should be subjected to more clinical research with patient observation and follow-up: firstly, this would help to select products of interest for further investigations in ethnopharmacology; secondly, it could translate into immediate recommendations for the population using the assessed local treatments. Contrary to a commonly held myth, clinical studies can be conducted at relatively low cost, if one works with local/regional research institutes and with doctoral students, focusing on meaningful clinical measures rather than sophisticated laboratory analyses. This paper describes special designs of clinical studies, appropriate for traditional medicines and tested in the field, including: the retrospective treatment – outcome population survey, the prognosis – outcome method (with modern physicians observing progress of patients treated by a traditional healer), the dose – escalating prospective study (detecting a dose–response phenomenon in humans). It is suggested that this approach offers the best cost-effective course of action for obtaining maximal benefits from traditional medicines, especially those used for treating endemic diseases.
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Objective To further characterize the acetylcholinesterase inhibitors (AChE-Is) pattern of Ptycho... more Objective To further characterize the acetylcholinesterase inhibitors (AChE-Is) pattern of Ptychopetalum olacoides ethanol extract (POEE) on the cytosolic globular monomer (G1) and membrane bound globular tetramer (G4) AChE isoforms in brain areas relevant for cognition. Methods The G1 and G4 AChE isoforms were prepared according to the reported methods and the determination of AChE activity used was adapted from colorimetric method. Results POEE mostly inhibited G1 in hippocampus (75%), and G4 in frontal cortex (58%) and striatum (75%) (P < 0.05). Kinetic analysis indicated that POEE-induced AChE inhibition in hippocampus was of a competitive nature for G1 but uncompetitive for G4. Conclusion Considering the high density of cholinergic projection to the cortex and striatum, and the usefulness of conserving cytosolic acetylcholine to replenish synaptic vesicles in a highly active cognition site such as hippocampus, we argue that this could be a desirable profile for a clinically relevant AChE-I.
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Alzheimer's disease (AD) is expected to affect more than 22 million people worldwide by 2025, cau... more Alzheimer's disease (AD) is expected to affect more than 22 million people worldwide by 2025, causing devastating suffering and enormous costs to families and society. AD is a multifactorial disease, with a complex pathological mosaic. In rodents, AD-like dementia can be induced by cerebral microinjection of A peptide, leading to amyloid deposits, amnesia and various features of neurodegeneration. Marapuama (Ptychopetalum olacoides) is regarded as a " brain tonic " in the Amazon region and shows a nootropic profile in rodents. Aim of the study: Because a specific extract (POEE) of Marapuama was shown to possess promnesic and anti-amnesic properties, the aim of this study was to verify if POEE is also effective against A 1–42-induced cognitive deficit in mice. Additionally, A deposits (Congo red), GFAP immunoreactivity (immunohisto-chemistry), and neurodegenerative changes in the hippocampal pyramidal layer (Nissl) were examined as measures of A 1–42-induced neurodegeneration. Materials and methods: CF1 mice were subjected to the experimental Alzheimer model with the A 1–42 i.c.v. administration. The effects of POEE 800 mg/kg were evaluated over 14 consecutive days of treatment. Results: The data show that 14 days of oral treatment with POEE (800 mg/kg) was effective in preventing A-induced cognitive impairment, without altering the levels of BDNF and with parallel reductions in A deposits and astrogliosis. CA1 hippocampus loss induced by A 1–42 was also diminished in POEE-treated mice. Conclusion: This study offers evidence of functional and neuroprotective effects of two weeks treatment with a Ptychopetalum olacoides extract against A peptide-induced neurotoxicity in mice. Given the multifactorial nature of neurodegeneration, the considerable potential for an AChE inhibitor displaying associated neuroprotective properties such as here reported warrants further clinic evaluation.
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Papers by Elaine Elisabetsky