Profiling hydroxycinnamic acid glycosides, iridoid glycosides, and phenylethanoid glycosides in baobab fruit pulp (Adansonia digitata).

The baobab (Adansonia digitata L.) is a magnificent tree revered throughout Africa and is becoming recognized for its high nutritional and medicinal values. Despite numerous reports on the pharmacological potential, little is known about its chemical compositions. In this study, four hydroxycinnamic acid glycosides (1-4), six iridoid glycosides (5-10), and three phenylethanoid glycosides (11-13) were isolated from the dried baobab fruit pulp. Their structures were determined by means of spectroscopic analyses, including HRMS, 1H and 13C NMR and 2D experiments (COSY, HSQC, HMBC, and ROESY). All 13 compounds isolated were reported for the first time in the genus of Adansonia. An ultra high-performance liquid chromatography high-resolution accurate-mass mass spectrometry (UHPLC HRAM MS) method was used to conduct further investigation of the chemical compositions of the hydro-alcohol baobab fruit pulp extract. Hydroxycinnamic acid glycosides, iridoid glycosides and phenylethanoid glycosides were found to be the main components in baobab fruit pulp.

Original mechanisms of antipsychotic action by the indole alkaloid alstonine (Picralima nitida).

Alstonine is the major component of plant based remedies that traditional psychiatrists use in Nigeria. Alstonine 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 pharmacodynamics of antipsychotic medications, the evidence indicates that alstonine does not bind to D2 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.

Effects of the putative antipsychotic alstonine on glutamate uptake in acute hippocampal slices.

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 (10µM), clozapine (10 and 100µM) or alstonine (1-100µM), alone or in combination with apomorphine (100µM), and 5-HT(2) receptor antagonists (0.01µM altanserin and 0.1µM 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.

Alstonine as an antipsychotic: effects on brain amines and metabolic changes.

Managing schizophrenia has never been a trivial matter. Furthermore, while classical antipsychotics induce extrapyramidal side effects and hyperprolactinaemia, atypical antipsychotics lead to diabetes, hyperlipidaemia, and weight gain. Moreover, even with newer drugs, a sizable proportion of patients do not show significant improvement. Alstonine is an indole alkaloid identified as the major component of a plant-based remedy used in Nigeria to treat the mentally ill. Alstonine presents a clear antipsychotic profile in rodents, apparently with differential effects in distinct dopaminergic pathways. The aim of this study was to complement the antipsychotic profile of alstonine, verifying its effects on brain amines in mouse frontal cortex and striatum. Additionally, we examined if alstonine induces some hormonal and metabolic changes common to antipsychotics. HPLC data reveal that alstonine increases serotonergic transmission and increases intraneuronal dopamine catabolism. In relation to possible side effects, preliminary data suggest that alstonine does not affect prolactin levels, does not induce gains in body weight, but prevents the expected fasting-induced decrease in glucose levels. Overall, this study reinforces the proposal that alstonine is a potential innovative antipsychotic, and that a comprehensive understanding of its neurochemical basis may open new avenues to developing newer antipsychotic medications.

Stability of cough linctus (streptol) formulated from named medicinal plant extracts.

Extracts of named medicinal herbs (Garcinia kola, Zingiber oificinale, Aframonum melequeta and Ocimum viride) were formulated into an antitussive preparation to alleviate cough. Some physical properties of the cough syrup formulation evaluated were: specific gravity, pH, viscosity, content uniformity, and shelf life. The specific gravity and viscosity of the formulations were stable on storage, with glycerin-based formulations having higher values. The pH of the formulation varied from 4.2 to 5.3 and was also stable on storage. Glycerin-based formulations had lower pH values. The total flavonoids content of Streptol was calculated based on GB1 and found to be 46 mg. The estimated shelf life of the Streptol cough syrup was 4.5 years.

The putative antipsychotic alstonine reverses social interaction withdrawal in mice.

