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1.
Respir Physiol Neurobiol ; 315: 104115, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37460080

RESUMO

Bicuculline and saclofen were microinjected into the rostral (rNTS) and caudal nucleus of the solitary tract (cNTS) in 17 anesthetized cats. Electromyograms (EMGs) of the diaphragm (DIA) and abdominal muscles (ABD), esophageal pressures (EP), and blood pressure were recorded and analyzed. Bilateral microinjections of 1 mM bicuculline in the rNTS significantly reduced the number of coughs (CN), amplitudes of DIA and ABD EMG, inspiratory and expiratory EP, and prolonged the duration of the cough expiratory phase (CTE) as well as the total cough cycle duration (CTtot). Bilateral microinjections of 2 mM saclofen reduced only cough expiratory efforts. Bilateral microinjection of bicuculline in the cNTS significantly reduced CN and amplitudes of ABD EMG and elongated CTE and CTtot. Bilateral microinjections of saclofen in cNTS had no significant effect on analyzed cough parameters. Our results confirm a different GABAergic inhibitory system in the rNTS and cNTS acting on mechanically induced cough in cats.


Assuntos
Tosse , Núcleo Solitário , Gatos , Animais , Tosse/tratamento farmacológico , Bicuculina/farmacologia , Antagonistas de Receptores de GABA-B/farmacologia , Antagonistas de Receptores de GABA-B/uso terapêutico , Baclofeno/farmacologia , Microinjeções
2.
Epilepsy Res ; 174: 106644, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33932748

RESUMO

INTRODUCTION: DL-3-hydroxy-3-phenylpentanamide (HEPP) and DL-3-hydroxy-3-(4'chlorophenyl)-pentanamide (Cl-HEPP) are phenyl-alcohol-amides that are metabotropic GABAB receptor (MGBR) antagonists and protective against absence seizures. This study aims to further characterize the anticonvulsant profile of these drugs. METHODS: HEPP and Cl-HEPP were evaluated in various standardized acute seizure and toxic tests in female Swiss-OF1 mice. RESULTS: Toxicities of HEPP and Cl-HEPP were limited; doses up to 30 mg/kg did not result in hypothermia, reduced spontaneous locomotor activity, or failure of the rotarod test, with doses >15 mg/kg potentiating pentobarbital-induced sleep. In maximal electroshock-induced seizures, 20 mg/kg Cl-HEPP protected 100 % of mice; lower doses shortened post-ictal recovery. Seizure protection occurred against subcutaneous pentylenetetrazole and picrotoxin, being limited against N-methyl-d-aspartate. In bicuculline test, clonic or fatal tonic seizures were decreased, onset delayed, and recovery improved; ED50 values (dose protecting 50 % of the animals) were 37.5 and 25 mg/kg for HEPP and Cl-HEPP, respectively. In magnesium deficiency-dependent audiogenic seizures (MDDAS), ED50 values were 3 and 8 mg/kg for Cl-HEPP and HEPP, respectively. The components of MDDAS (latency, wild running, seizure, and recovery phases) in unprotected animals were only minimally affected by near ED50 doses of Cl-HEPP and HEPP. DISCUSSION: HEPP and, to a greater extent, Cl-HEPP provide anti-seizure protections in several acute seizure tests in mice at nontoxic doses. These results are consistent with the action of these drugs on diverse molecular targets directly resulting from their MGBR antagonistic properties. However, other mechanisms might occur possibly for the protection given in the MES test. Finally, a similarity in the modulation of MDDAS components between the two phenyl alcohol amides and ethosuximide could also be based on the MGBR antagonistic properties of the former, given the recently re-evaluated therapeutic relevant targets of the latter.


