RESUMO
OBJECTIVES: Dementia, which is characterized by a progressive decline in cognitive function, is a major concern in aging societies. Although a number of treatments have been approved, an effective therapy to prevent the disorder is lacking. A supplement that improves cognitive function would benefit patients. The aim of this study was to assess whether auraptene, a citrus coumarin, has a protective effect on cognitive decline. DESIGN: A randomized, placebo-controlled, double-blind study SETTING: Outpatient medical check-up program for cognitive disorders PARTICIPANTS: 84 adult volunteers (they are cognitively normal) met inclusion and exclusion criteria to participate. INTERVENTION: 42 participants received auraptene enriched (containing 6.0 mg/day of auraptene) test juice, and another participants received placebo juice. MEASUREMENTS: 1) Mild Cognitive Impairment (MCI) Screen using the 10-word immediate recall test. 2) The Mini-Mental State Examination (MMSE). Cognitive assessment ware carried out baseline and at 24 weeks. RESULTS: Auraptene enriched test juice did not improve cognitive function after 24 weeks compared with baseline data. However, there was a significant difference in the percentage change in cognitive function between the test and placebo orange juice groups (6.3 ± 18.9 vs. -2.4 ± 14.8, P < 0.05). Multiple regression analysis demonstrated a significant independent relationship between the percentage change in the 10-word immediate recall test score and test juice consumption including baseline 10-word immediate recall test score in all subjects. CONCLUSION: This is the first study to assess the effectiveness of auraptene in the prevention of cognitive decline. Our results suggest that auraptene is a safe supplement for the prevention of cognitive decline.
Assuntos
Cognição/efeitos dos fármacos , Cumarínicos/farmacologia , Voluntários Saudáveis/psicologia , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Nootrópicos/farmacologiaRESUMO
BACKGROUND: To quantify changes in metamorphopsia and retinal contraction in eyes with idiopathic epiretinal membrane (ERM) before and after a spontaneous separation of ERM. METHODS: Among 92 eyes of 92 patients with idiopathic ERM who were followed up at our hospital, 5 eyes of 5 patients had experienced a spontaneous separation of ERM during the follow-up period. Patient's metamorphopsia was assessed horizontally and vertically by a metamorphopsia chart developed by our group, M-CHARTS, to obtain the horizontal (MH) and vertical (MV) metamorphopsia scores. Difference in the scores before and after the membrane separation represents change in patient's metamorphopsia. Changes in retinal contraction were also evaluated horizontally and vertically with our original software for fundus image analysis. The difference between M-CHARTS scores and distances of retinal vessel movements with before and after membrane separation were measured. RESULTS: All five subjects showed a decrease in the retinal contraction. Improved visual acuity was observed in three subjects, and no change was seen in the other two. Four subjects obtained better metamorphopsia scores after the membrane separation, while the other one was not detected with metamorphopsia by M-CHARTS either before or after the separation. In subjects with an improved MV, horizontal retinal movement was seen larger than the vertical movement. Similarly, the subjects with an improved MH indicated a larger vertical retinal movement than the horizontal movement. CONCLUSIONS: The direction of patient's metamorphopsia closely associated with the direction of retinal contraction before and after a spontaneous separation of ERM.
