RESUMO
BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.
Assuntos
Esclerose Múltipla/patologia , Adulto , Estudos de Coortes , Progressão da Doença , Endonucleases , Feminino , Seguimentos , Humanos , Imunoglobulina G/análise , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/líquido cefalorraquidiano , Proteínas Nucleares/análise , Bandas Oligoclonais/genética , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Análise de Sobrevida , Vitamina D/sangueRESUMO
The possible association of three DEFB1 gene polymorphisms with susceptibility to develop ulcerative colitis (UC) and Crohn's disease (CD) was investigated in Brazilian patients and controls. Although a clear and strong association between functional 5'-UTR DEFB1 SNPs and susceptibility/protection to IBDs cannot be drawn, our results suggest a possible involvement of DEFB1 gene in inflammatory bowel diseases, especially with the colonic localization of Crohn's disease.
Assuntos
Regiões 5' não Traduzidas , Doenças Inflamatórias Intestinais/genética , beta-Defensinas/genética , Adulto , Brasil , Estudos de Casos e Controles , Colite Ulcerativa/genética , Doença de Crohn/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
AIM: To compare electrocardiography (ECG)-gated computed tomography angiography (CTA) with ECG-gated magnetic resonance angiography (MRA) for assessment of the left atrium (LA) and pulmonary veins (PVs). MATERIAL AND METHODS: Twenty-nine consecutive patients who underwent both cardiac CTA and MRA were evaluated. Contrast-enhanced CTA was performed with prospective ECG-gating using a 320 detector row CT system. Contrast-enhanced MRA was performed with prospective ECG-gating using a 1.5 T MRI system equipped with a 32 channel cardiac coil. MRA was acquired during free-breathing with a navigator-gated inversion-recovery prepared steady-state free precession sequence. Two readers independently assessed the CTA and MRA images for vascular definition of the PVs (from 0, not visualized, to 4, excellent definition) and ostial PV diameters. Variants of LA anatomy were assessed in consensus. RESULTS: CTA was successfully performed in all patients with a mean radiation exposure of 5.1 ± 2.2 mSv. MRA was successfully performed in 27 of 29 patients (93 %). Visual definition of PVs was rated significantly higher on CTA compared to MRA (p < 0.0001; reader 1: excellent/good ratings of CTA versus MRA: 100% versus 86%; reader 2: excellent/good ratings of CTA versus MRA: 99% versus 89%). Assessment of ostial PV diameters showed good correlation between CTA and MRA (reader 1: Pearson r = 0.91; reader 2: Pearson r = 0.82). Moreover, agreement between both imaging methods for evaluation of variants of LA anatomy was high (agreement rate of 95% (95% CI: 92-99%). CONCLUSION: ECG-gated CTA provides higher image quality compared to ECG-gated MRA. Nevertheless, both CTA and MRA provided similar information of LA anatomy and ostial PV diameters.
