RESUMO
The globally important carbon sink of intact, old-growth tropical humid forests is declining because of climate change, deforestation and degradation from fire and logging1-3. Recovering tropical secondary and degraded forests now cover about 10% of the tropical forest area4, but how much carbon they accumulate remains uncertain. Here we quantify the aboveground carbon (AGC) sink of recovering forests across three main continuous tropical humid regions: the Amazon, Borneo and Central Africa5,6. On the basis of satellite data products4,7, our analysis encompasses the heterogeneous spatial and temporal patterns of growth in degraded and secondary forests, influenced by key environmental and anthropogenic drivers. In the first 20 years of recovery, regrowth rates in Borneo were up to 45% and 58% higher than in Central Africa and the Amazon, respectively. This is due to variables such as temperature, water deficit and disturbance regimes. We find that regrowing degraded and secondary forests accumulated 107 Tg C year-1 (90-130 Tg C year-1) between 1984 and 2018, counterbalancing 26% (21-34%) of carbon emissions from humid tropical forest loss during the same period. Protecting old-growth forests is therefore a priority. Furthermore, we estimate that conserving recovering degraded and secondary forests can have a feasible future carbon sink potential of 53 Tg C year-1 (44-62 Tg C year-1) across the main tropical regions studied.
Assuntos
Sequestro de Carbono , Carbono , Conservação dos Recursos Naturais , Florestas , Umidade , Árvores , Clima Tropical , Carbono/metabolismo , Conservação dos Recursos Naturais/métodos , Conservação dos Recursos Naturais/estatística & dados numéricos , Conservação dos Recursos Naturais/tendências , Árvores/metabolismo , Agricultura Florestal/estatística & dados numéricos , Imagens de Satélites , Temperatura , Floresta Úmida , Bornéu , África Central , BrasilRESUMO
Spaced training, which involves long inter-trial intervals, has positive effects on memories. One of the main attributes of long-term memories (LTM) is persistence. Here, to identify the process that promotes LTM persistence by spaced learning, we used the spatial object recognition (SOR) task in rats. The protocol consisted of a first strong training session that induced LTM formation (tested 1 day after training), but not LTM persistence (tested 7 or 14 days after training); and a second weak training session that promoted memory persistence when applied 1 day, but not 7 days, after the first training. We propose that the promotion of memory persistence is based on the Behavioral Tagging (BT) mechanism operating when the memory trace is retrieved. BT involves the setting of a tag induced by learning which gives rise to input selectivity, and the use of plasticity-related proteins (PRPs) to establish the mnemonic trace. We postulate that retraining will mainly retag the sites initially activated by the original learning, where the PRPs needed for memory expression and/or induced by retrieval would be used to maintain a persistent mnemonic trace. Our results suggest that the mechanism of memory expression, but not those of memory reinforcement or reconsolidation, is necessary to promote memory persistence after retraining. The molecular mechanisms involve ERKs1/2 activity to set the SOR learning tag, and the availability of GluA2-containing AMPA receptor. In conclusion, both the synthesis of PRPs and the setting of learning tags are key processes triggered by retraining that allow SOR memory persistence.
Assuntos
Memória de Longo Prazo , Memória Espacial , Animais , Hipocampo , Ratos , Ratos Wistar , Aprendizagem EspacialRESUMO
Tropical secondary forests sequester carbon up to 20 times faster than old-growth forests. This rate does not capture spatial regrowth patterns due to environmental and disturbance drivers. Here we quantify the influence of such drivers on the rate and spatial patterns of regrowth in the Brazilian Amazon using satellite data. Carbon sequestration rates of young secondary forests (<20 years) in the west are ~60% higher (3.0 ± 1.0 Mg C ha-1 yr-1) compared to those in the east (1.3 ± 0.3 Mg C ha-1 yr-1). Disturbances reduce regrowth rates by 8-55%. The 2017 secondary forest carbon stock, of 294 Tg C, could be 8% higher by avoiding fires and repeated deforestation. Maintaining the 2017 secondary forest area has the potential to accumulate ~19.0 Tg C yr-1 until 2030, contributing ~5.5% to Brazil's 2030 net emissions reduction target. Implementing legal mechanisms to protect and expand secondary forests whilst supporting old-growth conservation is, therefore, key to realising their potential as a nature-based climate solution.
