Revisão de plantas Brasileiras com comprovado efeito hipoglicemiante no controle do diabetes mellitus

Plants have been used in the cure of diseases from the origins of the humanity. At present, in Brazil, the use is common because of the difficulty of access of part of the population to medical assistance. It is commonly believed that the medicinal plants of traditional use were already tested and ratified by the long-lasting use by the human species, being considered effective medicines, presenting no collateral effects, not needful, therefore, of evaluation. The miraculous self-medication with medicinal plants goes to the point of substituting therapies in serious diseases such as those of hypoglycemic or anti-diabetic effect. For the test of medicinal plants, it is necessary to consider the material quality to be tested, the plant component used, extraction method, dosage, and the experimental species used. Several plants have already had hypoglycemic effects proven experimentally. The objective of this paper was to accomplish a revision of Brazilian medicinal plants, used popularly, as hypoglycemics that had effects proven in animals and in humans.

Can a Strychnos species be used as antiulcer agent? Ulcer healing action from alkaloid fraction of Strychnos pseudoquina St. Hil. (Loganiaceae)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Structure determination of a tetrahydro-beta-carboline of arthropod origin: A novel alkaloid-toxin subclass from the web of spider Nephila clavipes

The orb-web spiders are polyphagous animals in which the web plays a very important role in the capture of preys; oily droplets usually cover the capture-web of the spider Nephila clavipes and seem to be of great importance for prey capture. The knowledge of the chemical composition of these droplets is necessary to understand the function of this adhesive material in web mechanics and prey capture. A novel subclass of spider toxins, tetrahydro-beta-carboline, was identified among the weaponry of compounds present inside of oily droplets. This type of alkaloid is not common among the natural compounds of spider toxins. Apparently, when the prey arthropods get caught by the spider web, their bodies are covered with many adhesive oily droplets, which disrupt delivering the tetrahydro-beta-carboline to the direct contact with the prey integument. Toxicity assays demonstrated a potent lethal effect of the alkaloid toxin to the spider preys; topical applications of the teirahydro-beta-carboline at first caused clear signs of neurotoxicity, followed by the death of preys. The structure of the major component, a tetrahydro-beta-carboline, among the alkaloid toxins was elucidated by means of UV spectrophotometry, ESI mass spectrometry, H-1-NMR spectroscopy, and high-resolution mass spectrometry. The structure of the natural toxin was determined as 1-(2-guanidinoethyl)-1,2,3,4-tetrahydro-6-hydroxymethyl)-beta-carboline; the investigation of the pharmacological properties and neurotoxic actions of this compound may be used in the future as reference for the development of new drugs to be applied at level of pest control in agriculture.

CNS-selective noncompetitive cholinesterase inhibitors derived from the natural piperidine alkaloid (-)-spectaline

LASSBio-767 [(-)-3-O-acetyl-spectaline] and LASSBio-822 [(-)-3-O-tert-Boc-spectaline] were recently described as cholinesterase inhibitors derived from the natural piperidine alkaloid (-)-spectaline, obtained from the flowers of Senna spectabilis (Fabaccae). We investigated their mechanism of inhibition of acetylcholinesterase and their efficacy in reversing scopolamine-induced amnesia. Competition assays with the substrate acetylthiocholine showed a concentration-dependent reduction in rat brain cholinesterase V-max without changes in apparent K-m. The kinetic data for LASSBio-767 and LASSBio-822 were best fit by a model of simple linear noncompetitive inhibition with K-i of 6.1 mu M and 7.5 mu M, respectively. A dilution assay showed a fast and complete reversal of inhibition, independent of incubation time. Simulated docking of the compounds into the catalytic gorge of Torpedo acetylcholinesterase showed interactions with the peripheral anionic site, but not with the catalytic triad. Anti-amnestic effects in mice were assessed in a step-down passive avoidance test and in the Morris water maze 30 min after injection of scopolamine (1 mg/kg i.p.). Saline, LASSBio-767, or LASSBio-822 was administered 15 min before scopolamine. Both compounds reversed the scopolamine-induced reduction in step-down latency at 0.1 mg/kg i.p. LASSBio-767 reversed scopolamine-induced changes in water maze escape latency at 1 mg/kg i.p. or p.o., while its cholinergic side effects were absent or mild up to 30 mg/kg i.p. (LD50 above 100 mg/kg i.p.). Thus, the (-)-spectaline derivatives are potent cholinergic agents in vivo, with a unique profile combining noncompetitive cholinesterase inhibition and CNS selectivity, with few peripheral side effects. (C) 2007 Elsevier B.V. All rights reserved.

