Sedative effects of essential oils obtained from Baccharis uncinella.

CONTEXT: Essential oils (EOs) have been reported to possess pharmacological properties, of which those related to the central nervous system have been especially attributed to mono- and sesquiterpenes. Baccharis uncinella DC. (Asteraceae) is used by the Laklaño Indians (Santa Catarina, Brazil) for sedative purposes. Interestingly, the species does not seem to be used medicinally elsewhere in Brazil. OBJECTIVE: This study was designed to compare the composition and sedative properties of B. uncinella EOs obtained closer (BU-SC) and farther (BU-PR) to the Laklaño Indian Reserve. MATERIALS AND METHODS: BU-SC and BU-PR obtained by hydrodistillation were analyzed by CG-MS. Mice treated with BU-SC and BU-PR (50 and 100 mg/kg) were evaluated regarding pentobarbital-induced sleeping time, body temperature, and locomotion. RESULTS: BU-SC presents a higher monoterpene/sesquitherpene ratio (0.31); α-pinene (6.42%), limonene (7.21%), caryophyllene (26.13%), spathulenol (13.39%) and caryophyllene oxide (13.26%) were identified as major components. BU-PR presents a low monoterpene/sesquitepene ratio (0.004); spathulenol (32.93%), caryophyllene oxide (27.78%), viridiflorol (5.29%) and α-cadinol (2.42%) were identified as the main components. Both samples significantly (p < 0.05, ANOVA) decreased locomotion and body temperature, as well as increased sleeping time. The hypnotic activity was sensitive to the differences in monoterpene composition. CONCLUSIONS: In comparison with a sample collected in Paraná State, B. uncinella EO collected closer to the Laklaño Indians possess a composition that better justifies the claimed sedative properties. The study confirms the value of traditional information to guide bioactivity assessment in medicinal plants, and gives notice to the ecological factors that can interfere with the conclusions of such assessments.

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.

Ethnopharmacology in the Brazilian Amazon.

The potential pharmaceutical wealth of the Brazilian Amazon has attracted international attention from the general and scientific community. The role that ethnopharmacology can have in the discovery and development of new drugs from a region hosting such enormous cultural and biological diversity is discussed. A review is given of ethnopharmacological and ethnobotanical studies that have been conducted in the Brazilian Amazon over the past twenty years.

Beta-endorphin causes retrograde amnesia and is released from the rat brain by various forms of training and stimulation.

The endogenous opiate peptide, beta-endorphin (0.4, 1.0, 2.0, and 10.0 microgram/kg) was injected IP into rats immediately after training in a shuttle avoidance task, and its effect on memory retention was evaluated in test sessions carried out 24 h later. The drug was found to cause retrograde amnesia, the ED50 being 1.0 microgram/kg. Beta-endorphin immunoreactivity was measured in the hypothalamus and rest of the brain of rats submitted to training, or test sessions of shuttle avoidance learning, pseudoconditioning in the shuttle-box, tones alone, or foot-shocks alone. After training in any of the four paradigms, there was a marked (46-60%) depletion of beta-endorphin immunoreactivity in the rest of the brain. No changes were detected in the hypothalamus or after test sessions. The loss of beta-endorphin immunoreactivity may be attributed to release of this substance caused by the stimuli used for training. From the present findings, as well as previous observations on the memory-facilitating influence of the opiate receptor antagonist, naloxone, it is concluded that there is a physiological amnesic mechanism mediated by beta-endorphin (and perhaps other opoid peptides as well), which is triggered by the non-associative factors present in the various forms of learning.

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.

The role of opioid peptides in memory and learning.

Evidence is discussed which points to the existence of a physiologic amnesic mechanism mediated by beta-endorphin and perhaps by other opioid peptides as well. This mechanism is triggered by various forms of training and by either painful or painless stimulation. It may operate through the inhibition of central dopaminergic and beta-adrenergic systems that modulate the memory consolidation process. This amnesic mechanism in unrelated to the regulation of pain perception, and operates at opioid peptide levels several orders of magnitude below those that are needed to cause analgesia or other effects. In addition, shuttle avoidance and habituation learning seem to be dependent on a state induced by the release of beta-endorphin. It is possible that this may be related to the amnesic properties of this substance. Therefore, it appears that the endogenous opioid peptides may exert their primary function in the modulation of memory processes.

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).

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.

Effect of various forms of training and stimulation on the incorporation of 32P into the nuclear phosphoproteins of the rat brain.

Incorporation of 32P into acid-extractable nuclear proteins was measured in the hippocampus, caudate nucleus, rest of the brain, and liver of rats submitted to various different behavioral treatments in a shuttle-box. After 5 min of classical conditioning, of avoidance without CS-US pairing, and of avoidance with CS-US pairing (standard shuttle avoidance), there was an increased 32P uptake by acid-extractable nuclear proteins in the hippocampus and caudate nucleus. The effect disappeared between 5 and 25 min of training. After 25 min of buzzers alone, or of footshocks alone, a similar 32P uptake change was noted in the same brain structure, which raises doubts as to the specificity of the phenomenon in terms of learning mechanisms.

Effect of brain serotonin level on induced hippocampal paroxysmal activity in rats.

Experiments were performed to study the involvement of brain 5-HT in an experimental model of epilepsy induced by repeated electrical stimulation of the dorsal hippocampus of rats. The experiments included: (1) systemic injections of 5-hydroxytryptophan (5-HTP) and p-chlorophenylalanine (pCPA) and (2) electrolytic lesions of the midbrain raphe nuclei. The pCPA group showed a significant increase while animals which received systemic injections of 5-HTP showed a great reduction in the electrographic seizure activity. Although several reports have shown that midbrain raphe lesions do not modify the epileptic susceptibility, we observed a clear enhancement in the epileptiform activity in lesioned animals. The results presented here support the view that serotonergic systems may exert a tonic inhibitory effect on hippocampal epileptic activity.