Assuntos
Membrana Epirretiniana/fisiopatologia , Descolamento Retiniano/patologia , Transtornos da Visão/fisiopatologia , Adulto , Idoso , Membrana Epirretiniana/complicações , Membrana Epirretiniana/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Descolamento Retiniano/etiologia , Transtornos da Visão/etiologia , Acuidade Visual/fisiologiaRESUMO
A 48-year-old man without underlying disease developed mediastinitis and was treated by mediastinal drainage. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in a culture of the abscess material. He was treated with anti-MRSA antibiotics and the MRSA infection improved. Four weeks after the onset of MRSA infection, he developed rapidly progressive glomerulonephritis (RPGN) with nephrotic syndrome (NS). A renal biopsy showed endocapillary proliferative glomerulonephritis with IgA-predominant glomerular deposition. These clinicopathological findings were consistent with those in glomerulonephritis following MRSA infection (post-MRSA infection glomerulonephritis). The level of serum creatinine increased to 6.3 mg/dl, 7 weeks after the onset of RPGN. At that time, the eradication of MRSA infection was considered. He was given middle-dose steroid therapy. Thereafter, his RPGN with NS improved. MRSA infection did not recur. If the disease activity of post-MRSA infection glomerulonephritis persists after the disappearance of MRSA infection, the application of immunosuppressive therapy with steroids may be useful.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Antibacterianos/uso terapêutico , Glomerulonefrite/tratamento farmacológico , Imidazóis/uso terapêutico , Resistência a Meticilina , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Prednisolona/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Tetrazóis/uso terapêutico , Biópsia , Quimioterapia Combinada , Glomerulonefrite/microbiologia , Humanos , Masculino , Infecções Estafilocócicas/microbiologiaRESUMO
A 63-year-old man with systemic lupus erythematosus developed tubular proteinuria. All subclasses of serum IgG increased, and the largest IgG subclass increase was IgG4. A renal biopsy showed lupus nephritis (Class II) with severe tubulointerstitial nephritis (so-called predominant tubulointerstitial lupus nephritis, an unusual form of lupus nephritis). Immunofluorescence microscopy revealed positive granular staining for IgG, C3 and C1q in the mesangium and peritubular interstitium, and along the tubular basement membranes (TBM). Electron microscopy also showed electron-dense deposits in the mesangium and TBM. Immunophenotyping of interstitial infiltrating cells disclosed a predominance of T cells. CD8-positive cytotoxic T cells infiltrated the peritubular interstitium, and some of these cells infiltrated the tubules. B cell-rich lymphoid follicles were also observed. IgG subclass analyses showed glomerular IgG1, IgG2 and IgG4 deposition, positive staining of IgG4 in the peritubular interstitium and along the TBM, and abundant IgG1-, IgG3- and IgG4-positive plasma cells in the interstitium. The patient responded well to moderate-dose steroid therapy. This is the first report of immunophenotyping of interstitial infiltrates in predominant tubulointerstitial lupus nephritis. The results suggest CD8-positive cytotoxic T cell-mediated tubular injury. Furthermore, immune complexes containing IgG4 might be one of etiologic factors.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoglobulina G/imunologia , Rim/patologia , Nefrite Lúpica/patologia , Nefrite Intersticial/patologia , Biópsia , Linfócitos T CD8-Positivos/patologia , Humanos , Imunoglobulina G/análise , Imuno-Histoquímica , Nefrite Lúpica/imunologia , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/imunologiaRESUMO
We report a unique case of acute cholecystitis due to strangulation of a floating gallbladder by the lesser omentum, which could be detected by abdominal ultrasonography. We believe this case to be the first case of reported literatures in English.
Assuntos
Colecistite Aguda/etiologia , Vesícula Biliar/anormalidades , Adulto , Bromoexina , Colecistite Aguda/diagnóstico por imagem , Colecistografia , Feminino , Humanos , Omento , Anormalidade Torcional , UltrassonografiaRESUMO
The purpose of this study was to determine whether the gamma-aminobutyric acid (GABA) affects the rate of brain protein synthesis in male rats. Two experiments were done on five or three groups of young rats (5 wk) given the diets containing 20% casein administrated 0 mg, 25 mg, 50 mg, 100 mg or 200 mg/100 g body weight GABA dissolved in saline by oral gavage for 1 day (d) (Experiment 1), and given the diets contained 0%, 0.25% or 0.5% GABA added to the 20% casein diet (Experiment 2) for 10 d. The plasma concentration of growth hormone (GH) was the highest in rats administrated 50 mg and 100 mg/100 g body weight GABA. The concentration of serum GABA increased significantly with the supplementation groups. The fractional (Ks) rates of protein synthesis in brain regions, liver and gastrocnemius muscle increased significantly with the 20% casein + 0.25% GABA diet and still more 20% casein + 0.5% GABA compared with the 20% casein diet. In brain regions, liver and gastrocnemius muscle, the RNA activity [g protein synthesized/(g RNA . d)] significantly correlated with the fractional rate of protein synthesis. The RNA concentration (mg RNA/g protein) was not related to the fractional rate of protein synthesis in any organ. Our results suggest that the treatment of GABA to young male rats are likely to increase the concentrations of plasma GH and the rate of protein synthesis in the brain, and that RNA activity is at least partly related to the fractional rate of brain protein synthesis.
