Biomedical subjects

E Elisabetsky

Publications and source records attributed to E Elisabetsky.

At least 19 recordsLinked to original sources

PubMed2006

Nature-inspired indolyl-2-azabicyclo[2.2.2]oct-7-ene derivatives as promising agents for the attenuation of withdrawal symptoms: synthesis of 20-desethyl-20-hydroxymethyl-11-demethoxyibogaine.

Microwave assisted Diels-Alder cycloaddition of 5-Br-N-benzylpyridinone (2) with methyl acrylate is described to gain an easy access to 7-bromo-2-benzyl-3-oxo-2-aza-5 or 6-carbomethoxy bicyclo[2.2.2]oct-7-enes (3)-(6). The preparation of the ibogaine analogue 20-desethyl-(20-endo)-hydroxymethyl-11-demethoxyibogaine (17) is described by stereoselective hydrogenation of the C(7)-C(8) double bond. Biological evaluation showed an interesting in vitro binding profile toward dopamine transporter, serotonin transporter and opioid receptor systems accompanied by an antiwithdrawal effect in mice for hydroxymethyl 7-indolyl-2-aza-bicyclo[2.2.2]oct-2-ene (14). The simplification of the ibogaine structure appears as a promising approach toward the design of compounds that could reduce the withdrawal symptoms.

Animals↗

PubMed2006

The alkaloid alstonine: a review of its pharmacological properties.

Indole compounds, related to the metabolism of tryptophan, constitute an extensive family, and are found in bacteria, plants and animals. Indolic compounds possess significant and complex physiological roles, and especially indole alkaloids have historically constituted a class of major importance in the development of new plant derived drugs. The indole alkaloid alstonine has been identified as the major component of a plant-based remedy, used in Nigeria to treat mental illnesses by traditional psychiatrists. Although it is certainly difficult to compare the very concept of mental disorders in different cultures, the traditional use of alstonine is remarkably compatible with its profile in experimental animals. Even though alstonine in mice models shows a psychopharmacological profile closer to the newer atypical antipsychotic agents, it also shows important differences and what seems to be an exclusive mechanism of action, not entirely clarified at this point. Considering the seemingly unique mode of action of alstonine and that its traditional use can be viewed as indicative of bioavailability and safety, this review focuses on the effects of alstonine in the central nervous system, particularly on its unique profile as an antipsychotic agent. We suggest that a thorough understanding of traditional medical concepts of health and disease in general and traditional medical practices in particular, can lead to true innovation in paradigms of drug action and development. Overall, the study of this unique indole alkaloid may be considered as another example of the richness of medicinal plants and traditional medical systems in the discovery of new prototypic drugs.

Journal Article↗

PubMed2004

Ethnopharmacological studies of antimicrobial remedies in the south of Brazil.

This study reports the antimicrobial evaluation of the species most commonly used in Rio Grande do Sul (RS), the southernmost state of Brazil, for treating conditions likely to be associated with microorganisms. A four-stage process of documentation and evaluation was conducted: (a). review of RS ethnobotanical studies; (b). analysis of traditional uses; (c). literature survey on phytochemical and pharmacological data; (d). microbiological screening of selected plants. From the 149 species initially identified, 49 were cited as being used for microbial associated conditions in at least two other regions in RS, and 18 were further selected for screening. The crude methanol extract of these 18 plants were evaluated against seven microorganisms using the diffusion agar test. Extracts from Chaptalia nutans, Cordia monosperma, Echinodorus grandiflorus, Eugenia uniflora, Leonurus sibiricus, Luehea divaricata, Malva sylvestris, Ocotea odorifera, Parapiptadenia rigida, Pluchea sagittalis, Psidium cattleyanum and Senna neglecta were active against at least one microorganism. Although preliminary, these results are useful for rationalizing the use of medicinal plants in established systems of traditional medicine in primary health care.

Anti-Infective Agents↗

PubMed2004

Anxiolytic properties of the antipsychotic alkaloid alstonine.

