RESUMO
It is well recognized that stress or glucocorticoids hormones treatment can modulate memory performance in both directions, either impairing or enhancing it. Despite the high number of studies aiming at explaining the effects of glucocorticoids on memory, this has not yet been completely elucidated. Here, we demonstrate that a low daily dose of methylprednisolone (MP, 5mg/kg, i.p.) administered for 10-days favors aversive memory persistence in adult rats, without any effect on the exploring behavior, locomotor activity, anxiety levels and pain perception. Enhanced performance on the inhibitory avoidance task was correlated with long-term potentiation (LTP), a phenomenon that was strengthen in hippocampal slices of rats injected with MP (5mg/kg) during 10days. Additionally, in vitro incubation with MP (30-300µM) concentration-dependently increased intracellular [Ca2+]i in cultured hippocampal neurons depolarized by KCl (35mM). In conclusion, a low daily dose of MP for 10days may promote aversive memory persistence in rats.
Assuntos
Potenciação de Longa Duração/efeitos dos fármacos , Memória/efeitos dos fármacos , Metilprednisolona/farmacologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Cálcio/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Memória/classificação , Memória/fisiologia , Metilprednisolona/metabolismo , Ratos , Ratos Wistar , Sinapses/fisiologiaRESUMO
OBJECTIVES: To assess the antinociceptive activity of the neomycin derivatives neamine and 2-deoxystreptamine following intraspinal administration in rats. METHODS: We used the tail-flick test and measured the threshold to mechanical stimulation in models of incisional and neuropathic pain. KEY FINDINGS: The derivatives produced antinociception in the tail-flick test and reduced mechanical allodynia in models of incisional and neuropathic pain. The approximate ED50 in milligrams (confidence limits in parenthesis) in these tests were 1.35 mg (0.61; 2.95), 0.20 mg (0.14; 0.27) and 0.28 mg (0.12; 0.63) for neamine, and 1.05 mg (0.68; 1.60), 0.78 mg (0.776; 0.783) and 0.79 mg (0.46; 1.34) for 2-deoxystreptamine, respectively. Neamine was more potent than 2-deoxystreptamine in the incisional and neuropathic pain models, but they had similar potency in the tail-flick test. Tetra-azidoneamine, a neamine derivative in which free amino groups are replaced with azido groups, did not change the incisional mechanical allodynia. The reduction of incisional allodynia by neamine and 2-deoxystreptamine was transitorily antagonized by intrathecal administration of calcium chloride. CONCLUSIONS: The intraspinal administration of neamine and 2-deoxystreptamine is antinociceptive in rats. The presence of amino groups in the structure of these derivatives is fundamental to their antinociceptive effect, which may be due to a calcium antagonist activity.
Assuntos
Analgésicos/farmacologia , Framicetina/farmacologia , Neuralgia/prevenção & controle , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/prevenção & controle , Limiar da Dor/efeitos dos fármacos , Dor Pós-Operatória/prevenção & controle , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Framicetina/administração & dosagem , Framicetina/química , Hexosaminas/administração & dosagem , Hexosaminas/química , Hexosaminas/farmacologia , Injeções Espinhais , Masculino , Estrutura Molecular , Neuralgia/fisiopatologia , Dor Nociceptiva/fisiopatologia , Medição da Dor , Dor Pós-Operatória/fisiopatologia , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Ménière's disease (MD) is a progressive disease of the inner ear characterized by recurring attacks of disabling vertigo, hearing loss and tinnitus. Patients who do not respond to vestibular sedatives or steroids may require an intratympanic application of aminoglycoside antibiotics, which destroys the vestibular function of the affected ear in order to avoid the debilitating vertigo attacks. Although effective, this procedure causes hearing loss in almost one third of the patients due to the aminoglycosides cochlear toxicity. Here we describe the synthesis of two pseudodisaccharides structurally related to neamime aiming to mimic the aminoglycosides pharmacophore core by replacing their toxic amine by azide and hydroxyl groups. Products 1 and 2 selectively promoted 'in vivo' damage to vestibular tissues without causing hearing loss or cochlear toxicity. Therefore, these pseudodisaccharides stand as promising lead compounds for the development of a safer and more effective therapeutic procedure to manage the symptoms of MD severe dizziness.