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.

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.

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.

Sociopolitical, economical and ethical issues in medicinal plant research.

Medicinal plant research may be pursued with several goals: the understanding of a native medical system, the elucidation of the rational basis for the medicinal use of a certain plant species, the development of low cost phytotherapeutics, the discovery of prototypic drugs, and so on. More often than not, the research project starts with the collection of indigenous medical knowledge in various parts of the world and generates a dissertation, a scientific paper or a drug. Usually, indigenous knowledge was crucial to the development of such products; nevertheless, indigenous groups tend not to benefit from the achievements of research. Ethnopharmacology involves a series of sociopolitical, economic and ethical dilemmas, at various levels. Most research projects involve more than one country (e.g., field work in a remote part of an underdeveloped country). Frequently host country scientists, visiting scientists, and informants disagree about these dilemmas. As a result, such research efforts are perceived as scientific imperialism; scientists are accused of stealing plant materials and appropriating traditional plant knowledge for financial profit and/or professional advancement. Many governments, as well as indigenous societies are increasingly reluctant to permit such research. Increasingly, funding for field work utilizing indigenous informants is coming from industry. Historically neither native populations nor host countries have shared to a significant extent the financial benefits from any drug that reaches the market. Unless these issues are amply discussed and fairy resolved, medicinal plant research runs the risk of serving ethically questionable purposes.

The status of ethnopharmacology in Brazil.

Brazil is a country of interest to ethnopharmacology because of its great wealth of cultural and biological diversity. This paper describes relevant research activities in the areas of botany, chemistry, basic and clinical pharmacology, and discusses the key factors that shaped ethnopharmacology development in the country. Specific attention is given to analyzing ongoing attempts to include medicinal plant based formulations in the official health care system.

Use of contraceptive and related plants by the Kayapo Indians (Brazil).

Interest in plant sources of prototypic contraceptive compounds is evidenced by numerous investigations and research projects. We suggest that the success rates of programs devised to evaluate pharmacological effects of traditionally employed contraceptives would be increased if native concepts of conception/contraception were taken into account. If ethnomedical and ethnopharmacological data are not carefully analysed, selection of plants to be evaluated will include those with little cross-cultural application. Kayapo concepts of menstruation, fertility, and contraception are presented, uses of related plants in culturally different groups are also analysed in order to indicate promising fertility-regulating plants used by the Kayapo.

Medicinal plant genetic resources and international cooperation: the Brazilian perspective.

Brazil is a gene rich country, host to 24% of known primate species, between 10 and 15 million species of insects, and 22% of the world's higher plant species. The debate over how and by whom these resources should be protected has intensified over the last few years due to a growing awareness of the links between sustainable utilization of natural resources, conservation of biodiversity, and economic development. Within this context the pharmaceutical exploitation of natural products for drug development has a prominent place. For a significant portion of Brazilian society, fair cooperation is welcome and can facilitate drug discovery. Nevertheless, the complexity of the consequences of patenting and utilization of natural resources calls for a thorough cost/benefit analysis in order to promote policies that can ensure significant and long term benefits for the country.

Absence of alkaloids in Psychotria carthagenensis Jacq. (Rubiaceae).

Psychotria viridis and P. carthagenensis are often discussed in relation to the hallucinogenic beverage Ayahuasca, used for religious, medicinal and social purposes. The significance of including Psychotria species in this beverage has been understood on the basis of substantial amounts of tryptamine alkaloids detected on leaves of both P. viridis and P. carthagenensis. Nevertheless, there is a long lasting debate over the identification of which Psychotria species are actually traditionally employed. We here report that a P. carthagenensis leaf ethanol extract was found to be devoid of alkaloids. The extract significantly decreased mice body temperature (350 and 500 mg/kg). Toxicity assessment revealed that the extract induced sedation and slight ptoses (75% of animals treated with 1000 mg/kg). Lethality was not observed within 48 h. The data indicate that P. carthagenensis does have bioactive compound(s), possibly active at the central nervous system, but unlikely to be tryptamine alkaloids as in the case of P. viridis. Therefore, if P. carthagenensis is indeed used by ayahuasqueros, its chemical and pharmacological significance have yet to be elucidated.

Analgesic activity of Psychotria colorata (Willd. ex R. & S.) Muell. Arg. alkaloids.

An ethnopharmacological survey showed that home remedies prepared with flowers, fruits and roots of Psychotria colorata (Wild. ex R. & S.) Muell. Arg. (RUBIACEAE) are used by Amazonian caboclos as pain killers. These data led to the evaluation of analgesic activity of extracts of P. colorata, using the formalin, writhing and tail-flick methods. This paper reports the Naloxone reversible opioid-like analgesic activity of alkaloids present in leafs and flowers of P. colorata.

Anticonvulsant properties of gamma-decanolactone in mice.

Lactones have been proven to be bioactive. We have shown that compounds present in the essential oil from Aeollanthus suaveolens, used as an anticonvulsant in the Brazilian Amazon, has sedative properties. This paper reports on the evaluation of the systemic administration of gamma-decanolactone, structurally related to lactones present in the essential oil of A. suaveolens, on mice experimental models useful for detecting psychopharmacological activity. The results show that gamma-decanolactone has dose-dependent marked effects on the central nervous system, including hypnotic, anticonvulsant and hypothermic activity. The effects of gamma-decanolactone revealed by this evaluation point to the validity of exploring lactones as sources of new anticonvulsant agents.