Assuntos
Anticonvulsivantes , Convulsões , Animais , Anticonvulsivantes/uso terapêutico , Relação Dose-Resposta a Droga , Eletrochoque/efeitos adversos , Feminino , Antagonistas de Receptores de GABA-B/uso terapêutico , Camundongos , Pentilenotetrazol/toxicidade , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Ácido gama-Aminobutírico
3.
Molecules ; 25(13)2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32646032

RESUMO

The γ-aminobutyric acid (GABA) type B receptor (GABAB-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABAA receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). In recent decades, the receptor has been extensively studied with the intention being to understand pathophysiological roles, structural mechanisms and develop drugs. The dysfunction of the receptor is linked to a broad variety of disorders, including anxiety, depression, alcohol addiction, memory and cancer. Despite extensive efforts, few compounds are known to target the receptor, and only the agonist baclofen is approved for clinical use. The receptor is a mandatory heterodimer of the GABAB1 and GABAB2 subunits, and each subunit is composed of an extracellular Venus Flytrap domain (VFT) and a transmembrane domain of seven α-helices (7TM domain). In this review, we briefly present the existing knowledge about the receptor structure, activation and compounds targeting the receptor, emphasizing the role of the receptor in previous and future drug design and discovery efforts.


Assuntos
Baclofeno/química , Desenvolvimento de Medicamentos , Antagonistas de Receptores de GABA-B/química , Modelos Moleculares , Receptores de GABA-B/química , Baclofeno/uso terapêutico , Sítios de Ligação , Antagonistas de Receptores de GABA-B/uso terapêutico , Humanos , Ligantes , Conformação Proteica em alfa-Hélice , Receptores de GABA-B/metabolismo
4.
Epilepsy Res ; 149: 17-20, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30419552

RESUMO

Possible proconvulsant action of GABAB receptor antagonist CGP46381 was studied 3 and 13 days after status epilepticus elicited in 12-day-old rats. GABAA-dependent activity was tested by pentylenetetrazol administration and found different in 15-day-old rats after status epiolepticus but not in the older group. The interaction of the two GABAergic systems should be studied in detail.


Assuntos
Antagonistas de Receptores de GABA-B/uso terapêutico , Ácidos Fosfínicos/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Fatores Etários , Animais , Animais Recém-Nascidos , Convulsivantes/uso terapêutico , Modelos Animais de Doenças , Masculino , Pentilenotetrazol/toxicidade , Pilocarpina/toxicidade , Ratos , Ratos Wistar , Estado Epiléptico/induzido quimicamente
5.
Curr Opin Pharmacol ; 35: 101-104, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28807483

RESUMO

Evidence for the potential utility of GABAB antagonists has been assembled from a variety of sources, including clinical experience with the GABAB agonist baclofen, murine genetic GABAB knock-outs, rodent studies of GABAB receptor expression and function following treatment with antidepressant therapies, animal models of depression, and some functional and post mortem data from human subjects. Definitive testing of GABAB antagonists in depression, however, still awaits the development of potent, selective and brain-penetrant compounds for human testing.


Assuntos
Depressão/tratamento farmacológico , Antagonistas de Receptores de GABA-B/uso terapêutico , Animais , Depressão/metabolismo , Humanos , Receptores de GABA-B/metabolismo , Resultado do Tratamento
6.
J Emerg Med ; 52(4): e99-e100, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27789113

RESUMO

BACKGROUND: Oral baclofen toxicity is extremely rare, but can affect patients with renal disease due to the drug's predominant renal clearance of approximately 69-85%. Patients with severely impaired renal function typically develop symptoms soon after initiating baclofen therapy, even at relatively low doses. CASE REPORT: A 69-year-old woman with a history of hemodialysis-dependent end-stage renal disease presented to the Emergency Department with encephalopathy, ataxia, and dystonia after the addition of a recent baclofen prescription for back pain (10 mg twice daily). She had been taking baclofen as prescribed for approximately 1 week when, the day prior to admission, she had increased her dose to a total of 40 mg. Diagnostic studies demonstrated the patient had chronic, end-stage renal disease and a supratherapeutic concentration of baclofen. Signs and symptoms resolved with hemodialysis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is of critical importance for emergency physicians to appreciate impaired baclofen clearance in those with underlying renal disease to obviate the potential for significant drug toxicity.