Assuntos
Azidas/química , Azidas/farmacologia , Dissacarídeos/química , Dissacarídeos/farmacologia , Framicetina/química , Vertigem/tratamento farmacológico , Aminoglicosídeos/química , Animais , Azidas/síntese química , Técnicas de Química Sintética , Cóclea/citologia , Cóclea/efeitos dos fármacos , Dissacarídeos/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Cobaias , Células Ciliadas Auditivas/efeitos dos fármacos , Humanos , Doença de Meniere/tratamento farmacológico , Microscopia Eletrônica de Varredura , Mimetismo Molecular , Estrutura MolecularRESUMO
We examined the correlation between results obtained from the in vivo Draize test for ocular irritation and in vitro results obtained from the sheep red blood cell (RBC) haemolytic assay, which assesses haemolysis and protein denaturation in erythrocytes, induced by cosmetic products. We sought to validate the haemolytic assay as a preliminary test for identifying highly-irritative products, and also to evaluate the in vitro test as alternative assay for replacement of the in vivo test. In vitro and in vivo analyses were carried out on 19 cosmetic products, in order to correlate the lesions in the ocular structures with three in vitro parameters: (i) the extent of haemolysis (H50); (ii) the protein denaturation index (DI); and (iii) the H50/DI ratio, which reflects the irritation potential (IP). There was significant correlation between maximum average scores (MAS) and the parameters determined in vitro (r = 0.752-0.764). These results indicate that the RBC assay is a useful and rapid test for use as a screening method to assess the IP of cosmetic products, and for predicting the IP value with a high level of concordance (94.7%). The assay showed high sensitivity and specificity rates of 91.6% and 100%, respectively.
Assuntos
Alternativas aos Testes com Animais/métodos , Cosméticos/toxicidade , Olho/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Irritantes/toxicidade , Animais , Feminino , Irritantes/classificação , Masculino , Valor Preditivo dos Testes , Coelhos , OvinosRESUMO
Aminoglycoside antibiotic derivatives such as neamine, methyl neobiosaminide B, 2-deoxystreptamine, tetra-azidoneamine, tetra-N-acetylneamine, tetra-N-carboxy-benzylneamine, tetra-N-carboxy-methylneamine and tetra-p-methoxy-benzyliminoneamine were prepared and evaluated as to their cochlear and vestibular toxicity. Methyl neobiosaminide B, the most promising derivative in the series showed selective, cochlea-dissociated vestibulotoxic activity and was considered to be a potential lead compound for the treatment of Ménière's disease. Antimicrobial properties of the compounds, qualitatively evaluated against a group of pathogenic bacteria, indicated that neomycin B sulfate, neamine as a free base and methyl-neobiosaminide B dihydrochloride show a broader range of activity when compared to the other derivatives.
