Flavonoids as GABAA receptor ligands: the whole story?

Benzodiazepines are the most widely prescribed class of psychoactive drugs in current therapeutic use, despite the important unwanted side effects that they produce, such as sedation, myorelaxation, ataxia, amnesia, and ethanol and barbiturate potentiation and tolerance. They exert their therapeutic effects via binding to the benzodiazepine binding site of gamma-aminobutyric acid (GABA) type A receptors, and allosterically modulating the chloride flux through the ion channel complex. First isolated from plants used as tranquilizers in folkloric medicine, some natural flavonoids have been shown to possess selective affinity for the benzodiazepine binding site with a broad spectrum of central nervous system effects. Since the initial search for alternative benzodiazepine ligands amongst the flavonoids, a list of successful synthetic derivatives has been generated with enhanced activities. This review provides an update on research developments that have established the activity of natural and synthetic flavonoids on GABA type A receptors. Flavonoids are prominent drugs in the treatment of mental disorders, and can also be used as tools to study modulatory sites at GABA type A receptors and to develop GABA type A selective agents further.Fil: Wasowski, Cristina Lucia N.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Marder, Nora Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentin

Effect of 2’-nitroflavone on the expression of receptors associated with EGFR activity in breast cancer cells

Flavonoids were proposed as chemopreventive and chemotherapeutic agents per se or in combination with traditional antitumoral drugs. Epidermal growth factor receptor (EGFR) is associated with tumorigenesis of several tissues and it can be involved in the molecular mechanism of action of several flavonoids. With the aim of investigating if a combinatory therapy involving 2'-nitroflavone (2'NF), a synthetic flavonoid with antitumor properties, and EGFRinhibitors would be a possible effective treatment for breast cancer, we studied if this flavone modulates the expression of EGFR or other receptors that interact or modulate EGFR activity. MDA-MB-231 and MCF-7 breast cancer cells were treated with 2´NF at different concentrations for48 h. Afterwards, the protein content of EGFR, ErbB2, ER alpha, Met and IGF-IR were assessed by immunoblotting. Besides, PARP cleavage and phosphorylation of p38 were determined in the same experimental conditions. Results showed that 2´NF produced a reduction on the content ofErbB2 and IGF-IR in MDA-MB-231 cells, while in MCF-7 cells a decrease on the expression of EGFR, ErbB2 and ER alpha was observed. Both cell lines presented an increment in p38 phosphorylation and PARP cleavage upon 2'NF treatment. In conclusion, 2'NF demonstrated to have effects on the expression of receptors associated with EGFR activity which could justify a possible combinatorytherapy involving 2'NF and EGFR inhibitors.Fil: Cebrón, Julieta Rocío. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; ArgentinaFil: Bojorge, Mariana Andrea. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; ArgentinaFil: Marder, Nora Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; ArgentinaFil: Miquet, Johanna Gabriela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Gonzalez, Lorena. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaBuenos Aires Breast Cancer SymposiumArgentinaUniversidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y NeurocienciasInstituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina ExperimentalCentro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno"Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslaciona

Natural flavonoids inhibit the plasma membrane Ca 2+ -ATPase

Research on flavonoids from plant sources has recently sparked increasing interest because of their beneficial health properties. Different studies have shown that flavonoids change the intracellular Ca 2+ homeostasis linked to alterations in the function of mitochondria, Ca 2+ channels and Ca 2+ pumps. These findings hint at plasma membrane Ca 2+ -ATPase (PMCA) involvement, as it transports Ca 2+ actively to the extracellular medium coupled to ATP hydrolysis, thus maintaining ion cellular homeostasis. The present study aims to investigate the effect of several natural flavonoids on PMCA both in isolated protein systems and in living cells, and to establish the relationship between flavonoid structure and inhibitory activity on PMCA. Our results show that natural flavonoids inhibited purified and membranous PMCA with different effectiveness: quercetin and gossypin were the most potent and their inhibition mechanisms seem to be different, as quercetin does not prevent ATP binding whereas gossypin does. Moreover, PMCA activity was inhibited in human embryonic kidney cells which transiently overexpress PMCA, suggesting that the effects observed on isolated systems could occur in a complex structure like a living cell. In conclusion, this work reveals a novel molecular mechanism through which flavonoids inhibit PMCA, which leads to Ca 2+ homeostasis and signaling alterations in the cell.Fil: Ontiveros, Mallku Qhapaj. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Rinaldi, Debora Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Marder, Nora Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Espelt, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Mangialavori, Irene Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Vigil, Maximiliano Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Rossi, Juan Pablo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Ferreira Gomes, Mariela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentin

Tranquilizing medicinal plants: their CNS effects and active constituents - Our experience