Negative symptoms of schizophrenia are particularly problematic due to their deleterious impact on a patient's social life. The indol alkaloid alstonine, the major component of traditional remedies used for treating mental illnesses in Nigeria, presents a clear antipsychotic-like profile in mice, as well as anxiolytic properties. Considering that social interaction is the core of negative symptoms, and that anxiolytic drugs can improve social interaction behavior, the aim of this study was to evaluate the effects of alstonine in the social interaction and MK801-induced social withdrawal models in mice. Sub-chronic (but not acute) treatment with alstonine 0.5 mg/kg (but not 1.0 mg/kg) significantly increased social interaction in mice. Moreover, MK801-induced social withdrawal was completely prevented by sulpiride (10 mg/kg) and alstonine 1.0 mg/kg, and partially prevented by alstonine 0.5 mg/kg. The study indicates that alstonine not only increases social interaction in normal mice, but also averts social deficits attributable to negative symptoms of schizophrenia. This study reinforces and complements the antipsychotic-like profile of alstonine, and emphasizes its potential as a drug useful for the management of negative symptoms in schizophrenia.

Preparative isolation and identification of tyrosinase inhibitors from the seeds of Garcinia kola by high-speed counter-current chromatography.

In continuation of our search for bioactive natural products that can be used for the treatment of dermatological disorders associated with melanin hyperpigmentation, 50 extracts/fractions from 21 families of medicinal plants from West and Central Africa were evaluated for inhibitory activity against tyrosinase (E:C:1.14.18.1), the rate-limiting enzyme in melanin synthesis. Four extracts including the methanol extract of Garcinia kola seeds at 100 microg/ml displayed >60% inhibition of tyrosinase activity. Preparative high-speed counter-current chromatography with solvent system composed of n-hexane-ethyl acetate-methanol-water (3:5:3:5) successfully separated the most active extract from G. kola seed. By stepwise increase of the flow-rate of the mobile phase, five major biflavanones including GB-I-glucoside (1) GB-1a (2), GB-1 (3), GB-2 (4), kolaflavonone (5) were successfully isolated in 6 h. Compound (4) was the most potent (IC(50) 582 microM) and compared favorably with a reference tyrosinase inhibitor (kojic acid, IC(50) 130 microM).

Antimicrobial principle from Aframomum longifolius.

Antimicrobial activity-directed fractionation of the seeds of Aframomum longifolius (Zingiberaceae) afforded two new labdane-type diterpenoids, 15-hydroxy-15-methoxylabda-8(17), 12( E)-dien-16-al (aframolin A) ( 1) and 8beta(17)-epoxy-15,15-dimethoxylabd-12( E)-en-16-al (aframolin B) ( 2), together with the known diterpenes labda-8(17),12( E)-diene-15,16-dial ( 3) and aframodial ( 4). Their structures were determined by spectroscopic methods. Compound 4 showed significant antimicrobial activity against Cryptococcus neoformans, Staphylococcus aureus and methicillin-resistant S. aureus (MRS) while 1, 2 and 3 were found to be inactive.

Tabouensinium chloride, a novel quaternary pyranoquinoline alkaloid from Araliopsis tabouensis.

A novel pyranoquinoline alkaloid 3,4-dihydro-3-hydroxy-5-methoxy-2,2,10-trimethylpyrano [2,3-b]quinoline named tabouensinium chloride (1), was isolated from the stem bark of Araliopsis tabouensis along with twelve known quinoline alkaloids. In addition, the known flindisol, lupeol and beta-sitosterol glucoside were also identified. Their structures were deduced from spectral data.

Antimalarial activities and therapeutic properties of febrifugine analogs.