Assuntos
Aminoglicosídeos/toxicidade , Antibacterianos/toxicidade , Cóclea/efeitos dos fármacos , Vestíbulo do Labirinto/efeitos dos fármacos , Aminoglicosídeos/síntese química , Aminoglicosídeos/química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Bactérias/efeitos dos fármacos , Cóclea/ultraestrutura , Cobaias , Microscopia Eletrônica de Varredura , Relação Estrutura-AtividadeRESUMO
The venoms of some Bothrops species produce neuromuscular blockade in avian and mammalian nerve-muscle preparations in vitro. In this study, we compared the neuromuscular activities (myotoxicity and neurotoxicity) of venoms from several Brazilian species of Bothrops (B. jararaca, B. jararacussu, B. moojeni, B. erythromelas and B. neuwiedi) in chick isolated biventer cervicis muscle preparations and examined their neutralization by commercial antivenom. All of the venoms (50-200 microg/ml, n = 3 - 7 each) induced long-lasting, concentration-dependent muscle contracture and twitch-tension blockade, and also inhibited the muscle responses to acetylcholine and KCl. Preincubation of the venoms (200 microg/ml) with bothropic antivenom (0.2 ml) for 30 min at 37 degrees C prevented the twitch-tension blockade to different extents, with the protection varying from 0.5% (B. neuwiedi) to 88% (B. moojeni). Complete protection against the neuromuscular action of B. neuwiedi venom was observed only with a mixture of bothropic and crotalic antivenoms. The venoms caused either high (B. jararacussu, B. neuwiedi and B. moojeni) or low (B. jararaca and B. erythromelas) creatine kinase release. Morphologically, myonecrosis was greatest with B. jararacussu venom (98-100% of fibers damaged) and least with B. jararaca venom (74% damage). The extent of neutralization by bothropic antivenom was B. jararaca (93%)>B. erythromelas (65.8%)>B. moojeni (30.7%)>B. neuwiedi (20%)>B. jararacussu (no neutralization). Despite this variation in neutralization, enzyme-linked immunosorbent assays indicated similar immunoreactivities for the venoms, although immunoblots revealed quantitative variations in the bands detected. These results show that Bothrops venoms produce varying degrees of neuromuscular blockade in chick nerve-muscle preparations. The variable protection by antivenom against neuromuscular activity indicates that the components responsible for the neuromuscular action may differ among the venoms.
Assuntos
Antivenenos/farmacologia , Bothrops , Venenos de Crotalídeos/toxicidade , Contração Muscular/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Acetilcolina/antagonistas & inibidores , Animais , Brasil , Galinhas , Creatina Quinase/metabolismo , Venenos de Crotalídeos/antagonistas & inibidores , Eletroforese em Gel de Poliacrilamida , Ensaio de Imunoadsorção Enzimática , Immunoblotting , Dose Letal Mediana , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Necrose , Cloreto de Potássio/antagonistas & inibidoresRESUMO
Whereas the presynaptic action of Crotalus durissus terrificus venom is well-established, Bothrops venoms have historically been considered to have only postsynaptic and muscular effects. However, some studies have also suggested a presynaptic action for these venoms. In this work, we used chick biventer cervicis preparations to compare the presynaptic actions of two Bothrops venoms (B. insularis and B. neuwiedi) with that of C. d. terrificus venom. At 10 microg/ml, all venoms produced irreversible blockade of the twitch tension responses, with no reduction in acetylcholine (ACh)-induced contractures and only a slight decrease in potassium induced-contractures. The times (in min) required to produce 50% neuromuscular blockade (C. d. terrificus: 16.3+/-0.7, n = 8; B. insularis: 30.0+/-1.9, n = 5; B. neuwiedi: 42.0+/-2.0, n = 8; mean +/- SEM) were significantly different among the venoms (p < 0.01). Lowering the temperature at which the experiments were done (from 37 to 24 degrees C) prevented neuromuscular blockade by the three venoms, indicating that enzyme activity may be involved in this response. At concentrations capable of causing complete neuromuscular blockade, creatine kinase release remained close to levels seen in control preparations incubated with Krebs solution alone (500-1200 IU/l). Commercial crotalic antivenom, but not bothropic antivenom, protected against the neuromuscular blockade caused by B. insularis and B. neuwiedi venoms. These observations indicate that bothropic venoms may contain components which act presynaptically in a manner similar to C. d. terrificus venom, and that at low venom concentrations a direct action on skeletal muscle does not contribute to this presynaptic neurotoxicity.