Mental disorder is a psychological or behavioral pattern that occurs in an individual and is thought to cause distress or disability that is not expected as part of normal development or culture. Mental and neurological disorders are highly prevalent worldwide with 450 million people estimated to be suffering from them. They are responsible for about one per cent of deaths and they account for almost eleven per cent of disease burden the world over. Magnitude of neurological disorders is huge and they are priority health problems globally. The extension of life expectancy and the ageing of the general populations in both developed and developing countries are likely to increase the prevalence of many chronic and progressive physical and mental conditions including neurological disorders. The proportionate share of the total global burden of disease due to neuropsychiatric disorders is projected to rise to 14.7% by 2020 (World Health Organization, WHO). There are many different categories of mental disorders, and many different facets of human behavior and personality that can become disordered. Mental illnesses are classified according to the symptoms that a patient experiences, as well as the clinical features of the illness. Some of the major categories of mental illness include anxiety disorders, cognitive disorders, developmental disorders, dissociative disorders, mood disorders, personality disorders, schizophrenia and substance abuse disorders. Anxiety is defined as a subjective emotional state of uneasiness, not pleasant and even fearful. When the anxiety reaches pathological levels the subject experiments conductual changes, apprehension, motor troubles, sweating, hypertension, etc. The term sedation implies a general slowing down of cognitive functioning, whereas a hypnotic specifically means the induction of sleep itself. Tranquilization, on the other hand, signifies emotional calming, that may or may not lead to sleep, but does not induce the feeling of drowsiness. So calmness of mind may the better facilitate normal physiological sleep mechanisms to function; whilst stress of any kind will mediate against them. Traditional medicine has many cures for these ailments, most of them based on herbal preparations, but also modern medicinal chemistry has provided several drugs which are more or less effective, for the same purpose. The most spectacular success was achieved in 1957 with the synthesis of the benzodiazepines (Sternbach 1978), which still are, after 50 years of intense clinical research and use, the near-best medication to treat mental disorders. Benzodiazepines, however, also produce several side-effects like sedation, muscle relaxation, alcohol incompatibility, amnesia and addiction (Woods et al. 1992). These drawbacks have to be carefully considered in clinical therapeutical applications. Although benzodiazepines are laboratory products they were found also in nature and, appropriately, their first detection was in the mammalian brain (Sangameswaran et al. 1986). They were then identified in many other sources like foods; rumen, plasma and cow´s and human´s milk (Medina and Paladini 1993). When we attempted detection of benzodiazepines in several plants, including some used to prepare tranquilizing infusions, unexpectedly discovered that some flavonoids present in them, were ligands for the benzodiazepine binding site of the gamma amino butyric acid receptor type A (GABAA) (Medina et al. 1989 and the reviews: Medina et al., 1997 and 1998; Paladini et al., 1999; Marder and Paladini 2002). A search for novel pharmacotherapy from medicinal plants for psychiatric illnesses has progressed significantly in the last twenty years. This is reflected in the large number of herbal preparations for which psychotherapeutic potential has been evaluated in a variety of animal models. A considerable number of herbal constituents whose behavioral effects and pharmacological actions have been well characterized may be good candidates for further investigations that may ultimately result in clinical use. Herbal remedies that have demonstrable psychotherapeutic activities have provided a potential to psychiatric pharmaceuticals and deserve increased attention in future studies. This chapter deals with plants possessing central nervous system (CNS) effects. However, because of the huge amount of plants belonging to this category, we decided to select a few plants and to focus our attention on them, mostly concerning the constituents that have significant therapeutic effects in animal models of CNS disorders.Fil: Marder, Nora Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Wasowski, Cristina Lucia N.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentin

Central nervous system activities of two diterpenes isolated from Aloysia virgata

Using the guide of a competitive assay for the benzodiazepine binding site in the γ-aminobutyric acid type A receptor (GABAA), two active diterpenes were isolated from the aerial parts of Aloysia virgata (Ruíz & Pavón) A.L. Jussieu var. platyphylla (Briquet) Moldenke. These compounds, identified as (16R)-16,17,18-trihydroxyphyllocladan-3-one (1) and (16R)-16,17-dihydroxyphyllocladan-3-one (2) on the basis of spectral data, competitively inhibited the binding of [3H]-FNZ to the benzodiazepine binding site with Ki ± S.E.M. values of 56 ± 19 μM and 111 ± 13 μM, respectively. The behavioral actions of these diterpenes, intraperitoneally (i.p.) administered in mice, were examined in the plus-maze, holeboard, locomotor activity and light/dark tests. Compound 1 exhibited anxiolytic-like effects in mice evidenced by a significant increase of the parameters measured in the holeboard test (the number of head dips at 0.3 mg/kg and 3 mg/kg, the rears at 1 mg/kg and the time spent head-dipping at 3 mg/kg), in the plus-maze assay (the percentage of open arm entries at 1 mg/kg) and in the light/dark test (the time in light and the number of transitions at 1 mg/kg). Compound 2 augmented the number of rearings in the holeboard apparatus (at 0.3 mg/kg and 1 mg/kg) and the locomotor activity (at 1 mg/kg). These results reveal the presence of neuroactive compounds in Aloysia virgata.Fil: Wasowski, Cristina Lucia N.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marder, Nora Mariel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Anxiolytic-like effects of <i>Tilia petiolaris</i> DC : Inflorescences Infusion