Assuntos
Ração Animal , Encéfalo/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Ácido gama-Aminobutírico/administração & dosagem , Envelhecimento , Animais , Peso Corporal , Química Encefálica , Proteínas Alimentares/metabolismo , Hormônio do Crescimento/metabolismo , Masculino , RNA/metabolismo , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
A 69-year-old female with a 3-year history of polycythemia vera (PV) developed nephrotic syndrome. A renal biopsy showed focal and segmental glomerulosclerosis (FSGS). The patient was treated with prednisolone and myelosuppressive agents. Thereafter, parallel improvement of the two conditions was observed. After 4-year treatment, proteinuria disappeared. To our knowledge, there are five reported cases of FSGS associated with PV. Among them, three patients suffered from progressive azotemia. We suggest that steroid therapy with myelosuppressive agents can resolve the renal lesion in patients with PV.
Assuntos
Glomerulosclerose Segmentar e Focal/complicações , Policitemia Vera/complicações , Idoso , Feminino , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Policitemia Vera/patologiaRESUMO
In a rat forced swimming test (FS), we examined the effect of repeated injections of ACTH (adrenocorticotropic hormone) for 14 days on the decreased duration of immobility time produced by imipramine and desipramine. Both imipramine (15 and 30 mg/kg, p.o.) and desipramine (15 and 30 mg/kg, p.o.) significantly decreased the duration of immobility time in the FS. On the other hand, ACTH (100 microg/kg, i.p.) alone did not affect the duration of immobility time in FS. When ACTH (100 microg/kg, i.p.) was injected for 14 days before the 15-min swim session, it counteracted the decreased duration of immobility time induced by both imipramine and desipramine. Thus, ACTH seems to play a key role in decreasing the duration of immobility time of antidepressants in this test.
Assuntos
Hormônio Adrenocorticotrópico/farmacologia , Antidepressivos Tricíclicos/farmacologia , Desipramina/farmacologia , Teste de Esforço/efeitos dos fármacos , Imipramina/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Imobilização/fisiologia , Masculino , Atividade Motora/fisiologia , Ratos , Ratos Wistar , Natação/fisiologia , Fatores de TempoRESUMO
Chronic administration of antidepressants has been shown to reduce the number of escape failures in the rat learned helplessness test (LH). In the present study we investigated the role of D1, D2 and D3 receptors in mediating this effect. In our first series of experiments, we demonstrated that SKF38393, D1 receptor agonist, in a dose of 2.5 mg/kg (i.p.) and quinpirole, D2 receptor agonist in a dose of 0.5 mg/kg (i.p.), significantly decreased the number of escape failures in LH, and these were reversed by SCH23390 (0.015 mg/kg), D1 receptor antagonist, and by sulpiride (25 mg/kg), D2 receptor antagonist, respectively. In contrast, 7-OH-DPAT, a D3 receptor agonist, in a dose of 10 mg/kg (i.p.) did not affect the number of escape failures in LH. In a second series of experiments, we showed that eight days of repeated treatment with imipramine (10 mg/kg, p.o.), fluvoxamine (1.25 mg/kg, p.o.) and tranylcypromine (1.25 mg/kg, p.o.) significantly decreased the number of escape failures in LH. The decrease in escape failures seen with use of imipramine and tranylcypromine was reversed by sulpiride in LH, but not by SCH23390. On the other hand, the effect of fluvoxamine was reversed by both SCH23390 and sulpiride. These findings indicate that stimulation of D1 and D2 receptors decreased the number of escape failures in LH, respectively. Thus, D2 and/or D1 receptors are probably involved in the decreased number of escape failures in case of repeated treatment with antidepressants in LH.