Febrifugine is the active principal isolated 50 years ago from the Chinese herb chang shan (Dichroa febrifuga Lour), which has been used as an antimalarial in Chinese traditional medicine for more than 2,000 years. However, intensive study of the properties of febrifugine has been hindered for decades due to its side effects. We report new findings on the effects of febrifugine analogs compared with those of febrifugine extracted from the dry roots of D. febrifuga. The properties of the extracted febrifugine were comparable to those obtained from the standard febrifugine provided by our collaborators. A febrifugine structure-based computer search of the Walter Reed Chemical Information System identified 10 analogs that inhibited parasite growth in vitro, with 50% inhibitory concentrations ranging from 0.141 to 290 ng/ml. The host macrophages (J744 cells) were 50 to 100 times less sensitive to the febrifugine analogs than the parasites. Neuronal (NG108) cells were even more insensitive to these drugs (selectivity indices, >1,000), indicating that a feasible therapeutic index for humans could be established. The analogs, particularly halofuginone, notably reduced parasitemias to undetectable levels and displayed curative effects in Plasmodium berghei-infected mice. Recrudescence of the parasites after treatment with the febrifugine analogs was the key factor that caused the death of most of the mice in groups receiving an effective dose. Subcutaneous treatments with the analogs did not cause irritation of the gastrointestinal tract when the animals were treated with doses within the antimalarial dose range. In summary, these analogs appear to be promising lead antimalarial compounds that require intensive study for optimization for further down-selection and development.

Novel antimicrobial diterpenoids from Turraeanthus africanus.

The dichloromethane-methanol (1/1) extract of the stem bark of Turraeanthus africanus (Meliaceae) showed remarkable antimicrobial activity against Cryptococcus neoformans, Staphylococcus aureus and methicillin-resistant S. aureus. Phytochemical investigation of this extract afforded six new diterpenoid derivatives, (+)-16-acetoxy-12,15-epoxylabda-8(17),12,14-triene ( 3), [16( E),12 S,15 R]-16-acetoxy-12,15-epoxy-15-isopropoxy- ent-labda-8(17),13(16)-diene (turraeanin A, 4), [16( E),12 R,15 S]-16-acetoxy-12,15-epoxy-15-isopropoxy- ent-labda-8(17),13(16)-diene (turraeanin B, 5), [16( E),12 S,15 R]-16-acetoxy-12,15-epoxy-15-methoxy- ent-labda-8(17),13(16)-diene (turraeanin C, 6), [16( E),12 R,15 S]-16-acetoxy-12,15-epoxy-15-methoxy- ent-labda-8(17),13(16)-diene (turraeanin D, 7) and (12 S,13 S,15 R)-12,15-epoxy-15-methoxy- ent-labd-8(17)-en-16-al (turraeanin E, 9) together with the known compounds, 15,16-epoxy- ent-labda-8(17),13(16),14-triene ( 1), (+)-pumiloxide ( 2), ent-labda-8(17),12 ( E)-diene-15,16-dial ( 8) and 16-acetoxy-12( R),15-epoxy-15beta-hydroxylabda-8(17),13 (16)-diene ( 10). Compound 10 was obtained as its acetoxy derivative ( 10a) and compound 11 was the product of hydrolysis of 6. Antimicrobial activity of the isolates was assayed and compounds 8, 9, 10a and 11 exhibited significant activities.

Antiplasmodial agents from the leaves of Glossocalyx brevipes.

A phytochemical study of the methylene chloride/methanol (1/1) extract of the leaves of Glossocalyx brevipes Benth. (Monimiaceae) afforded three new derivatives of homogentisic acid, methyl 2-(1'beta-geranyl-5'beta-hydroxy-2'-oxocyclohex-3'-enyl)acetate (1), 2-(1'beta-geranyl-5'beta-hydroxy-2'-oxocyclohex-3'-enyl)acetic acid (2), methyl 2-(1'beta-geranyl-5'beta-hydroxy-4'beta-methoxy-2'-oxocyclohexyl)acetate (3), and two known alkaloids, aristololactam BII and liriodenine. Compounds 1 and 2 and liriodenine showed modest in vitro activity against Plasmodium falciparum.