RESUMO
OBJECTIVES: During the last years, the association between apolipoprotein E (APOE) polymorphism and disease severity in multiple sclerosis (MS) has been studied with conflicting results. As a result of a considerable individual variation in the clinical course of MS, there is no consensus method for measuring progression using single assessments of disability. Recently, Multiple Sclerosis Severity Score (MSSS) method has been proposed for comparing disease progression using single data. We evaluate in our population if there is any correlation between APOE genotype and severity according to MSSS. METHODS: We studied 82 patients followed up in our Neurology Unit throughout the year 2005, diagnosed with MS, and with disease duration of at least 2 years. We collected data concerning demographic and clinical variables including age of onset, disease duration, Expanded Disability Status Scale (EDSS) score and the total number of relapses. When reached, we determined the latency to EDSS scores of 4.0 and 6.0. We calculated progression index (PI) and relapse rate (RR). We ascertained MSSS for our patients in the global MSSS table. RESULTS: We found four patients heterozygous for the E2 allele and 16 for the E4 allele. No patient was homozygous for E2 or E4. RR (P = 0.017 with 95% CI: 0.005-0.57) and PI (P = 0.016 with 95% CI: 0.004-0.38) were significantly lower in E4 carriers. MSSS scores were not associated with carriership of E2 or E4. CONCLUSION: Our results show no effect of the APOE genotype on the severity of MS measured by MSSS, as a recently published meta-analysis has noticed. So, our data do not support a role for APOE in MS severity, in spite of the seeming influence shown using other measures such as PI. MSSS is probably the best method to measure severity with a single measure of disability and should be used more frequently when performing genetic research.
Assuntos
Apolipoproteínas E/genética , Predisposição Genética para Doença/genética , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Adolescente , Adulto , Idoso , Apolipoproteína E2/genética , Apolipoproteína E4/genética , Análise Mutacional de DNA , Avaliação da Deficiência , Progressão da Doença , Feminino , Frequência do Gene/genética , Marcadores Genéticos/genética , Testes Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/fisiopatologia , Valor Preditivo dos Testes , Recidiva , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
In this study, the influence of GABAergic agents, imipramine and their interactions on memory retention have been investigated. Intracerebroventricular (i.c.v.; 1-6 microg/rat) or intraperitoneal (i.p.; 5-40 mg/kg) injection of imipramine decreased memory retention. i.c.v. administration of GABA receptor agonists baclofen and muscimol also reduced memory retention. The combination of i.p. or i.c.v. injection of imipramine with a low dose of muscimol (1 microg/rat, i.c.v.) induced a higher decrease in memory retention. The higher dose of GABA(B) receptor antagonist CGP35348 [p-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid] (10 microg/rat) increased memory retention by itself, and decreased the response induced by baclofen or imipramine. Bicuculline (1, 2 and 4 microg/rat, i.c.v.) tends to increase memory retention by itself. Furthermore, bicuculline in same doses reduced the response induced by muscimol or imipramine, but it did not show interaction with the latter drugs. It is concluded that the GABA(B) receptor mechanism is involved in memory impairment induced by imipramine.