Assuntos
Bothrops , Venenos de Crotalídeos/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/inervação , Junção Neuromuscular/efeitos dos fármacos , Animais , Galinhas , Venenos de Crotalídeos/administração & dosagem , Relação Dose-Resposta a Droga , MasculinoRESUMO
Phoneutria nigriventer venom (PNV) contracts vascular tissues and increases arterial blood pressure. This study aimed to investigate the mechanisms involved on PNV-induced contractions of rabbit mesenteric and celiac arteries. Strips of mesenteric and celiac arteries were suspended in a cascade system and superfused with warmed and oxygenated Krebs solution. PNV was dialyzed in order to exclude the participation of biogenic amines in the contractions elicited by the venom. Noradrenaline (NA, 30-300 pmol), PNV (1-10 microg), Bay K-8644 (0.3-3 nmol) and KCl (10-100 micromol) dose-dependently contracted the preparations. Ca(2+)-free solution reduced by 38 and 83% the PNV-induced contractions of mesenteric and celiac arteries, respectively. Subsequent infusion of EGTA (0.2 mM) suppressed the residual contractions. Nifedipine (1 microM) and verapamil (10 microM) abolished PNV- and Bay K-8644-evoked contractions, whereas those induced by NA were reduced to a lesser extent. Lanthanum chloride (0.2 mM) inhibited by 75-90% the mesenteric and celiac contractions mediated by PNV. Caffeine (2 mM) fully blocked contractions induced by NA (95% mean inhibition), but only partly reduced those induced by PNV (35% mean inhibition). Ryanodine (10 microM) inhibited by 50% the contractions evoked by NA, but had no effect on the PNV-induced contractions in both tissues. Our findings indicate that PNV contracts vascular smooth muscle mainly due to increased influx of Ca(2+) from extracellular sources.
Assuntos
Agonistas dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Venenos de Aranha/toxicidade , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Animais , Quelantes/farmacologia , Ácido Egtázico/farmacologia , Lantânio/farmacologia , Masculino , Contração Muscular/fisiologia , Norepinefrina/fisiologia , Cloreto de Potássio/farmacologia , CoelhosRESUMO
A partir del trabajo pioneiro de Vital-Brazil y Corrado (1957), quienes sugieron una posible interacción entre los antibióticos aminoglucósidos (AAG) y el unión neuromuscular, los autores hacen una revisión de los estudios que demuestran un natagonismo de tipo competitivo entre los AAG y el ion calcio. Debido a la baja liposolubilidad de los AAG y a la incapacidad para atravesar barreras biológicas, ese antagonismo debe ocurrir, exclusivamente, en la superficie de las mebranas, más específicamente en los sitios de unión del ion situados próximos al orificio externo de los canales de calcio del sub-tipo N, o sea, los mismos sitios de interacción de la W -conotoxina. Por su elevada hidrosolubilidad, los AAG son fácilmente dislocados de sus sitios de unión, determinado la reversión rápida de sus efectos calcio-dependientes. Esta propiedad es el factor primoridal para justificar su empleo como herramienta para el análisis farmacológico en la investigación del papel biológico del calcio a nivel de la superficie de las membranas. Tal empleo ofrece ventajas con respecto a los cationes inorgánicos di y trivalents =Mg2+, Mn2+, Cd2+, Ni2+, La3+, etc. -pues estos últimos, no obstante ser antagonistas competitivos del ion calcio, pueden inducir efectos bifásicos por su capacidad de atravesar las membranas y substitutir y/o aumentar la concentración de Ca2+ intracelular. Los AAG también presentan ventajas comparados con los inadecuadamente denominados antagonistas "específicos" del calcio-derivados del verapamil y de la dihidropiridina - pues estos últimos, además de poder causar efectos bifásicos, antagonizan el calcio de forma no-competitiva. Por último, los autores enfatizan que la relevancia del antagonismo Ca2+ -AAG no se limita sólo a aspectos básicos, sino que incluye también implicaciones terapéuticas, pues establece alternativas capaces de reducir los efectos colaterales tóxicos de este importante grupo de antibióticos