Assuntos
Técnicas de Imagem de Sincronização Cardíaca/métodos , Angiografia Coronária/métodos , Átrios do Coração/patologia , Angiografia por Ressonância Magnética/métodos , Veias Pulmonares/patologia , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Meios de Contraste , Feminino , Gadolínio , Átrios do Coração/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos , Veias Pulmonares/diagnóstico por imagem , Doses de RadiaçãoRESUMO
OBJECTIVE: To evaluate the antiinflammatory effects of RC-3095 in 2 experimental models of arthritis, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA), and to determine the mechanisms of action involved. METHODS: RC-3095 was administered daily to mice with CIA and mice with AIA, after induction of disease with methylated bovine serum albumin. Disease incidence and severity were assessed using a clinical index and evaluation of histologic features, respectively. In mice with CIA, gastrin-releasing peptide receptor (GRPR) was detected by immunohistochemical analysis, while in mice with AIA, migration of neutrophils, presence of glycosaminoglycans, and lymphocyte proliferation, determined using the MTT assay, were assessed. Expression of cytokines interleukin-17 (IL-17), IL-1ß, and tumor necrosis factor α (TNFα) was evaluated in all mouse knees using enzyme-linked immunosorbent assay. Treg cell production was assessed by flow cytometry in the joints of mice with AIA. RESULTS: In mice with AIA, administration of RC-3095 reduced neutrophil migration, mechanical hypernociception, and proteoglycan loss. These findings were associated with inhibition of the levels of all 3 proinflammatory cytokines, decreased lymphocyte proliferation, and increased Treg cell numbers. In the CIA model, treatment with RC-3095 led to a significant reduction in arthritis clinical scores and the severity of disease determined histologically. Synovial inflammation, synovial hyperplasia, pannus formation, and extensive erosive changes were all dramatically reduced in the arthritic mice treated with RC-3095. Furthermore, arthritic mice treated with RC-3095 showed a significant reduction in the concentrations of IL-17, IL-1ß, and TNFα, and showed a diminished expression of GRPR. CONCLUSION: These findings suggest that the GRP pathway has a significant role in chronic arthritis, and its inhibition can be explored as a possible therapeutic strategy in rheumatoid arthritis.
Assuntos
Artrite Experimental/tratamento farmacológico , Bombesina/análogos & derivados , Fragmentos de Peptídeos/uso terapêutico , Receptores da Bombesina/antagonistas & inibidores , Animais , Bombesina/uso terapêutico , Cartilagem Articular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Articulações/efeitos dos fármacos , Masculino , Camundongos , Neutrófilos/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Resultado do TratamentoRESUMO
The gas-phase reaction chemistry of using 1-methylsilacyclobutane (MSCB) in the hot-wire chemical vapor deposition (CVD) process has been investigated by studying the decomposition of MSCB on a heated tungsten filament and subsequent gas-phase reactions in a reactor. Three pathways exist to decompose MSCB on the filament to form ethene/methylsilene, propene/methylsilylene, and methyl radicals. The activation energies for forming propene and methyl radical, respectively, are determined to be 68.7 ± 1.3 and 46.7 ± 2.5 kJ·mol(-1), which demonstrates the catalytic nature of the decomposition. The secondary gas-phase reactions in the hot-wire CVD reactor are characterized by the competition between a free radical chain reaction and the cycloaddition of silene reactive species produced either from the primary decomposition of MSCB on the filament or the isomerization of silylene species. At lower filament temperatures of 1000-1100 °C and short reaction time (t ≤ 15 min), the free radical chain reaction is equally important as the silene chemistry. With increasing filament temperature and reaction time, silene chemistry predominates.
Assuntos
Ciclobutanos/química , Silanos/química , Silene/química , Radicais Livres/química , Estrutura Molecular , Temperatura , VolatilizaçãoRESUMO
Prostate cancer is the second most common cancer in men, with a significant increase in incidence and mortality in men over 50 years of age. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study is to evaluate the association between the KIR genes and HLA alleles in patients with prostate cancer and healthy controls. Two hundred patients with prostate cancer and 185 healthy controls were typed for HLA class I and KIR genes by PCR-SSP. When both groups were compared, no significant differences were found for HLA-C group 1 and group 2, HLA-Bw4, HLA-A3 and A11. No difference was seen either in KIR frequency between patients with prostate cancer and controls. In conclusion, our data suggest no potential role for the KIR gene system in prostate cancer.