Assuntos
Sequestro de Carbono , Carbono/metabolismo , Mudança Climática , Florestas , Clima Tropical , Algoritmos , Biomassa , Brasil , Conservação dos Recursos Naturais/métodos , Ecossistema , Incêndios , Agricultura Florestal , Geografia , Modelos Teóricos , Imagens de Satélites/métodos , Árvores/crescimento & desenvolvimento , Árvores/metabolismoRESUMO
The restoration and reforestation of 12 million hectares of forests by 2030 are amongst the leading mitigation strategies for reducing carbon emissions within the Brazilian Nationally Determined Contribution targets assumed under the Paris Agreement. Understanding the dynamics of forest cover, which steeply decreased between 1985 and 2018 throughout Brazil, is essential for estimating the global carbon balance and quantifying the provision of ecosystem services. To know the long-term increment, extent, and age of secondary forests is crucial; however, these variables are yet poorly quantified. Here we developed a 30-m spatial resolution dataset of the annual increment, extent, and age of secondary forests for Brazil over the 1986-2018 period. Land-use and land-cover maps from MapBiomas Project (Collection 4.1) were used as input data for our algorithm, implemented in the Google Earth Engine platform. This dataset provides critical spatially explicit information for supporting carbon emissions reduction, biodiversity, and restoration policies, enabling environmental science applications, territorial planning, and subsidizing environmental law enforcement.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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One of the top challenges in education and neuroscience consists in translating laboratory results into strategies to improve learning and memory in teaching environments. In that sense, during the last two decades, researchers have discovered specific temporal windows around learning, during which the intervention with some experiences induces modulatory effects on the formation and/or persistence of memory. Based on these results, the aim of the present study was to design a specific strategy to improve the memory of students in a high-school scenario, by assessing the effect of a novel situation experienced close to learning. We found that the long-term memory about a geometrical figure was more precise in the group of students that faced a novel situation 1 h before or after learning the figure than the control group of students who did not face the novelty. This enhancement was probably triggered by processes acting on memory formation mechanisms that remained evident 45 days after learning, indicating that the improvement was sustained over time. In addition, our results showed that novelty no longer improved the memory if it was experienced 4 h before or after learning. However, far beyond this window of efficacy, when it was faced around 10 h after learning, the novel experience improved the memory persistence tested 7 days later. In summary, our findings characterized different temporal windows of the effectiveness of novelty acting on memory processing, providing a simple and inexpensive strategy that could be used to improve memory formation and persistence in high-school students.
RESUMO
The influence of a given event on long-term memory formation of another one has been a relevant topic of study in the neuroscience field in recent years. Students at school learn contents which are usually tested in exam format. However, exam elevates the arousal state of the students acting as a mild stressor that could influence another memory formation ongoing process. Thus, in this study we examine in high school students the effect of exams on long-term retention of unrelated information, learned at different times before or after the exams. Our results show that exams are not innocuous and that they could improve or reduce the retention of temporarily associated content. These effects did not show gender differences. Our findings should alert teachers about the side effects of exams on the learning of other content within the same school day.
RESUMO
Rats exposed to a novel environment just prior to or 1-2 h, but not 4 or 6 h, before retention testing exhibited an enhanced retrieval of a one-trial inhibitory avoidance training. The bilateral intrahippocampal infusion of PD098059, an inhibitor of mitogen-activated protein kinase (MAPK), the specific upstream activator of p42 and p44 MAPKs, given 10 min before the exposure to the novel environment, blocked the enhancing effect of novelty on memory retrieval. In addition, prenovelty infusion of DL-2-amino-5-phosphonovalerate (APV), an antagonist of glutamate NMDA receptors, produced similar effects. The exposure to the novel environment is associated with an activation of p42 and p44 MAPKs and an increase in the phosphorylation state of the transcription factor cAMP response element binding protein (CREB). No changes were observed in cAMP-dependent protein kinase (PKA) activity or in alpha-CAMKII activation. Taken together, our results indicate that novelty activates hippocampal MAPKs, which are necessary, along with glutamate NMDA receptors, for the enhancing effect of novelty on retrieval.