Assuntos
Antidepressivos/farmacologia , Reação de Fuga/efeitos dos fármacos , Fluvoxamina/farmacologia , Desamparo Aprendido , Imipramina/farmacologia , Receptores Dopaminérgicos/efeitos dos fármacos , Tranilcipromina/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Benzazepinas/farmacologia , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Reação de Fuga/fisiologia , Masculino , Quimpirol/farmacologia , Ratos , Ratos Wistar , Sulpirida/farmacologia , Tetra-Hidronaftalenos/farmacologiaRESUMO
This study was designed to evaluate the antidepressant activity of various antidepressants using the learned helplessness test (LH) or the forced swimming test (FS) in rats. Repeated treatment of the tricyclic antidepressants imipramine (10 mg/kg, p.o.), clomipramine (0.625 mg/kg, p.o.), amitriptyline (10 mg/kg, p.o.) and amoxapine (20 mg/kg, p.o.) reduced the number of escape failures in the LH group, respectively. Repeated treatment of an atypical antidepressant, mianserin (2.5 and 5 mg/kg, p.o.), and one of the selective serotonin reuptake inhibitors (SSRI), fluvoxamine (1.25 mg/kg, p.o.), also reduced the number of escape failures in the LH group. In the FS, repeated treatment of imipramine (5, 10 mg/kg, p.o.), amitriptyline (5, 10 mg/kg, p.o.) and mianserin (10 mg/kg) significantly decreased the duration of immobility time. On the other hand, repeated treatment of amoxapine (5-20 mg/kg), clomipramine (0.1325-1.25 mg/kg, p.o.) and fluvoxamine (0.3125-1.25 mg/kg, p.o.) failed to decrease the duration of immobility time in the FS group. In conclusion, these results suggest that the LH group is sensitive to agents with a variety of antidepressant properties compared to the FS group in rats.
Assuntos
Depressão/fisiopatologia , Desamparo Aprendido , Atividade Motora/fisiologia , Amoxapina/farmacologia , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Clomipramina/farmacologia , Depressão/prevenção & controle , Depressão/psicologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fluvoxamina/farmacologia , Imipramina/farmacologia , Masculino , Mianserina/farmacologia , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , NataçãoRESUMO
Although many antipsychotics have affinities for sigma receptors, the transportation pathway of exogenous sigma(1) receptor ligands to intracellular type-1 sigma receptors are not fully understood. In this study, sigma(1) receptor ligand uptakes were studied using primary cultured neuronal cells. [(3)H](+)-pentazocine and [(3)H](R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377), used as a selective sigma(1) receptor ligands, were taken up in a time-, energy- and temperature-dependent manner, suggesting that active transport mechanisms were involved in their uptakes. sigma(1) receptor ligands taken up into primary cultured neuronal cells were not restricted to agonists, but also concerned antagonists. The uptakes of these ligands were mainly Na(+)-independent. Kinetic analysis of [(3)H](+)-pentazocine and [(3)H]MS-377 uptake showed K(m) values (microM) of 0.27 and 0.32, and V(max) values (pmol/mg protein/min) of 17.4 and 9.4, respectively. Although both ligands were incorporated, the pharmacological properties of these two ligands were different. Uptake of [(3)H](+)-pentazocine was inhibited in the range 0.4-7.1 microM by all the sigma(1) receptor ligands used, including N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a selective sigma(1) receptor ligand. In contrast, the inhibition of [(3)H]MS-377 uptake was potently inhibited by haloperidol, characterized by supersensitivity (IC(50), approximately 2 nM) and was inhibited by NE-100 with low sensitivity (IC(50), 4.5 microM). Moreover, kinetic analysis revealed that NE-100 inhibited [(3)H]MS-377 uptake in a noncompetitive manner, suggesting that NE-100 acted at a site different from the uptake sites of [(3)H]MS-377. These findings suggest that there are at least two uptake pathways for sigma(1) receptor ligands in primary cultured neuronal cells (i.e. a haloperidol-sensitive pathway and another, unclear, pathway). In addition, pretreatment of cells with a calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7), a myosin light chain kinase inhibitor, 1-(5-chloronaphthalene-1-sulfonyl)homopiperazine (ML-9), or microsomal Ca(2+)-ATPase inhibitors resulted in a reduction of the amount of sigma receptor ligand uptake. These findings suggest that the Ca(2+) pump on the endoplasmic reticulum and/or calmodulin-related events might be involved in the regulation of the uptake of sigma receptor ligands into primary neuronal cells.