Anxiolytic properties may be a crucial feature of newer antipsychotics associated with the improvement of negative symptoms in schizophrenic patients. The indole alkaloid alstonine acts as an atypical antipsychotic in behavioral models, but differs in its dopamine and serotonin binding profile. The purpose of this study was to verify if alstonine possesses anxiolytic properties in mice. The hole-board and light/dark models were used; moreover, the participation of D(1), 5-HT(2), NMDA and gamma-aminobutyric acid (GABA) receptors was likewise investigated. Alstonine clearly behaves as anxiolytic in both hole-board and light/dark situations. Pretreatment with the 5-HT(2A/2C) serotonin receptor antagonist ritanserin reverted the effects of alstonine in both the hole-board and light/dark models, suggesting the involvement of these receptors in the alstonine mechanism of action. The involvement of glutamate NMDA receptors should also be considered, given that alstonine partially reversed the increase in locomotion induced by MK-801 in the hole board, as well as MK-801-induced hyperlocomotion in motor activity apparatus.

Alkaloids↗

PubMed2002

Anxiogenic properties of Ptychopetalum olacoides Benth. (Marapuama).

Alcohol infusions of roots of Ptychopetalum olacoides Benth. (PO), known as Marapuama or Muirapuama, are used in the Brazilian Amazon as a 'nerve tonic'. Over the years PO has been found increasingly in phytoformulations and regarded as a stimulant, claimed to enhance physical and mental performances. This study determined that a P. olacoides ethanol extract (30, 100 and 300 mg/kg) decreased exploratory behaviour in the hole-board test, without interfering with locomotion or motor coordination (rota-rod test). The data are comparable to that obtained with pentylenetetrazol (40 mg/kg), suggesting an anxiogenic effect of P. olacoides.

Animals↗

PubMed2002

Synthesis and antinociceptive activity of chimonanthines and pyrrolidinoindoline-type alkaloids.

Hodgkinsine, a trimeric pyrrolidinoindoline type alkaloid, present as a major constituent of Psychotria spp. (Rubiaceae), has shown to produce dose-dependent, naloxone reversible, analgesic effect in thermal models of nociception and in the capsaicin-induced pain. SAR studies have been initiated by synthesizing the three diastereomeric dimers (chimonanthines) (11-13) which were evaluated in vitro and in vivo along with the synthetic intermediates. Strong binding affinities for mu opioid receptors were found for (-)- and (+)-chimonanthine monourethanes (9 and 10), whereas (-)-, (+)- and (meso)-chimonanthine (11-13) and hodgkinsine displayed low affinity. In vivo data have shown that only (+)-chimonanthine (12) and calycosidine resemble the analgesic profile found for hodgkinsine.

Alkaloids↗

PubMed2001

Ibogaine alters synaptosomal and glial glutamate release and uptake.

Ibogaine has aroused expectations as a potentially innovative medication for drug addiction. It has been proposed that antagonism of the NMDA receptor by ibogaine may be one of the mechanisms underlying its antiaddictive properties; glutamate has also been implicated in ibogaine-induced neurotoxicity. We here report the effects of ibogaine on [3H]glutamate release and uptake in cortical and cerebellar synaptosomes, as well as in cortical astrocyte cultures, from mice and rats. Ibogaine (2-1000 microM) had no effects on glutamate uptake or release by rat synaptosomes. However, ibogaine (500-1000 microM) significantly inhibited the glutamate uptake and stimulated the release of glutamate by cortical (but not cerebellar) synaptosomes of mice. In addition, ibogaine (1000 microM) nearly abolished glutamate uptake by cortical astrocyte cultures from rats and mice. The data provide direct evidence of glutamate involvement in ibogaine-induced neurotoxicity.

Animals↗

PubMed2001

Effects of linalool on [(3)H]MK801 and [(3)H] muscimol binding in mouse cortical membranes.

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 intraperitoneal 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 linalool 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.

Acyclic Monoterpenes↗

PubMed2001

Effects of linalool on glutamate release and uptake in mouse cortical synaptosomes.

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 [3H]glutamate and [3H]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 [3H]glutamate release (basal and potassium-stimulated) and [3H]glutamate uptake in mice cortical synaptosomes. Linalool significantly reduced potassium-stimulated glutamate release as well as glutamate uptake, not interfering with basal glutamate release. The data indicates that linalool may interfere with several relevant elements of the glutamatergic transmission, including detriment of the K+-stimulated glutamate release.