Assuntos
Comportamento Exploratório/fisiologia , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Hipocampo/citologia , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios/enzimologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
A large number of structurally different classes of ligands, many of them sharing the main characteristics of the benzodiazepine (BDZ) nucleus, are active in the modulation of anxiety, sedation, convulsion, myorelaxation, hypnotic and amnesic states in mammals. These compounds have high affinity for the benzodiazepine binding site (BDZ-bs) of the GABA(A) receptor complex. Since 1989 onwards our laboratories established that some natural flavonoids were ligands for the BDZ-bs which exhibit medium to high affinity in vitro and anxiolytic activity in vivo. Further research resulted in the production of synthetic flavonoid derivatives with increased biochemical and pharmacological activities. The currently accepted receptor/pharmacophore model of the BDZ-bs (Zhang, W.; Koeler, K. F.; Zhang, P.; Cook, J. M. Drug Des. Dev. 1995, 12, 193) accounts for the general requirements that should be met by this receptor for ligand recognition. In this paper we present a model pharmacophore which defines the characteristics for a ligand to be able to interact and bind to a flavone site, in the GABA(A) receptor. closely related to the BDZ-bs. A model of a flavone binding site has already been described (Dekermendjian, K.; Kahnberg, P.; Witt, M. R.; Sterner, O.; Nielsen, M.; Liljerfors, T. J. Med. Chem. 1999, 42, 4343). However, this alternative model is based only on graphic superposition techniques using as template a non-BDZ agonist. In this investigation all the natural and synthetic flavonoids found to be ligands for the BDZ-bs have been compared with the classical BDZ diazepam. A QSAR regression analysis of the parameters that describe the interaction demonstrates the relevance of the electronic effects for the ligand binding, and shows that they are associated with the negatively charged oxygen atom of the carbonyl group of the flavonoids and with the nature of the substituent in position 3'.
Assuntos
Benzodiazepinas/metabolismo , Flavonoides/metabolismo , Receptores de GABA-A/metabolismo , Animais , Ansiolíticos/metabolismo , Sítios de Ligação , Diazepam/química , Interações Medicamentosas , Flunitrazepam/metabolismo , Ligantes , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Ensaio Radioligante , Ratos , Sinaptossomos/metabolismoRESUMO
To determine whether neonatal intracranial injection of apotransferrin (aTf), which increases myelin deposition, has behavioral effects in rats, 3-day-old rats were intracranially injected with 350 ng of aTf and tested at 25 and 60 days of age. An anxiolytic-like behavior was observed in aTf-treated rats, evidenced by an increase in the exploration of open arms in the plus maze test without changes in the locomotor activity. This behavioral profile persists until adulthood. Intraperitoneal injection of 0.75 mg/kg of picrotoxin, a GABA(A) receptor channel antagonist, abolished this anxiolytic-like behavior, indicating that neonatal aTf induces a long-lasting increase in GABA(A) receptor functionality.
Assuntos
Apoproteínas/metabolismo , Apoproteínas/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Bainha de Mielina/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Transferrina/metabolismo , Transferrina/farmacologia , Animais , Animais Recém-Nascidos , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Antagonistas GABAérgicos/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Bainha de Mielina/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Picrotoxina/farmacologia , Ratos , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismoRESUMO
It has been recently demonstrated that ubiquitin-proteasome-mediated proteolysis is required for long-term synaptic facilitation in Aplysia. Here we show that the hippocampal blockade of this proteolytic pathway is also required for the formation of long-term memory in the rat. Bilateral infusion of lactacystin, a specific proteasome inhibitor, to the CA1 region caused full retrograde amnesia for a one-trial inhibitory avoidance learning when given 1, 4 or 7h, but not 10 h, after training. Proteasome inhibitor I produced similar effects. In addition, inhibitory avoidance training resulted in an increased ubiquitination and 26S proteasome proteolytic activity and a decrease in the levels of IkappaB, a substrate of the ubiquitin-proteasome cascade, in hippocampus 4 h after training. Together, these findings indicate that the ubiquitin-proteasome cascade is crucial for the establishment of LTM in the behaving animal.