Assuntos
Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Imipramina/farmacologia , Retenção Psicológica/efeitos dos fármacos , Ácido gama-Aminobutírico/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Relação Dose-Resposta a Droga , Agonistas dos Receptores de GABA-B , Antagonistas de Receptores de GABA-B , Imipramina/toxicidade , Masculino , Transtornos da Memória/induzido quimicamente , Ratos , Ratos Wistar , Receptores de GABA-B/fisiologia , Retenção Psicológica/fisiologiaRESUMO
The effect of post-training intrahippocampal injection of gamma-aminobutyric acid (GABA) receptor agonists and antagonists, immediately after a training session on memory retention of passive avoidance learning in rats, was measured in the presence and absence of physostigmine. Post-training treatments were carried out in all the experiments. The different doses of the GABAA receptor agonist muscimol (2, 4 and 6 microg/rat) decreased memory retention in rats dose-dependently. The higher response was obtained with 6 microg/rat of the drug. When the GABAA receptor antagonist bicuculline (0.5, 1, 2 and 4 microg/rat) was administered, only one dose of the drug (1 microg/rat) increased memory retention; however, the antagonist reduced the effect of muscimol. The GABAB receptor agonist, baclofen (0.25, 0.5, 1 and 2 microg/rat) also reduced memory retention in the animals. Intrahippocampal injection of lower doses of the GABAB receptor antagonist CGP35348 (P-[3-aminopropyl]-p-diethoxymethyl-phosphinic acid) (2.5, 5, 10 microg/rat) did not effect memory retention, although the higher doses of the drug (25 and 50 microg/rat) decreased memory retention. The doses of antagonist (2.5, 5 and 10 microg/rat), which did not elicit any response alone, reduced the effect of baclofen. The inhibitory response of CGP35348 was also decreased by bicuculline. In another series of experiments, physostigmine improved memory retention. The GABA receptor agonists, muscimol and baclofen, as well as the GABA receptor antagonists bicuculline and CGP35348, decreased the effect of physostigmine. Atropine decreased memory retention by itself and potentiated the response of muscimol and baclofen. It is concluded that GABAA and GABAB receptor activation may be involved in the impairment of memory retention.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , GABAérgicos/farmacologia , Hipocampo/fisiologia , Memória/efeitos dos fármacos , Animais , Baclofeno/farmacologia , Bicuculina/farmacologia , Colinérgicos/farmacologia , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , GABAérgicos/administração & dosagem , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Masculino , Microinjeções , Muscimol/farmacologia , Compostos Organofosforados/farmacologia , Fisostigmina/farmacologia , Ratos , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-B/efeitos dos fármacosRESUMO
The effect of GABA receptor agonists and antagonists on anxiety behavior in rats in the elevated-plus-maze has been investigated. The increase in two parameters of %open arm entries (%OAE) and %time spent in the open arms (%OAT) and decrease in the %time spent in closed arm (%CAT) was considered as antianxiety effects. Intracerebroventricular (i.c.v.) injection of different doses of the GABA(A) receptor agonist muscimol (0.25, 0.5, and 1 microg/rat) increased %OAE and %OAT and decreased %CAT in rats dose-dependently. The higher response was obtained with 1 microg/rat of the drug. Neither icv (0.05, 0.1, and 0.2 microg/rat) nor intraperitoneal (i.p.) (1, 2, and 4 mg/kg) injection of the GABA(B) receptor agonist baclofen altered %OAE, %OAT, and %CAT. However, the GABA(B) receptor antagonist CGP35348 (5, 10, and 30 microg/rat i.c.v.) increased %OAE and %OAT and decreased %CAT in the animals. The response induced by injection of muscimol (0.5 microg/rat i.c.v.) or administration of CGP35348 (10 microg/rat i.c.v.) was reduced by i.c.v. (1, 2, and 4 microg/rat) or i.p. (0.25, 0.5, and 0.75 mg/kg) injection of the GABA(A) receptor antagonist bicuculline, except the effect of CGP35348 on %CAT which was not significantly altered by i.p. administration of bicuculline. Ip but not i.c.v. administration of bicuculline by itself reduced both %OAE and %OAT but did not alter %CAT. None of the drugs altered the locomotor activity of the animals. The current findings support our hypothesis that the anxiolytic effects of GABA(B) antagonist are mediated by autoreceptor blockade-induced release of endogenous GABA, which in turn activates postsynaptic GABA(A) receptors.
Assuntos
Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A , Agonistas dos Receptores de GABA-B , Animais , Ansiedade/psicologia , Baclofeno/farmacologia , Bicuculina/administração & dosagem , Bicuculina/farmacologia , Antagonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos/farmacologia , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Muscimol/administração & dosagem , Muscimol/farmacologia , Compostos Organofosforados/farmacologia , Ratos , Ratos WistarRESUMO
We compared the fractionations obtained by three different methods of dosage of thyroid hormones and we concluded that trichloracetic PBI is very rapid, (about 15 minutes) excluding the length of calculation of radio activity), is easy to execute, and uses inexpensive materials. Separation by exchanging resins of ions is also very rapid (15 min.), a little more precise, but the cost of operation is much higher. Separation by sephadex G25 is very time consuming (one day), and much more meticulous; its cost is equally high.