Assuntos
Neurônios/metabolismo , Pentazocina/farmacocinética , Piperazinas/farmacocinética , Pirrolidinas/farmacocinética , Receptores sigma/metabolismo , Tartaratos , Animais , Anisóis/farmacocinética , Arsenicais/farmacologia , Transporte Biológico/efeitos dos fármacos , Cálcio/metabolismo , Cálcio/farmacologia , ATPases Transportadoras de Cálcio/antagonistas & inibidores , Calmodulina/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Haloperidol/farmacocinética , Hidroquinonas/farmacologia , Cinética , Ligantes , Neurônios/citologia , Neurônios/efeitos dos fármacos , Ouabaína/farmacologia , Propilaminas/farmacocinética , Ratos , Sódio/farmacologia , Sulfonamidas/farmacologia , Tapsigargina/farmacologia , Fatores de Tempo , Trítio , Receptor Sigma-1RESUMO
Neuropharmacological profiles of 5-(2-[4-(6-fluoro-1H-indole-3-yl) piperidine-1-yl] ethyl)-4-(4-fluorophenyl) thiazole-2-carboxylic acid amide (NRA0562) in rats were examined using electrophysiological and immunohistochemical methods. The firing rates of the substantia nigra pars compacta (A9) and the ventral tegmental area (A10) dopamine neurons were inhibited by methamphetamine (1 mg/kg, i.v.). NRA0562 dose-dependently reversed the inhibitory effects of methamphetamine on A9 and on A10 dopamine neurons. NRA0562 was more potent to reverse the inhibitory effects of methamphetamine on A10 (ED(50)=0.3 mg/kg) than on A9 (ED(50)=0.9 mg/kg) dopamine neurons. NRA0562 produced significant increases in Fos-like immunoreactivity in both the nucleus accumbens and the dorsolateral striatum. The difference between the number of Fos-like immunoreactivity produced by NRA0562 in the nucleus accumbens vs. dorsolateral striatum, referred to as the atypical index, was positive. Similar results could be observed with risperidone, an atypical antipsychotic. These results suggest that NRA0562 may have the atypical antipsychotic activities seen with risperidone, but without the liability of motor side effects typical of classical antipsychotics.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Antipsicóticos/farmacologia , Piperidinas/farmacologia , Tiazóis/farmacologia , Animais , Corpo Estriado/química , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Imuno-Histoquímica , Masculino , Metanfetamina/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Risperidona/farmacologiaRESUMO
Recently, various non-peptide corticotropin-releasing factor(1) (CRF(1)) receptor antagonists have been reported. Structure-affinity relationships (SARs) of non-peptide CRF(1) antagonists suggest that such antagonists can be constructed of three units: a hydrophobic unit (Up-Area), a proton accepting unit (Central-Area), and an aromatic unit (Down-Area). We previously presented 4-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives including potent CRF receptor ligands 1a and 1b and proposed that the 4-aryl-1,2,3,6-tetrahydropyridino moiety might be useful as a substituent in the Up-Area. Our interest shifted to 5-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives 2, among which compound 2m (CRA0165) had highest affinity for CRF(1) receptors (IC(50)=11nM). We report here the design, synthesis and SARs of derivatives 2.