Infusions of the inflorescences of Tilia are widely used for their tranquilizing properties around the world and have been regarded as non-toxic. Despite the widespread use of the tea of silver Linden in folk medicine, the number of scientific studies for the evaluation of its therapeutic utilization is limited. In an attempt to add experimental confirmation to its popular medicinal use, the central nervous system related effects of the chronic ingestion of the infusion of Tilia petiolaris DC. inflorescences were evaluated in the holeboard, locomotor activity and light-dark tests in mice. The infusion induced significant increases in the exploration of holes and in the time spent head-dipping in the holeboard assay. Moreover, it significantly increased the time spent in the light area in the light-dark test. These results suggest that the infusion of Tilia petiolaris DC. inflorescences exerts an anxiolytic-like activity in mice.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Anxiolytic-like effects of Tilia petiolaris DC. inflorescences infusion

Infusions of the inflorescences of Tilia are widely used for their tranquilizing properties around the world and have been regarded as non-toxic. Despite the widespread use of the tea of silver Linden in folk medicine, the number of scientific studies for the evaluation of its therapeutic utilization is limited. In an attempt to add experimental confirmation to its popular medicinal use, the central nervous system related effects of the chronic ingestion of the infusion of Tilia petiolaris DC. inflorescences were evaluated in the holeboard, locomotor activity and light-dark tests in mice. The infusion induced significant increases in the exploration of holes and in the time spent head-dipping in the holeboard assay. Moreover, it significantly increased the time spent in the light area in the light-dark test. These results suggest that the infusion of Tilia petiolaris DC. inflorescences exerts an anxiolytic-like activity in mice.Fil: Loscalzo, Leonardo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Wasowski, Cristina Lucia N.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Marder, Nora Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentin

Chronic intraperitoneal and oral treatments with hesperidin induce central nervous system effects in mice

Hesperidin (HN) is a flavanone glycoside abundantly found in citrus fruits. This flavonoid mediated central nervous system activity following intraperitoneal (i.p.) acute treatment. The responses of mice after the chronic i.p. (4 and 30 mg/kg/day) or the oral intake administration of this drug (20, 50 and 100 mg/kg/day) were studied by using the holeboard, the plus-maze and the locomotor activity tests. Hesperidin, chronically administered by the i.p. route, exerted a decrease in the locomotor and exploratory activities, thus evidencing a depressant activity. In turn, the chronic oral intake of this flavonoid induced anxiolytic-like effects. These varied responses could be attributed to the different routes of administration that could lead to the production of diverse active metabolites.Fil: Wasowski, Cristina Lucia N.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Loscalzo, Leonardo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Higgs, Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Marder, Nora Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentin

In vitro binding affinities of a series of flavonoids for mu-opioid receptors. Antinociceptive effect of the synthetic flavonoid 3,3-dibromoflavanone in mice

The pharmacotherapy for the treatment of pain is an active area of investigation. There are effective drugs to treat this problem, but there is also a need to find alternative treatments free of undesirable side effects. In the present work the capacity of a series of flavonoids to bind to the m opioid receptor was evaluated. The most active compound, 3,3-dibromoflavanone (31), a synthetic flavonoid, presented a significant inhibition of the binding of the selective m opioid ligand [3 H]DAMGO, with a Ki of 0.846 0.263 mM. Flavanone 31 was further synthesized using a simple and cheap procedure with good yield. Its in vivo effects in mice, after acute treatments, were studied using antinociceptive and behavioral assays. It showed no sedative, anxiolytic, motor incoordination effects or inhibition of the gastrointestinal transit in mice at the doses tested. It evidenced antinociceptive activity on the acetic acid-induced nociception, hot plate and formalin tests (at 10 mg/kg and 30 mg/kg). The results showed that the 5-HT2 receptor and the adrenoceptors seem unlikely to be involved in its antinociceptive effects. Naltrexone, a nonselective opioid receptors antagonist, totally blocked compound 31 antinociceptive effects on the hot plate test, but naltrindole (d opioid antagonist) and nor-binaltorphimine (k opioid antagonist) did not. These findings demonstrated that 3,3-dibromoflavanone (31), at doses that did not interfere with the motor performance, exerted clear dose dependent antinociception when assessed in the chemical and thermal models of nociception in mice and it seems that its action is related to the activation of the m opioid receptor.Fil: Higgs, Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Wasowski, Cristina Lucia N.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Loscalzo, Leonardo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Marder, Nora Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; Argentin