Assuntos
Testes de Função Tireóidea/métodos , Animais , Cromatografia em Gel , Cromatografia por Troca Iônica , Feminino , Ratos , Hormônios Tireóideos/sangue , Ácido TricloroacéticoRESUMO
The purpose of this study was to evaluate whether nicotinic acetylcholine receptors of the dorsal hippocampus and the basolateral amygdala (BLA) can potentiate ethanol response in the conditioned place preference (CPP) paradigm. I.p. administration of different doses of ethanol (0.25-1 g/kg) did not induce CPP. However, the higher dose of the drug (1.5 g/kg i.p.) induced place aversion. Furthermore, microinjection of nicotine (0.5-1 microg/rat) into both CA1 regions (intra-CA1) and the BLA (intra-BLA) did not produce a significant CPP. Interestingly, intra-CA1 or -BLA administration of nicotine plus ethanol (0.5 g/kg) during conditioning phase significantly induced a strong CPP. Microinjection of mecamylamine, the nicotinic acetylcholine receptor antagonist, into the CA1 regions or into the BLA did not alter CPP. However, intra-CA1 or -BLA microinjection of mecamylamine (1-4 microg/rat) reversed the response induced by the microinjection of nicotine (1 microg/rat, intra-CA1 or -BLA) plus ethanol (0.5 g/kg i.p.) in the CPP paradigm. On the other hand, the microinjection of nicotine (0.5-1.5 microg/rat) into the BLA, but not into the CA1 regions before the testing phase potentiated the response of ethanol on the expression of conditioned place preference. Moreover, intra-CA1 administration of nicotine plus ethanol increased the locomotor activity on the test day which was reversed by pretreatment with mecamylamine, while other treatments had no effect on locomotor activity. It can be concluded that the activation of nicotinic acetylcholine receptors of the dorsal hippocampus and the basolateral amygdala can potentiate the ethanol response in the CPP paradigm.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Etanol/farmacologia , Receptores Nicotínicos/fisiologia , Tonsila do Cerebelo/metabolismo , Animais , Região CA1 Hipocampal/metabolismo , Condicionamento Clássico/fisiologia , Masculino , Mecamilamina/farmacologia , Microinjeções , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Ratos , Ratos Wistar , RecompensaRESUMO
The effects of an intraperitoneal (i.p.) injection of different doses of sildenafil, a cyclic guanosin monophosphate (cGMP) specific phosphodiesterase type 5 (PDE 5) inhibitor, on memory retention of young (2-month-old) and middle aged (12-month-old) male Wistar rats were investigated. Passive avoidance behaviour was studied in a one trial learning, step--through type, passive avoidance task utilizing the natural preference of rats for a dark environment. In each category (young or middle-aged) different groups of rats received vehicle or sildenafil (1, 3, 10, 20 mg*kg(-1), i.p.) immediately after training and one group remained uninjected serwing as control. Retention latencies were measured 48 h later. To asses a possible non-specific proactive effect of sildenafil, the response latencies in a group of rats not receiving foot shock were also tested. The results showed that the post-training i.p. administration of sildenafil did not facilitate retention performance of a passive avoidance response in both young and middle aged rats compared to control or vehicle groups. Also, sildenafil did not affect response latencies in rats not having received the footshock on the training trial, indicating that sildenafil does not show a non-specific proactive affect on retention performance. The comparison of retention time between young and middle aged rats showed that the memory of the latter had been significantly reduced. In conclusion, this study suggests that sildenafil has no effects on memory retention in Wistar rats.