Assuntos
Cisteína Endopeptidases/metabolismo , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Complexos Multienzimáticos/metabolismo , Neurônios/metabolismo , Ratos Wistar/metabolismo , Ubiquitina/metabolismo , Amnésia Retrógrada/induzido quimicamente , Amnésia Retrógrada/metabolismo , Amnésia Retrógrada/fisiopatologia , Animais , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Complexos Multienzimáticos/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Peptídeo Hidrolases/efeitos dos fármacos , Peptídeo Hidrolases/metabolismo , Complexo de Endopeptidases do Proteassoma , Ratos , Ratos Wistar/anatomia & histologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
From mollusks to mammals the activation of cAMP response element-binding protein (CREB) appears to be an important step in the formation of long-term memory (LTM). Here we show that a 5 min exposure to a novel environment (open field) 1 hr after acquisition of a one-trial inhibitory avoidance training hinders both the formation of LTM for the avoidance task and the increase in the phosphorylation state of hippocampal Ser 133 CREB [phosphorylated CREB (pCREB)] associated with the avoidance training. To determine whether this LTM deficit is attributable to the reduced pCREB level, rats were bilaterally cannulated to deliver Sp-adenosine 3', 5'-cyclic monophosphothioate (Sp-cAMPS), an activator of PKA. Infusion of Sp-Adenosine 3',5'-cyclic monophosphothioate Sp-cAMPS to CA1 region increased hippocampal pCREB levels and restored normal LTM of avoidance learning in rats exposed to novelty. Moreover, a 5 min exposure to the open field 10 min before the avoidance training interferes with the amnesic effect of a second 5 min exposure to the open field 1 hr after avoidance training and restores the hippocampal levels of pCREB. In contrast, the avoidance training-associated activation of extracellular signal-regulated kinases (p42 and p44 mitogen-activated protein kinases) in the hippocampus is not altered by novelty. Together, these findings suggest that novelty regulates LTM formation by modulating the phosphorylation state of CREB in the hippocampus.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , AMP Cíclico/análogos & derivados , Hipocampo/fisiologia , Memória/fisiologia , Amnésia Retrógrada/tratamento farmacológico , Amnésia Retrógrada/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Biomarcadores , AMP Cíclico/administração & dosagem , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Hipocampo/química , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Infusões Parenterais , Masculino , Memória/efeitos dos fármacos , Microinjeções , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Retenção Psicológica/efeitos dos fármacos , Retenção Psicológica/fisiologia , Tionucleotídeos/administração & dosagem , TempoRESUMO
Long-term habituation to a novel environment is one of the most elementary forms of nonassociative learning. Here we studied the effect of pre- or posttraining intrahippocampal administration of drugs acting on specific molecular targets on the retention of habituation to a 5-min exposure to an open field measured 24 h later. We also determined whether the exposure to a novel environment resulted in the activation of the same intracellular signaling cascades previously shown to be activated during hippocampal-dependent associative learning. The immediate posttraining bilateral infusion of CNQX (1 microg/side), an AMPA/kainate glutamate receptor antagonist, or of muscimol (0.03 microg/side), a GABA(A) receptor agonist, into the CA1 region of the dorsal hippocampus impaired long-term memory of habituation. The NMDA receptor antagonist AP5 (5 microg/side) impaired habituation when infused 15 min before, but not when infused immediately after, the 5-min training session. In addition, KN-62 (3.6 ng/side), an inhibitor of calcium calmodulin-dependent protein kinase II (CaMKII), was amnesic when infused 15 min before or immediately and 3 h after training. In contrast, the cAMP-dependent protein kinase (PKA) inhibitor Rp-cAMPS, the mitogen-activated protein kinase kinase (MAPKK) inhibitor PD098059, and the protein synthesis inhibitor anisomycin, at doses that fully block memory formation of inhibitory avoidance learning, did not affect habituation to a novel environment. The detection of spatial novelty is associated with a sequential activation of PKA, ERKs (p44 and p42 MAPKs) and CaMKII and the phosphorylation of c-AMP responsive element-binding protein (CREB) in the hippocampus. These findings suggest that memory formation of spatial habituation depends on the functional integrity of NMDA and AMPA/kainate receptors and CaMKII activity in the CA1 region of the hippocampus and that the detection of spatial novelty is accompanied by the activation of at least three different hippocampal protein kinase signaling cascades.
Assuntos
Hipocampo/fisiologia , Aprendizagem/fisiologia , Memória/fisiologia , Transdução de Sinais/fisiologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Meio Ambiente , Ativação Enzimática/fisiologia , Habituação Psicofisiológica/fisiologia , Masculino , Proteínas Quinases/metabolismo , Ratos , Ratos Wistar , Receptores de AMPA/fisiologia , Receptores de Ácido Caínico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Percepção Espacial/fisiologiaRESUMO
6,3'-dibromoflavone and 6-nitro-3'-bromoflavone inhibited [(3)H]flunitrazepam binding to the benzodiazepine binding site of the gamma amino butyric acid receptor complex with K(i) values between 17 and 36 nM in different brain regions. Their gamma amino butyric acid ratio for [(3)H]flunitrazepam binding to cerebral cortex membranes indicated partial agonistic properties. Both compounds had similar pharmacological effects: they produced anxiolytic-like effects at low doses but did not alter locomotor activity or muscle tonicity; sedation was caused only at doses higher than 30 mg/kg in mice. These synthetic flavone derivatives join an existing family of 6,3'-disubstituted flavone compounds with high affinity for the benzodiazepine binding site and partial agonistic profiles.