Assuntos
Baclofeno/toxicidade , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Idoso , Ataxia/etiologia , Dor nas Costas/tratamento farmacológico , Baclofeno/uso terapêutico , Encefalopatias/etiologia , Confusão/etiologia , Distonia/etiologia , Serviço Hospitalar de Emergência/organização & administração , Feminino , Antagonistas de Receptores de GABA-B/farmacologia , Antagonistas de Receptores de GABA-B/uso terapêutico , Humanos , Rigidez Muscular/etiologia , Parassimpatolíticos/farmacologia , Parassimpatolíticos/uso terapêutico , Diálise Renal/métodos
7.
Neural Plast ; 2015: 924728, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26451259

RESUMO

Chronic compression of dorsal root ganglion (CCD) results in neuropathic pain. We investigated the role of spinal GABA in CCD-induced pain using rats with unilateral CCD. A stereological analysis revealed that the proportion of GABA-immunoreactive neurons to total neurons at L4/5 laminae I-III on the injured side decreased in the early phase of CCD (post-CCD week 1) and then returned to the sham-control level in the late phase (post-CCD week 18). In the early phase, the rats showed an increase in both mechanical sensitivity of the hind paw and spinal WDR neuronal excitability on the injured side, and such increase was suppressed by spinally applied muscimol (GABA-A agonist, 5 nmol) and baclofen (GABA-B agonist, 25 nmol), indicating the reduced spinal GABAergic inhibition involved. In the late phase, the CCD-induced increase in mechanical sensitivity and neuronal excitability returned to pre-CCD levels, and such recovered responses were enhanced by spinally applied bicuculline (GABA-A antagonist, 15 nmol) and CGP52432 (GABA-B antagonist, 15 nmol), indicating the regained spinal GABAergic inhibition involved. In conclusion, the alteration of spinal GABAergic inhibition following CCD and leading to a gradual reduction over time of CCD-induced mechanical hypersensitivity is most likely due to changes in GABA content in spinal GABA neurons.


Assuntos
Antagonistas GABAérgicos/uso terapêutico , Gânglios Espinais/fisiopatologia , Hiperalgesia/tratamento farmacológico , Compressão da Medula Espinal/tratamento farmacológico , Medula Espinal/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzilaminas/uso terapêutico , Bicuculina/uso terapêutico , Antagonistas de Receptores de GABA-A/uso terapêutico , Antagonistas de Receptores de GABA-B/uso terapêutico , Membro Posterior/inervação , Membro Posterior/patologia , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Masculino , Medição da Dor/efeitos dos fármacos , Ácidos Fosfínicos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Compressão da Medula Espinal/etiologia , Compressão da Medula Espinal/fisiopatologia , Ácido gama-Aminobutírico/metabolismo
8.
Biomed Res Int ; 2015: 207312, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25649745

RESUMO

The aim was to investigate the effects of the GABAB receptor antagonist, CGP46381, on form-deprivation myopia (FDM) in guinea pigs. Twenty-four guinea pigs had monocular visual deprivation induced using a diffuser for 11 days (day 14 to 25). The deprived eyes were treated with daily subconjunctival injections (100 µl) of either 2% CGP46381, 0.2% CGP46381, or saline or received no injection. The fellow eyes were left untreated. Another six animals received no treatment. At the start and end of the treatment period, ocular refractions were measured using retinoscopy and vitreous chamber depth (VCD) and axial length (AL) using A-scan ultrasound. All of the deprived eyes developed relative myopia (treated versus untreated eyes, P < 0.05). The amount of myopia was significantly affected by the drug treatment (one-way ANOVA, P < 0.0001). The highest dose tested, 2% CGP46381, significantly inhibited myopia development compared to saline (2% CGP46381: -1.08 ± 0.40 D, saline: -4.33 ± 0.67 D, P < 0.01). The majority of these effects were due to less AL (2% CGP46381: 0.03 ± 0.01 mm, saline: 0.13 ± 0.02 mm, P < 0.01) and VCD (2% CGP46381: 0.02 ± 0.01 mm, saline: 0.08 ± 0.01 mm, P < 0.01) elongation. The lower dose tested, 0.2% CGP46381, did not significantly inhibit FDM (P > 0.05). Subconjunctival injections of CGP46381 inhibit FDM development in guinea pigs in a dose-dependent manner.