Assuntos
Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Desenho de Fármacos , Lobo Frontal/metabolismo , Técnicas In Vitro , Concentração Inibidora 50 , Ligantes , Conformação Molecular , Estrutura Molecular , Miocárdio/metabolismo , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Piridinas/síntese química , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Relação Estrutura-AtividadeRESUMO
Structure-affinity relationships (SARs) of non-peptide CRF(1) antagonists suggest that such antagonists can be constructed of three units: a hydrophobic unit (Up-Area), a proton accepting unit (Central-Area), and an aromatic unit (Down-Area). Recently, various non-peptide corticotropin-releasing factor(1) (CRF(1)) receptor antagonists obtained by modification of the Central-Area have been reported. In contrast, we modified the Up-Area and presented 4- or 5-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives including potent CRF receptor ligands 1a-c, and proposed that the 4- or 5-aryl-1,2,3,6-tetrahydropyridino moiety might be useful as a substituent in the Up-Area. Our interest shifted to the chemical modification in which the pyrimidine ring of 1a-c was replaced by other heterocycles, purine ring of 2, 3H-1,2,3-triazolo[4,5-d]pyrimidine ring of 3, purin-8-one ring of 4 and 7H-pyrrolo[2,3-d]pyrimidine ring of 5. Among them, 5-aryl-1,2,3,6-tetrahydropyridinopurine compound 6j (CRA0186) had the highest affinity for CRF(1) receptors (IC(50)=20nM). We report here the synthesis and SARs of derivatives 6-9.
Assuntos
Purinas/síntese química , Purinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Marcadores de Afinidade , Animais , Desenho de Fármacos , Lobo Frontal/metabolismo , Técnicas In Vitro , Concentração Inibidora 50 , Miocárdio/metabolismo , Ligação Proteica/fisiologia , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Relação Estrutura-AtividadeRESUMO
The effects of virol A (VA), a toxic component of Cicuta virosa (water hemlock), on the GABA-induced Cl(-) current (I(GABA)) in acutely dissociated rat hippocampal CA1 neurons were investigated using whole-cell patch-clamp techniques. VA reversibly reduced I(GABA) and the muscimol (Mus)-induced current (I(Mus)) in a concentration-dependent manner. The IC(50) values for VA against I(GABA) and I(Mus) were 9.6x10(-7) and 9.8x10(-7) M, respectively. VA shifted the EC(50) value of I(GABA) from 6.5x10(-6) to 2.1x10(-5) M, whereas it had no effect on the maximum response, thereby suggesting that VA inhibited I(GABA) in a competitive manner. VA had no apparent effect on current-voltage relationships for I(GABA), thus indicating the lack of voltage-dependency. On the other hand, application of VA (10(-6) M) did not additionally reduce the I(GABA) suppressed by >10(-5) M picrotoxin. VA but not bicuculline accelerated the decay phase of I(GABA), as was seen with picrotoxin. Moreover, pre-application of 10(-5) M VA reduced I(GABA). VA did not inhibit that induced by glycine (10(-4) M). These results indicate that VA inhibits I(GABA) by acting both on the GABA agonist site and on the Cl(-) channel of the GABA(A) receptor-channel complex. VA is a structurally novel type of compound that selectively inhibits the GABA(A) receptor-Cl(-) channel complexes in mammalian central nervous system neurons.
Assuntos
Apiaceae/química , Canais de Cloreto/antagonistas & inibidores , Álcoois Graxos/farmacologia , Antagonistas GABAérgicos/farmacologia , Hipocampo/metabolismo , Neurônios/metabolismo , Plantas Tóxicas/química , Animais , Ligação Competitiva/efeitos dos fármacos , Eletrofisiologia , Álcoois Graxos/metabolismo , Antagonistas GABAérgicos/metabolismo , Glicina/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Ácido gama-Aminobutírico/farmacologiaRESUMO
We have recently isolated a cDNA encoding a short isoform of the corticotropin-releasing factor (CRF) receptor subtype, referred to as CRF(2)alpha-tr, from the rat amygdala. The present study determined the localization of the truncated receptor mRNA in the rat brain by in situ hybridization histochemistry. The results showed significant levels of hybridization in the lateral septum, central nucleus of the amygdala, cortico-amygdaloid nucleus, ventromedial nucleus of the hypothalamus (VMH), and frontal cortex. In the physiological study, antidepressive drugs increased the expression of CRF(2)alpha-tr mRNA and the total binding activity to CRF in the rat amygdala. These findings suggest that CRF(2)alpha-tr may regulate endogeneous CRF release in the amygdala.