Assuntos
Encéfalo/metabolismo , Flavonoides/metabolismo , Receptores de GABA-A/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Flavonoides/farmacologia , Técnicas In Vitro , Cinética , Ligantes , Masculino , Camundongos , Ratos , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
6-Chloro-3'-nitroflavone integrates a list of nearly 70 flavone derivatives synthesized in our laboratories. The effects of 6-chloro-3'-nitroflavone on the benzodiazepine binding sites (BDZ-BSs) of the GABA(A) receptor were examined in vitro and in vivo. 6-Chloro-3'-nitroflavone inhibited the [3H]flunitrazepam ([3H]FNZ) binding to rat cerebral cortex membranes with a Ki of 6.68 nM and the addition of GABA to extensively washed membranes did not modify its affinity for the BDZ-BSs (GABA-shift = 1.16+/-0.12). The binding assays performed in rat striatal and cerebellar brain membranes showed that this compound has similar affinity to different populations of BDZ-BSs. Electrophysiological experiments revealed that 6-chloro-3'-nitroflavone did not affect GABA(A)-receptors (GABA(A)-Rs) responses recorded in Xenopus oocytes expressing alpha1beta2gamma2s subunits, but blocked the potentiation exerted by diazepam (DZ) on GABA-activated chloride currents. In vivo experiments showed that 6-chloro-3'-nitroflavone did not possess anxiolytic, anticonvulsant, sedative, myorelaxant actions in mice or amnestic effects in rats; however, 6-chloro-3'-nitroflavone antagonized diazepam-induced antianxiety action, anticonvulsion, short-term, and long-term amnesia and motor incoordination. These biochemical, electrophysiological, and pharmacological results suggest that 6-chloro-3'-nitroflavone behaves as an antagonist of the BDZ-BSs.
Assuntos
Diazepam/farmacologia , Flavonoides/farmacologia , Flunitrazepam/metabolismo , Moduladores GABAérgicos/farmacologia , Aprendizagem/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Animais , Anticonvulsivantes , Diazepam/uso terapêutico , Antagonistas de Receptores de GABA-A , Masculino , Camundongos , Ratos , Ratos Wistar , Convulsões/tratamento farmacológico , XenopusRESUMO
6-Methyl-3'-bromoflavone inhibited [(3)H]flunitrazepam binding to the benzodiazepine binding site of the GABA(A) receptor (BDZ-bs) with Ki values between 10 and 50 nM in different brain regions. The GABA ratio of 1.03 for [(3)H]flunitrazepam binding to cerebral cortex, 0.76 for cerebellum, 0.7 for hippocampus, 0.7 for striatum, and 0.8 for spinal cord indicated an antagonistic or weak inverse agonistic profile of 6-methyl-3'-bromoflavone on BDZ-bs. Unlike classical benzodiazepines, it had no anticonvulsant, anxiolytic, myorelaxant, sedative, amnestic or motor incoordination effects. However, it antagonized the muscle relaxant, the sedative effect, and the changes in locomotor activity induced by diazepam. Taken together, these findings suggest that 6-methyl-3'-bromoflavone has an antagonistic profile on the BDZ-bs.
Assuntos
Encéfalo/metabolismo , Flavonoides/farmacologia , Antagonistas GABAérgicos/farmacologia , Receptores de GABA-A/metabolismo , Medula Espinal/metabolismo , Sinaptossomos/metabolismo , Animais , Sítios de Ligação , Ligação Competitiva , Cerebelo/metabolismo , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Flavonoides/síntese química , Flavonoides/química , Flunitrazepam/farmacocinética , Antagonistas de Receptores de GABA-A , Hipocampo/metabolismo , Membranas Intracelulares/metabolismo , Cinética , Ligantes , Masculino , CamundongosRESUMO
Rats selected as "anxious", "nonanxious," or normal according to their behavior in an elevated plus maze were submitted to memory tasks and the densities of central benzodiazepine receptors in the amygdala and the hippocampus were studied. Anxious rats exibited better retention scores in the inhibitory avoidance task while nonanxious rats exibited worse retention scores in inhibitory and two-way active avoidance tasks compared to normal rats. No significant differences were detected in the retention scores for habituation to an open field. Nonanxious rats presented a lower benzodiazepine receptor density in the hippocampus but not in the amygdala compared to the other groups. These data suggest that the benzodiazepine receptors are involved in the effect of "anxiety" or emotional states on memory storage processes.