Assuntos
Percepção de Forma/efeitos dos fármacos , Antagonistas de Receptores de GABA-B/farmacologia , Antagonistas de Receptores de GABA-B/uso terapêutico , Miopia/tratamento farmacológico , Miopia/fisiopatologia , Ácidos Fosfínicos/uso terapêutico , Receptores de GABA-B/metabolismo , Animais , Comprimento Axial do Olho/efeitos dos fármacos , Comprimento Axial do Olho/fisiopatologia , Cobaias , Ácidos Fosfínicos/farmacologia , Refração Ocular/efeitos dos fármacos , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/fisiopatologia
9.
Neuropharmacology ; 81: 31-41, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24486711

RESUMO

Previous studies from our laboratory showed that anxiety-related responses induced by nicotine (NIC), measured by the elevated plus maze, were abolished by 2-OH-saclofen (GABAB receptor antagonist) (1 mg/kg; ip) or the lack of GABAB receptors (GABAB1 knockout mice). Based on these behavioral data, the aims of the present study were: 1) to evaluate the possible neurochemical changes (dopamine, DA, serotonin, 5-HT, 3,4-dihydroxyphenylacetic acid, DOPAC, 5-hydroxyindoleacetic acid, 5-HIAA and noradrenaline, NA) and the c-Fos expression induced by the anxiolytic (0.05 mg/kg) or anxiogenic (0.8 mg/kg) doses of NIC in the dorsal raphe (DRN) and lateral septal (LSN) nucleus; 2) to study the possible involvement of GABAB receptors on the neurochemical alterations and c-Fos expression induced by NIC (0.05 and 0.8 mg/kg), using both pharmacological (2-OH-saclofen) and genetic (mice GABAB1 knockout) approaches. The results revealed that in wild-type mice, NIC (0.05 mg/kg) increased the concentration of 5-HT and 5-HIAA (p < 0.05) in the DRN, and NIC (0.8 mg/kg) increased the levels of 5-HT (p < 0.01) and NA (p < 0.05) in the LSN. Additionally, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors abolished these neurochemical changes induced by NIC (p < 0.01, p < 0.05, respectively). On the other hand, NIC 0.05 and 0.8 mg/kg increased (p < 0.01) the c-Fos expression in the DRN and LSN respectively, in wild-type mice. In addition, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors prevented the c-Fos alterations induced by NIC (p < 0.01). In summary, both approaches show that GABAB receptors would participate in the modulation of anxiolytic- and anxiogenic-like responses induced by NIC, suggesting the potential therapeutic target of these receptors for the tobacco addiction treatment.


Assuntos
Ansiedade/tratamento farmacológico , Baclofeno/análogos & derivados , Antagonistas de Receptores de GABA-B/uso terapêutico , Neurotransmissores/metabolismo , Receptores de GABA-B/genética , Receptores de GABA-B/metabolismo , Análise de Variância , Animais , Ansiedade/induzido quimicamente , Ansiedade/genética , Baclofeno/uso terapêutico , Modelos Animais de Doenças , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Proteínas Proto-Oncogênicas c-fos/metabolismo , Núcleos Septais/efeitos dos fármacos , Núcleos Septais/metabolismo
10.
Dig Dis Sci ; 58(7): 1909-15, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23508979

RESUMO

BACKGROUND: It was well known that angiotension II can inhibit hepatic stellate cell activation. The GABAB receptor was upregulated when the hepatic stellate cell line was stimulated by angiotension II in our previous study. But the role of the GABAB receptor in liver fibrosis has never been reported. AIM: In the present study, we investigated the effects of this receptor on carbon tetrachloride-induced liver fibrosis in rats. METHODS: The rats were divided into four groups including GABAB receptor agonist, antangonist, model and control group. α-smooth muscle actin (α-SMA) and GABAB receptor expression levels were detected by immunohistochemistry and real-time polymerase chain reaction. Liver function tests were performed once blood samples was taken; Western blot analysis was used to detect protein expression level of α-SMA and TGF-ß1. RESULTS: We found baclofen ameliorated the CCl4-induced rats's liver fibrosis. The highest liver enzymes and α-SMA protein levels were found in the CGP35348 group. CONCLUSION: The GABAB receptor may have a protective role in the liver.