Acyclic Monoterpenes↗

PubMed2001

Involvement of NMDA receptors in the analgesic properties of psychotridine.

We have previously reported that the alkaloid extract of Psychotria colorata (Willd. ex R. & S.) Muell. Arg., had marked dose-dependent, opioid-like activity. Phytochemical analyses of P. colorata flowers and leaves identified several pyrrolidinoindoline alkaloids, including psychotridine. To further investigate the activity and mechanism of action of Psychotria alkaloids, we studied the effects of psychotridine on thermal and chemical models of analgesia. In the tail-flick model, psychotridine presents a dose-dependent analgesic effect; the effect is not reversed by prior treatment with naloxone. Psychotridine dose-dependently decreased capsaicin-induced pain. Performance in the rotarod test showed that psychotridine does not induce motor deficits at doses effective in analgesia models. Psychotridine inhibited [3H]MK-801 (dizocilpine) binding to cortex membranes in a dose-dependent manner. Binding is completely abolished at 300 nM. The data rule out opioid activity, and the inhibition of capsaicin-induced pain and of radioligand binding strongly suggest the participation of NMDA receptors in psychotridine-induced analgesia.

Alkaloids↗

PubMed2001

Interference of propylene glycol with the hole-board test.

Experimental drugs and/or plant extracts are often dissolved in solvents, including propylene glycol. Nevertheless, there is evidence for psychoactive properties of this alcohol. In this study we found that in the hole-board test 10% propylene glycol did not modify the head-dipping behavior. However, 30% propylene glycol induced an increase in the number of head-dips (46.92 +/- 2.37 compared to 33.83 +/- 4.39, P<0.05, ANOVA/Student-Newman-Keuls), an effect comparable to that obtained with 0.5 mg/kg diazepam (from 33.83 +/- 4.39 to 54 +/- 3.8, P<0.01, ANOVA/Student-Newman-Keuls). These results demonstrate that 30% propylene glycol has significant anxiolytic effects in this model and therefore cannot be used as an innocuous solvent.

Animals↗

PubMed2000

Antiepileptogenic properties of phenobarbital: behavior and neurochemical analysis.

Chronic in vivo models of epilepsy provide a suitable strategy for quantifying epileptogenesis, as well as investigating neurochemical changes associated with neuronal plasticity that leads to seizuring conditions. The aim of this paper was to investigate antiepileptogenic properties of phenobarbital, focusing on the neurochemical changes associated with repeated seizures induced by low convulsive dose of pentylenetetrazol (PTZ) (60 mg/kg, sc) in mice. Phenobarbital (10 and 30 mg/kg, ip) significantly diminished the severity of seizures induced by PTZ. Repeated PTZ administration was associated with an increase in [3H]glutamate binding (B(max) 196.6+/-10.2 pmol/mgxcontrol B(max) 137.7+/-17.0 pmol/mg). Regarding NMDA receptors, repeated PTZ administration was likewise associated with an increase in [3H]MK-801 binding (0.55+/-0.02 pmol/mgxcontrol 0.32+/-0.01 pmol/mg). In addition, phenobarbital (10 mg/kg) prevented the increase in [3H]glutamate binding (B(max) 133.7+/-11.4 pmol/mg), as well as in [3H]MK-801 binding (phenobarbital 10 and 30 mg/kg, 0.33+/-0.01 and 0.34+/-0.01 pmol/mg, respectively). This study reveals an interesting capability of phenobarbital in interfering with the establishment of both the behavioral expression and associated neurochemical changes induced by the repeated administration of low convulsive dose of PTZ, which may be important in the context of preventing epileptogenesis.

Animals↗

PubMed2000

Long-lasting ibogaine protection against NMDA-induced convulsions in mice.