Anti-angiogenic effects of pterogynidine alkaloid isolated from Alchornea glandulosa

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Isolation and chemical characterization of PwTx-II: A novel alkaloid toxin from the venom of the spider Parawixia bistriata (Araneidae, Araneae)

Brazil has many species of spiders belonging to Araneidae family however, very little is known about the composition, chemical structure and mechanisms of action of the main venom components of these spiders. The main objective of this work was to isolate and to perform the chemical characterization of a novel beta-carboline toxin from the venom of the spider Parawixia bistriata, a typical species of the Brazilian 'cerrado'. The toxin was purified by RP-HPLC and structurally elucidated by using a combination of different spectroscopic techniques (UV, ESI-MS/MS and H-1 NMR), which permitted the assignment of the molecular structure of a novel spider venom toxin, identified as 1-4-guanidinobutoxy-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline, and referred to here as PwTx-II. This compound is toxic to insects (LD50 = 12 +/- 3 eta g/mg honeybee), neurotoxic, convulsive and lethal to rats (LD50 = 9.75 mg/kg of male Wistar rat). (c) 2005 Elsevier Ltd. All rights reserved.

Antinociceptive profile of (-)-spectaline: A piperidine alkaloid from Cassia leptophylla

The antinociceptive activity of (-)-spectaline (1), a piperidine alkaloid isolated from Cassia leptophylla Vog. (Leguminosae), was investigated. We have also studied the acute oral toxicity of 1 in mice and it did not show any signals of toxicity in doses lower than 400 mumol/kg. The antinociceptive effect of 1 was evaluated on chemical (acetic acid, formalin and capsaicin) and thermal (hot plate and tail flick) pain models in mice, using classical standard drugs. Dipyrone ID50 = 14.68 mumol/kg (4.8 mg/kg), in-domethacin ID50 = 0.78 mumol/kg (0.28 mg/kg) and (-)-spectaline ID50 = 48.49 mumol/kg (15.75 mg/kg), all produced a significant inhibition of acetic acid-induced abdominal writhing in mice. (-)-Spectaline was inactive in the hyperalgesic model of formalin and did not show any central analgesic activity (hot plate and tail flick models). In the capsaicin-induced neurogenic pain model, (-)-spectaline presented an important inhibitory effect with an ID50 = 20.81 mug/paw and dipyrone ID50 = 19.89 mug/ paw. The ensemble of results permitted us to identify 1 as an antinociceptive compound. The mechanism underlying this antinociceptive effect of 1 remains unknown, but the results suggest that such an effect could be related to pathways associated to vanilloid receptor systems.

Plant derived alkaloid (-)-cassine induces anti-inflammatory and anti-hyperalgesics effects in both acute and chronic inflammatory and neuropathic pain models

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

A new imidazole alkaloid and other constituents from Pilocarpus grandiflorus and their antifungal activity