Assuntos
Cirrose Hepática/metabolismo , Fígado/metabolismo , Receptores de GABA-B/metabolismo , Actinas/metabolismo , Animais , Baclofeno/farmacologia , Baclofeno/uso terapêutico , Biomarcadores/metabolismo , Western Blotting , Tetracloreto de Carbono , Esquema de Medicação , Agonistas dos Receptores de GABA-B/farmacologia , Agonistas dos Receptores de GABA-B/uso terapêutico , Antagonistas de Receptores de GABA-B/farmacologia , Antagonistas de Receptores de GABA-B/uso terapêutico , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Testes de Função Hepática , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta1/metabolismo
11.
J Inherit Metab Dis ; 36(3): 401-10, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22739941

RESUMO

This review summarizes a presentation made at the retirement Symposium of Prof. Dr. Cornelis Jakobs in November of 2011, highlighting the progress toward clinical trials in succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder first recognized in 1981. Active and potential clinical interventions, including vigabatrin, L-cycloserine, the GHB receptor antagonist NCS-382, and the ketogenic diet, are discussed. Several biomarkers to gauge clinical efficacy have been identified, including cerebrospinal fluid metabolites, neuropsychiatric testing, MRI, EEG, and measures of GABAergic function including (11 C)flumazenil positron emission tomography (PET) and transcranial magnetic stimulation (TMS). Thirty years after its discovery, encompassing extensive studies in both patients and the corresponding murine model, we are now running an open-label trial of taurine intervention, and are poised to undertake a phase II trial of the GABAB receptor antagonist SGS742.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Succinato-Semialdeído Desidrogenase/deficiência , Ácido gama-Aminobutírico/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/história , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Animais , Ensaios Clínicos como Assunto , Deficiências do Desenvolvimento , Antagonistas de Receptores de GABA-B/uso terapêutico , História do Século XX , História do Século XXI , Humanos , Camundongos , Modelos Biológicos , Succinato-Semialdeído Desidrogenase/história , Succinato-Semialdeído Desidrogenase/metabolismo , Fatores de Tempo , Ácido gama-Aminobutírico/deficiência
12.
Pharmacol Rev ; 63(1): 59-126, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21228259

RESUMO

Allosteric receptor modulation is an attractive concept in drug targeting because it offers important potential advantages over conventional orthosteric agonism or antagonism. Allosteric ligands modulate receptor function by binding to a site distinct from the recognition site for the endogenous agonist. They often have no effect on their own and therefore act only in conjunction with physiological receptor activation. This article reviews the current status of allosteric modulation at family C G-protein coupled receptors in the light of their specific structural features on the one hand and current concepts in receptor theory on the other hand. Family C G-protein-coupled receptors are characterized by a large extracellular domain containing the orthosteric agonist binding site known as the "venus flytrap module" because of its bilobal structure and the dynamics of its activation mechanism. Mutational analysis and chimeric constructs have revealed that allosteric modulators of the calcium-sensing, metabotropic glutamate and GABA(B) receptors bind to the seven transmembrane domain, through which they modify signal transduction after receptor activation. This is in contrast to taste-enhancing molecules, which bind to different parts of sweet and umami receptors. The complexity of interactions between orthosteric and allosteric ligands is revealed by a number of adequate biochemical and electrophysiological assay systems. Many allosteric family C GPCR modulators show in vivo efficacy in behavioral models for a variety of clinical indications. The positive allosteric calcium sensing receptor modulator cinacalcet is the first drug of this type to enter the market and therefore provides proof of principle in humans.


Assuntos
Receptores Acoplados a Proteínas G/metabolismo , Regulação Alostérica , Animais , Agonistas dos Receptores de GABA-B/farmacologia , Agonistas dos Receptores de GABA-B/uso terapêutico , Antagonistas de Receptores de GABA-B/farmacologia , Antagonistas de Receptores de GABA-B/uso terapêutico , Humanos , Ligantes , Terapia de Alvo Molecular , Receptores de Detecção de Cálcio/agonistas , Receptores de Detecção de Cálcio/antagonistas & inibidores , Receptores de Detecção de Cálcio/química , Receptores de Detecção de Cálcio/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/química , Receptores de GABA-B/metabolismo , Papilas Gustativas/efeitos dos fármacos , Papilas Gustativas/metabolismo
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