Assuntos
Inibidores de Fosfodiesterase/farmacologia , Piperazinas/farmacologia , Retenção Psicológica/efeitos dos fármacos , Fatores Etários , Animais , Aprendizagem da Esquiva , Masculino , Purinas , Ratos , Citrato de Sildenafila , SulfonasRESUMO
BACKGROUND: Angiotensin Converting Enzyme Inhibitors (ACEIs) like enalapril are extremely effective in the treatment of hypertension and heart failure. One of the most important side-effects of these drugs which can lead to cessation of therapy is a persistant dry cough, induced because of increased bradykinin levels in the lung. Although antitussive alkaloids like codeine are effective in suppressing this cough, they too present a wide range of side-effects, most notably addiction. OBJECTIVE: In a previous work we were able to show that noscapine, a non-narcotic antitussive agent, was able to decrease enalapril induced cough in guinea pigs. In this work, papaverine, another non-narcotic alkaloid found in opium latex was tested in the guinea pig model for antitussive activity. METHOD: Cough was induced in enalapril pretreated guinea pigs by forcing the animals to inspire capsaicin aerosol in an air-tight chamber. Coughs were recorded in control animals and in those which had received different doses of papaverine. Characteristic changes in chamber air pressure, were detected by a pressure transducer. RESULTS: . At low doses (0.5 and 0.25 mg/kg) papaverine was able to decrease enalapril induced cough. CONCLUSION. This effect was not mediated by the action of the drug on mu receptors and was only observed in animals treated with enalapril.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Tosse/tratamento farmacológico , Enalapril/efeitos adversos , Papaverina/uso terapêutico , Vasodilatadores/uso terapêutico , Animais , Tosse/etiologia , Cobaias , Masculino , Papaverina/administração & dosagemRESUMO
The aim of the present experiments was to investigate whether repeated intra-hippocampal CA1 (intra-CA1) administration of dopaminergic agents can affect morphine-induced conditioned place preference (CPP). Effects of repeated intra-CA1 injections of dopamine (DA) receptor agonists and antagonists on morphine-induced CPP in rats were investigated using an unbiased 3-day schedule of place conditioning. Animals receiving once-daily subcutaneous (s.c.) injections of morphine (1-9 mg/kg) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner: the maximum response was observed with 3 mg/kg morphine. Three days' intra-CA1 injections of apomorphine (0.25-1 microg/rat) followed by 5 days free of the drug, significantly decreased morphine CPP (1 and 3 mg/kg, s.c.). Moreover, pre-treatment with the highest dose of apomorphine (1 microg/rat) altered the effect of morphine to an aversive response. The morphine (1 and 3 mg/kg) CPP was also significantly decreased in animals that previously received three intra-CA1 injections of SKF 38393 (2-9 microg/rat), quinpirole (1-3 microg/rat) or sulpiride (1-3 microg/rat), and significantly increased in animals that had previously received three intra-CA1 injections of SCH 23390 (0.02 microg/rat). The 3-day pre-treatment with apomorphine, SKF 38393 or quinpirole reduced locomotor activity in the test session, while SCH 23390 and sulpiride did not have any influence on locomotor activity. It is concluded that repeated injections of DA receptor agents in the dorsal hippocampus, followed by 5 days free of the drugs, can affect morphine reward.
Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Apomorfina/farmacologia , Condicionamento Clássico , Agonistas de Dopamina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Morfina/farmacologia , Entorpecentes/farmacologia , Quimpirol/farmacologia , Animais , Apomorfina/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Injeções Subcutâneas , Masculino , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Ratos , Ratos Wistar , Reforço Psicológico , Percepção EspacialRESUMO
Angiotensin Converting Enzyme Inhibitors (ACEI) like captopril and enalapril, can induce persistant cough in man. Noscapine, an antitussive alkaloid, can be used to suppress ACEI-induced cough. Some workers have suggested a role for bradykinin in precipitation of ACE-induced cough. Work carried out in our laboratory has shown noscapine to be a non-competitive inhibitor of bradykinin in guinea pig ileum. It is therefore possible that noscapine suppresses cough by blocking the effect of bradykinin receptor activation in the airways. Guinea pigs were placed in a cough-chamber connected to an air pump and a pressure transducer. Capsaicin was sprayed into the chamber and cough was recorded as a distinctive change in air pressure inside the cough-chamber. Animals treated with 1 mg/kg captopril and enalapril for 7 days, showed increased cough response. Ten microgram/kg FR190997, a non-peptide agonist of the bradykinin B2 receptor, also increased the cough response. Noscapine at 0.5, 1 and 2 mg/kg was able to reverse the effects of ACEI and FR190997. Naloxone, a specific opioid receptor inhibitor, did not block the antitussive effects of noscapine in enalapril or FR190997 treated guinea pigs. This antitussive effect of noscapine is not mediated via the mu, kappa or delta opioid receptors. It is therefore possible that noscapine exerts its antitussive action by interfering with the bradykinin cough mediation.