The stems of Pilocarpus grandiflorus have afforded the new imidazole alkaloid 4,6-dehydro-1,2,4,5-tetrahydro-2,5-dioxopilocarpine in addition to the 17 known compounds germanicol, β-amiryn, ocotillone, stigmast-4-en-3-one, 3β-hydroxy-stigmast-5-en-7-one, 6β-hydroxy-stigmast-4-en-3-one, β-sitosterol, scopoletin, 3-(1′,1′-dimethylallyl)-scopoletin, elisin, dictamine, 4-methoxy-2-quinolone, platydesmine, syringaresinol, syringaldehyde, syringic acid and vanillic acid. Their structures were elucidated on the basis of chemical and spectroscopic evidence. The phenolic compounds vanillic acid and syringaldehyde and the furoquinoline alkaloid platydesmine exhibited antifungal activity against Leucoagaricus gongylophorus, the symbiotic fungus of leaf-cutting ants (Atta sexdens rubropilosa). © 2005 Verlag der Zeitschrift für Naturforschung.

7-Hydroxycassine: A new 2,6-dialkylpiperidin-3-ol alkaloid and other constituents isolated from flowers and fruits of senna spectabilis (Fabaceae)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

A new tropane alkaloid and other constituents of Erythroxylum rimosum (Erythroxylaceae)

A new tropane alkaloid, named the 7β-acetoxy-3β,6β- dibenzoyloxytropane (1), was isolated from a methanol extract of Erythroxylum rimosum O.E. Schulz leaves. Other known compounds were detected, including quercetin, kaempferol-3-O-α-l-arabinofuranoside, (+)-catechin, epicatechin, quercetin-3-O-α-arabinofuranoside, quercetin-3-O-α- arabinopyranoside, quercetin-3-O-β-arabinopyranoside, quercetin-3-β- glucopyranoside, kaempferol, quercetin-3-O-β-galactopyranoside, β-sitosterol, α-amyrin, β-amyrin, and the ester derivatives of these two amyrins. Compound 1 exhibited weak inhibition of acetylcholinesterase. Structural identification was performed using IR, ESIHRMS and one- and two-dimensional NMR data analyses and confirmed by comparison with literature data. © 2013 Phytochemical Society of Europe.

Nitensidine A, a guanidine alkaloid from Pterogyne nitens, induces osteoclastic cell death

Nitensidine A is a guanidine alkaloid isolated from Pterogyne nitens, a common plant in South America. To gain insight into the biological activity of P. nitens-produced compounds, we examined herein their biological effects on osteoclasts, multinucleated giant cells that regulate bone metabolism by resorbing bone. Among four guanidine alkaloids (i.e., galegine, nitensidine A, pterogynidine, and pterogynine), nitensidine A and pterogynine exhibited anti-osteoclastic effects at 10 μM by reducing the number of osteoclasts on the culture plate whereas galegine and pterogynidine did not. The anti-osteoclastic activities of nitensidine A and pterogynine were exerted in a concentration-dependent manner, whereas nitensidine A exhibited an approximate threefold stronger effect than pterogynine (IC50 values: nitensidine A, 0.93 ± 0.024 μM; pterogynine, 2.7 ± 0.40 μM). In the present study, the anti-osteoclastic effects of two synthetic nitensidine A derivatives (nitensidine AT and AU) were also examined to gain insight into the structural features of nitensidine A that exert an anti-osteoclastic effect. The anti-osteoclastic effect of nitensidine A was greatly reduced by substituting the imino nitrogen atom in nitensidine A with sulfur or oxygen. According to the differences in chemical structures and anti-osteoclastic effects of the four guanidine alkaloids and the two synthetic nitensidine A derivatives, it is suggested that the number, binding site, and polymerization degree of isoprenyl moiety in the guanidine alkaloids and the imino nitrogen atom cooperatively contribute to their anti-osteoclastic effects. © 2013 Springer Science+Business Media Dordrecht.