Assuntos
Ansiedade/genética , Nível de Alerta/genética , Habituação Psicofisiológica/genética , Rememoração Mental/fisiologia , Seleção Genética , Tonsila do Cerebelo/fisiologia , Animais , Mapeamento Encefálico , Expressão Gênica/fisiologia , Habituação Psicofisiológica/fisiologia , Hipocampo/fisiologia , Humanos , Masculino , Aprendizagem em Labirinto/fisiologia , Modelos Genéticos , Ratos , Ratos Wistar , Receptores de GABA-A/genética , Receptores de GABA-A/fisiologia , Retenção Psicológica/fisiologiaRESUMO
The list of activities of plant flavonoids did not include effects on the central nervous system (CNS) up to 1990, when our laboratory described the existence of natural anxiolytic flavonoids. The first of these was chrysin (5,7-dihydroxyflavone), followed by apigenin (5,7,4'-trihydroxyflavone) and flavone itself. Semisynthetic derivatives of flavone obtained by introducing halogens, nitro groups or both in its molecule, give rise to high affinity ligands for the benzodiazepine receptor, active in-vivo; 6,3'-dinitroflavone, for example, is an anxiolytic drug 30 times more potent than diazepam. The data collected in this paper make clear that some natural flavonoids are CNS-active molecules and that the chemical modification of the flavone nucleus dramatically increases their anxiolytic potency.
Assuntos
Ansiolíticos/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Flavonoides/farmacologia , Ansiolíticos/química , Camomila , Flavonoides/química , Humanos , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Plantas MedicinaisRESUMO
6-Bromo-3'-nitroflavone is a synthetic flavone derivative that selectively recognizes benzodiazepine receptors and has potent anxiolytic-like effects. Here, we describe in detail its pharmacological characterization. When i.p. injected in mice, 6-bromo-3'-nitroflavone (0.01-0.3 mg/kg) had an anxiolytic-like effect in the elevated plus-maze test. This effect was blocked by the specific benzodiazepine receptor antagonist, flumazenil. In addition, it exhibited anxiolytic-like actions when given orally (1 mg/kg). 6-Bromo-3'-nitroflavone did not exhibit myorelaxant effects (up to 30 mg/kg, i.p.). Unlike diazepam, this flavonoid produced no anterograde amnesia in a one-trial inhibitory avoidance learning. On the other hand, 6-bromo-3'-nitroflavone possessed mild anticonvulsant activity (0.1 mg/kg, i.p.) and provoked sedative-depressant actions only at doses 100-1000 times higher than those producing anxiolytic-like effects. 6-Bromo-3'-nitroflavone (0.1-1 mM) produced a lower potentiation of gamma-amino-butyric acid (GABA)-stimulated 36Cl- influx (126-138%) in comparison to diazepam (0.1 mM: 166%) in cerebral cortical membrane vesicles. Taken together, these findings suggest that 6-bromo-3'-nitroflavone has anxiolytic-like action possibly behaving as a partial agonist of the benzodiazepine receptors.
Assuntos
Ansiolíticos/farmacologia , Flavonoides/farmacologia , Agonistas de Receptores de GABA-A , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Flavonoides/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Pentobarbital/farmacologia , Pentilenotetrazol/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Sono/efeitos dos fármacos , Sono/fisiologiaRESUMO
Solution phase combinatorial synthesis of flavone derivatives and evaluation of their affinity for the central benzodiazepine receptors is described. The libraries preparation is simple and provides a convenient method for rapid compound generation and screening. Thirty one new compounds were obtained of which the most promising, as high affinity benzodiazepine receptor ligands, were 6-bromo-3'-fluoroflavone; 6,3'-dichloroflavone; 6-bromo-3'-chloroflavone and 6-chloro-3'-bromoflavone.