Ibogaine, a putative antiaddictive drug, is remarkable in its apparent ability to downgrade withdrawal symptoms and drug craving for extended periods of time after a single dose. Ibogaine acts as a non-competitive NMDA receptor antagonist, while NMDA has been implicated in long lasting changes in neuronal function and in the physiological basis of drug addiction. The purpose of this study was to verify if persistent changes in NMDA receptors could be shown in vivo and in vitro after a single administration of ibogaine. The time course of ibogaine effects were examined on NMDA-induced seizures and [3H] MK-801 binding to cortical membranes in mice 30 min, 24, 48, and 72 h post treatment. Ibogaine (80 mg/kg, ip) was effective in inhibiting convulsions induced by NMDA at 24 and 72 hours post administration. Likewise, [3H] MK-801 binding was significantly decreased at 24 and 72 h post ibogaine. No significant differences from controls were found at 30 min or 48 h post ibogaine. This long lasting and complex pattern of modulation of NMDA receptors prompted by a single dose of ibogaine may be associated to its antiaddictive properties.

Animals↗

PubMed2000

Antinociceptive profile of hodgkinsine.

To further understand the mechanism of analgesic activity and structural requirements of pyrrolidinoindoline alkaloids identified in Psychotria colorata, we here report the analgesic activity of the trimer hodgkinsine on thermal and chemical models of analgesia. Results show that hodgkinsine produces a dose-dependent naloxone reversible analgesic effect in thermal models of nociception, suggesting that activation of opioid receptors participates in hodgkinsine's mode of action. Hodgkinsine shows a potent dose-dependent analgesic activity against capsaicin-induced pain, indicating the participation of NMDA receptors in hodgkinsine-induced analgesia. Such a dual mechanism of action may be of interest for developing innovative analgesics.

Analgesics, Non-Narcotic↗

PubMed1999

Anticonvulsant properties of linalool in glutamate-related seizure models.

In order to investigate the pharmacodynamic basis of the previously-established anticonvulsant properties of linalool, we examined the effects of this compound on behavioral and neurochemical aspects of glutamate expression in experimental seizure models. Specifically, linalool effects were investigated to determine its inhibition of (i) L-[3H]glutamate binding at CNS (central nervous system membranes), (ii) N-methyl-D-aspartate (NMDA)-induced convulsions, (iii) quinolinic acid (QUIN)-induced convulsions, and the behavioral and neurochemical correlates of PTZ-kindling. The data indicate that linalool modulates glutamate activation expression in vitro (competitive antagonism of L-[3H]glutamate binding) and in vivo (delayed NMDA convulsions and blockage of QUIN convulsions). Linalool partially inhibited and significantly delayed the behavioral expression of PTZ-kindling, but did not modify the PTZ-kindling-induced increase in L-[3H]glutamate binding.

Acyclic Monoterpenes↗

PubMed1999

Antipsychotic profile of alstonine: ethnopharmacology of a traditional Nigerian botanical remedy.

Although recently developed drugs have brought significant improvement, the treatment of psychotic disorders still presents serious drawbacks. Since inherent complexity and lack of satisfactory understanding of the underlying pathophysiology impose limits for rational drug design, resourceful approaches in the search for antipsychotics are pertinent. This paper reports pharmacological properties of alstonine, a heteroyohimbine type alkaloid, which exhibited an antipsychotic-like profile, inhibiting amphetamine-induced lethality, apomorphine-induced stereotypy and potentiating barbiturate-induced sleeping time. Atypical features of alstonine were the prevention of haloperidol-induced catalepsy and lack of direct interaction with D1, D2 and 5-HT2A receptors, classically linked to antipsychotic mechanism of action.

Animals↗

PubMed1998

Pyrrolidinoindoline Alkaloids from Psychotria colorata1

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).

Journal Article↗

PubMed1998

Antipsychotic-like profile of alstonine.

Although recently developed drugs have brought significant improvement, the treatment of psychotic disorders still presents serious drawbacks. Because inherent complexity and lack of satisfactory understanding of the underlying pathophysiology impose limits for rational drug design, resourceful approaches in the search for antipsychotics are pertinent. This article reports pharmacological properties of alstonine, a heteroyohimbine-type alkaloid, which exhibited an antipsychotic-like profile, inhibiting amphetamine-induced lethality, apomorphine-induced stereotypy, and potentiating barbiturate-induced sleeping time. Atypical features of alstonine were the prevention of haloperidol-induced catalepsy and lack of direct interaction with D1, D2 and 5-HT2A receptors, classically linked to antipsychotic mechanism of action.

Amphetamine↗