Pulmonary and hepatic lesions caused by the dehydropyrrolizidine alkaloid-producing plants Crotalaria juncea and Crotalaria retusa in donkeys

The effects and susceptibility of donkeys to Crotalaria juncea and Crotalaria retusa poisoning were determined at high and low doses. Seeds of C. juncea containing 0.074% of dehydropyrrolizidine alkaloids (DHPAs) (isohemijunceines 0.05%, trichodesmine 0.016%, and junceine 0.008%) were administered to three donkeys at 0.3, 0.6 and 1g/kg body weight (g/kg) daily for 365 days. No clinical signs were observed and, on liver and lung biopsies, the only lesion was a mild liver megalocytosis in the donkeys ingesting 0.6 and 1g/kg/day. Two other donkeys that received daily doses of 3 and 5g seed/kg showed initial respiratory signs 70 and 40 days after the start of the administration, respectively. The donkeys were euthanized following severe respiratory signs and the main lung lesions were proliferation of Clara cells and interstitial fibrosis. Three donkeys ingested seeds of C. retusa containing 5.99% of monocrotaline at daily doses of 0.025, 0.05 and 0.1g/kg for 365 days. No clinical signs were observed and, on liver and lung biopsies, the only lesion was moderate liver megalocytosis in each of the three donkeys. One donkey that received a single dose of 5g/kg of C. retusa seeds and another that received 1g/kg daily for 7 days both showed severe clinical signs and died with diffuse centrilobular liver necrosis. No lung lesions were observed. Another donkey that received a single dose of 2.5g/kg of C. retusa seeds showed no clinical signs. The hepatic and pneumotoxic effects observed are consistent with an etiology involving DHPAs. Furthermore, the occurrence of lung or liver lesions correlates with the type of DHPAs contained in the seeds. Similarly as has been reported for horses, the data herein suggest that in donkeys some DHPAs are metabolized in the liver causing liver disease, whereas others are metabolized in the lung by Clara cells causing lung disease. © 2013 Elsevier Ltd.

Nitensidine A, a guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1

The Pterogyne nitens (Fabaceae) tree, native to South America, has been found to produce guanidine alkaloids as well as bioactive flavonols such as kaempferol, quercetin, and rutin. In the present study, we examined the possibility of interaction between human ATP-binding cassette (ABC) transporter ABCB1 and four guanidine alkaloids isolated from P. nitens (i.e., galegine, nitensidine A, pterogynidine, and pterogynine) using human T cell lymphoblast-like leukemia cell line CCRF-CEM and its multi-drug resistant (MDR) counterpart CEM/ADR5000. In XTT assays, CEM/ADR5000 cells were resistant to the four guanidine alkaloids compared to CCRF-CEM cells, although the four guanidine alkaloids exhibited some level of cytotoxicity against both CCRF-CEM and CEM/ADR5000 cells. In ATPase assays, three of the four guanidine alkaloids were found to stimulate the ATPase activity of ABCB1. Notably, nitensidine A was clearly found to stimulate the ATPase activity of ABCB1 as strongly as the control drug, verapamil. Furthermore, the cytotoxic effect of nitensidine A on CEM/ADR5000 cells was synergistically enhanced by verapamil. Nitensidine A inhibited the extrusion of calcein by ABCB1. In the present study, the possibility of interaction between ABCB1 and two synthetic nitensidine A analogs (nitensidine AT and AU) were examined to gain insight into the mechanism by which nitensidine A stimulates the ATPase activity of ABCB1. The ABCB1-dependent ATPase activity stimulated by nitensidine A was greatly reduced by substituting sulfur (S) or oxygen (O) for the imino nitrogen atom (N) in nitensidine A. Molecular docking studies on human ABCB1 showed that, guanidine alkaloids from P. nitens dock to the same binding pocket as verapamil. Nitensidine A and its analogs exhibit similar binding energies to verapamil. Taken together, this research clearly indicates that nitensidine A is a novel substrate for ABCB1. The present results also suggest that the number, binding site, and polymerization degree of the isoprenyl moiety in the guanidine alkaloids and the imino nitrogen atom cooperatively contribute to their stimulation of ABCB1's ATPase activity. © 2013 Elsevier GmbH. All rights reserved.