Assuntos
Encéfalo/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Sequência de Aminoácidos , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Antidepressivos Tricíclicos/farmacologia , Sequência de Bases , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Hormônio Liberador da Corticotropina/metabolismo , Desipramina/farmacologia , Humanos , Imipramina/farmacologia , Hibridização In Situ , Dados de Sequência Molecular , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/genética , Ratos , Receptores de Hormônio Liberador da Corticotropina/química , Receptores de Hormônio Liberador da Corticotropina/genética , Deleção de Sequência/genéticaRESUMO
(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4, LY354740), a highly selective and orally active group II metabotropic glutamate receptor (mGluR) agonist, has increased interest in the study of group II mGluRs. Our interest focused on a conformationally constrained form of compound 4, because it appeared that the rigid form resulted in not only selectivity for group II mGluR but was orally active. Therefore, we introduced a fluorine atom to compound 4, based on the molecular size (close resemblance to hydrogen atom) and electronegativity (effects on the electron distribution in the molecule) of this atom and carbon-fluorine bond energy. Compound (+)-7 (MGS0008), the best compound among 3-fluoro derivatives 7-10, retained the agonist activity of compound 4 for mGluR2 and mGluR3 ((+)-7: EC(50) = 29.4 +/- 3.3 nM and 45.4 +/- 8.4 nM for mGluR2 and mGluR3, respectively; 4: EC(50) = 18.3 +/- 1.6 nM and 62.8 +/- 12 nM for mGluR2 and mGluR3, respectively) and increased the oral activity of compound 4 ((+)-7: ED(50) = 5.1 mg/kg and 0.26 mg/kg for phencyclidine (PCP)-induced hyperactivity and PCP-induced head-weaving behavior, respectively; 4: ED(50) = >100 mg/kg and 3.0 mg/kg for PCP-induced hyperactivity and PCP-induced head-weaving behavior, respectively). In addition, a compound [(3)H]-(+)-7 binding study using mGluR2 or 3 expressed in CHO cells was successful ((+)-7: K(i) = 47.7 +/- 17 nM and 65.9 +/- 7.1 nM for mGluR2 and mGluR3, respectively; 4: K(i) = 23.4 +/- 7.1 nM and 53.5 +/- 13 nM for mGluR2 and mGluR3, respectively). On the basis of a successful result of compound 7, we focused on the introduction of a fluorine atom on the C6 position of compound 4. (1R,2S,5R, 6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ((-)-11) exhibited a high degree of agonist activity for group II mGluRs equal to that of compound 4 or 7 ((-)-11: K(i) = 16.6 +/- 5.6 and 80.9 +/- 31 nM for mGluR2 and mGluR3, respectively). Our interest shifted to modification on CH(2) at C4 position of compound 11, since replacement of the CH(2) group with either an oxygen atom or sulfur atom yielded compound 5 or 6, resulting in increased agonist activity. We selected a carbonyl group instead of CH(2) at the C4 position of compound 11. The carbonyl group might slightly change the relative conformation of three functional groups, the amino group and two carboxylic acids, which have important roles in mediating the interaction between group II mGluRs and their ligand, compared with the CH(2) group of 4, oxygen atom of 5, and sulfur atom of 6. (1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1. 0]hexane-2,6-dicarboxylic acid monohydrate ((+)-14, MGS0028) exhibited a remarkably high degree of agonist activity for mGluR2 (K(i) = 0.570 +/- 0.10 nM) and mGluR3 (K(i) = 2.07 +/- 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (K(i) = >100 000 nM). Furthermore, compound (+)-14 strongly inhibited phencyclidine (PCP)-induced head-weaving behavior (ED(50) = 0.090 microg/kg) and hyperactivity (ED(50) = 0.30 mg/kg) in rats. Thus, (+)-7 and (+)-14 are potent, selective, and orally active group II mGluR agonists and might be useful not only for exploring the functions of mGluRs but in the treatment of schizophrenia.