Assuntos
Humanos , Animais , Cobaias , Coelhos , Antibacterianos/farmacologia , Cálcio/fisiologia , Agonistas dos Canais de Cálcio/farmacologia , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/toxicidade , Ligação Competitiva , Cálcio/metabolismo , Contração Isométrica , Contração Muscular , Músculos/fisiologiaRESUMO
A partir del trabajo pioneiro de Vital-Brazil y Corrado (1957), quienes sugieron una posible interacción entre los antibióticos aminoglucósidos (AAG) y el unión neuromuscular, los autores hacen una revisión de los estudios que demuestran un natagonismo de tipo competitivo entre los AAG y el ion calcio. Debido a la baja liposolubilidad de los AAG y a la incapacidad para atravesar barreras biológicas, ese antagonismo debe ocurrir, exclusivamente, en la superficie de las mebranas, más específicamente en los sitios de unión del ion situados próximos al orificio externo de los canales de calcio del sub-tipo N, o sea, los mismos sitios de interacción de la W -conotoxina. Por su elevada hidrosolubilidad, los AAG son fácilmente dislocados de sus sitios de unión, determinado la reversión rápida de sus efectos calcio-dependientes. Esta propiedad es el factor primoridal para justificar su empleo como herramienta para el análisis farmacológico en la investigación del papel biológico del calcio a nivel de la superficie de las membranas. Tal empleo ofrece ventajas con respecto a los cationes inorgánicos di y trivalents =Mg2+, Mn2+, Cd2+, Ni2+, La3+, etc. -pues estos últimos, no obstante ser antagonistas competitivos del ion calcio, pueden inducir efectos bifásicos por su capacidad de atravesar las membranas y substitutir y/o aumentar la concentración de Ca2+ intracelular. Los AAG también presentan ventajas comparados con los inadecuadamente denominados antagonistas "específicos" del calcio-derivados del verapamil y de la dihidropiridina - pues estos últimos, además de poder causar efectos bifásicos, antagonizan el calcio de forma no-competitiva. Por último, los autores enfatizan que la relevancia del antagonismo Ca2+ -AAG no se limita sólo a aspectos básicos, sino que incluye también implicaciones terapéuticas, pues establece alternativas capaces de reducir los efectos colaterales tóxicos de este importante grupo de antibióticos (AU)
Assuntos
Humanos , Animais , Cobaias , Coelhos , Antibacterianos/farmacologia , Cálcio/fisiologia , Antibacterianos/metabolismo , Antibacterianos/química , Antibacterianos/toxicidade , Cálcio/metabolismo , Ligação Competitiva , Músculos/fisiologia , Contração Muscular/efeitos dos fármacos , Agonistas dos Canais de Cálcio/farmacologia , Contração Isométrica/efeitos dos fármacosRESUMO
Tem-se reportado que na hipertensäo induzida pela gravidez existiria uma significativa diminuiçäo do cálcio iônico sérico, e se tem sugerido um papel do mineral na etiopatogenia da mencionada doença. No presente trabalho estudaram-se os níveis do cálcio iônico, cálcio total, PTH, calcitonina e proteínas no soro de grávidas normotensas (n = 10), pré-eclâmpticas (n = 6) e mulheres näo grávidas (n = 11). As concentraçöes de cálcio iônico sérico das mulheres grávidas normotensas foram similares às das pré-eclâmpticas (4,49 ñ 0,07 mg% e 4,53 ñ 0,17 mg%, respectivamente), porém nos dois grupos foram significativamente menores em relaçäo às näo grávidas (4,79 ñ 0,11 p <0,001). Os níveis de cálcio total, proteínas totais e albumina foram igualmente menores nas grávidas que nas näo grávidas. O PTH esteve incrementado nas mulheres grávidas normais e especialmente nas pré-eclâmpticas (63,6 ñ 15 pmol/l e 85,3 ñ 47,4 pmol/l, respectivamente)