Assuntos
Antipsicóticos/síntese química , Compostos Bicíclicos com Pontes/síntese química , Ácidos Dicarboxílicos/síntese química , Agonistas de Aminoácidos Excitatórios/síntese química , Receptores de Glutamato Metabotrópico/agonistas , Administração Oral , Animais , Antipsicóticos/química , Antipsicóticos/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Células CHO , Cálcio/metabolismo , Cricetinae , Cristalografia por Raios X , AMP Cíclico/biossíntese , Ácidos Dicarboxílicos/química , Ácidos Dicarboxílicos/farmacologia , Agonistas de Aminoácidos Excitatórios/química , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Inositol 1,4,5-Trifosfato/biossíntese , Ensaio Radioligante , Ratos , Esquizofrenia/tratamento farmacológico , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The main biological role of angiotensin II type 2 receptor (AT2) has not been established. We made use of targeted disruption of the mouse AT2 gene to examine the functional role of the AT2 receptor in the central nervous system (CNS). We have previously shown that AT2-deficient mice displayed anxiety-like behavior in comparisons with wild-type mice. In the present study, we analyzed the pain threshold, learning behavior and brain edema formation using the tail-flick test, the tail-pinch test, the passive avoidance task and cold injury, respectively. In the passive avoidance task and cold injury, no differences were found between wild-type mice and AT2-deficient mice. In contrast, the pain threshold was significantly lower in AT2-deficient mice, compared with findings in wild-type mice. The immunohistochemical distribution of beta-endorphin in the brain was analyzed quantitatively in AT2-deficient mice and wild-type mice, using microphotometry. The fluorescence intensity of beta-endorphin in the arcuate nucleus of the medial basal hypothalamus (ARC) was significantly lower in AT2-deficient mice, compared with findings in wild-type mice. We found that the AT2 receptor does not influence learning behavior and brain edema formation. As AT2-deficient mice have increased sensitivity to pain and decreased levels of brain beta-endorphin, AT2 receptors may perhaps mediate regulation of the pain threshold.
Assuntos
Aprendizagem da Esquiva/fisiologia , Edema Encefálico/metabolismo , Limiar da Dor/fisiologia , Receptores de Angiotensina/fisiologia , Animais , Encéfalo/metabolismo , Edema Encefálico/etiologia , Edema Encefálico/patologia , Temperatura Baixa , Fluoresceína-5-Isotiocianato , Heterozigoto , Masculino , Camundongos , Camundongos Knockout , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/deficiência , Cauda , beta-Endorfina/metabolismoRESUMO
As immediate-early genes (IEGs) are thought to play a critical role in mediating stimulus-induced neural plasticity, IEG response induced by methamphetamine (METH) has been characterized to define the changes in gene expression that may underlie its long-lasting behavioral effects. Although activation of several transcription factor IEGs has been described, little is known about effector IEGs. Here, we have examined whether METH administration affects expression of an effector IEG arc (activity-regulated, cytoskeleton-associated) that encodes a protein with homology to spectrin. Using in situ hybridization, we observed that METH caused a rapid and transient dose-dependent increase in arc mRNA level in the striatum and cortex that was abolished by pretreatment with the specific dopamine D1 receptor antagonist SCH-23390 but not by an atypical neuroleptic clozapine. METH induced arc mRNA in layers IV and VI of the cortex which dopamine receptor are localized to. These results suggest that D1 receptors are coupled to activation of arc gene, which may be involved in functional or structural alterations underlying neural plasticity triggered by METH.