Assuntos
Frequência do Gene , Genes MHC Classe I , Genótipo , Neoplasias da Próstata/genética , Receptores KIR/genética , Brasil/epidemiologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Estudos de Associação Genética/métodos , Teste de Histocompatibilidade/métodos , Humanos , Células Matadoras Naturais , Ligantes , Masculino , Reação em Cadeia da Polimerase/métodosRESUMO
Killer immunoglobulin-like receptors (KIR) regulate the activity of natural killer and T cells through an interaction with specific human leucocyte antigen (HLA) class I molecules on target cells. Diversity in KIR gene content, KIR allelic and haplotype polymorphism has been observed between different ethnic groups. However, most population studies on KIR variability have focused on Europe and Asia, while Americas, Oceania and Africa remain poorly studied. The aim of this study was to analyse the variability of KIR genes in 200 healthy nonrelated individuals from the Southern Brazilian population. KIR genes and HLA-A, -B and -Cw were genotyped using polymerase chain reaction-sequence-specific primers. Southern Brazilian population demonstrated several similarities to states that are closer geographically and distinct differences with Northern Brazil in the frequency of genes KIR2DS1, 2DS2, 2DS3, 2DS5, 3DL1, 3DS1, 2DL1 and 2DL2. The activating gene KIR2DS5 was the least frequent locus found in our group. Interaction of KIR/HLA was more common in the 2DS1-/2DL1+/C2+ association. This study demonstrated the diversity of KIR genes and of KIR/HLA association in a Caucasian group of Southern Brazil, establishing differences and similarities to other different populations.
Assuntos
Variação Genética , Receptores KIR/genética , População Branca/genética , Adolescente , Adulto , Brasil , Feminino , Frequência do Gene , Genótipo , Antígenos HLA-A/genética , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica , Adulto JovemRESUMO
Increasing evidence indicates that iron deposition in the brain might play a role in cognitive dysfunction associated with neurodegenerative disorders and aging. Previous studies have not examined whether iron-induced memory deficits can be attenuated by acute treatments with memory-enhancing agents. Phosphodiesterase type 4 (PDE4) inhibitors such as rolipram (ROL) ameliorate memory impairments in several rodent models of amnesia and have been proposed as candidate cognitive-enhancing drugs. Here we show that a single posttraining systemic injection of ROL dose-dependently attenuates the impairment of memory for novel object recognition (NOR) in rats given neonatal iron loading, a model of iron-induced cognitive impairment. Posttraining administration of ROL also recovered NOR deficits associated with aging in rats. These findings provide the first evidence that stimulation of an intracellular second messenger signaling pathway can attenuate iron-induced memory impairment, and support the view that PDE4 inhibitors might ameliorate cognitive dysfunction associated with aging and neurodegenerative disorders.
Assuntos
Envelhecimento/efeitos dos fármacos , Ferro/efeitos adversos , Transtornos da Memória/etiologia , Reconhecimento Visual de Modelos/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Rolipram/farmacologia , Fatores Etários , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Transtornos da Memória/tratamento farmacológico , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Fatores de TempoRESUMO
OBJECTIVE: To determine the effects of RC-3095 in clinical and histopathologic parameters and inflammatory mediators on complete Freund's adjuvant-induced arthritis (CFA). METHODS: The arthritis was induced by injection of CFA into the left hind footpad. The animals were divided into control, vehicle injected control, placebo group (saline subcutaneously 50ml/kg, once daily for 8 days after modeling), treatment group (0.3mg/kg of RC-3095 subcutaneously, once daily for 8 days after induction). Clinical evaluation was accomplished daily, through scoring of the paw edema. The animals were sacrificed 15 days after induction for collection of hind foot joints for histology. We used a histological scoring system which was previously described, and interferon (INF)-gamma, interleukin (IL)-1beta, tumor necrosis factor (TNF), interleukin (IL)-6 and interleukin (IL)-10 were measured by ELISA. RESULTS: There was a significant inhibition of joint histological findings in the RC-3095 treated group, including synovial inflammatory infiltration and hyperplasia, cartilage and bone erosion. IFN-gamma, IL-1beta, TNF, IL-6 and IL-10 serum levels were significantly lower in the treated group. Paw swelling and subcutaneous inflammation, evaluated clinically, were not different between CFA-induced groups. CONCLUSIONS: RC-3095 was able to improve experimental arthritis, attenuate joint damage and decrease serum levels of IFN-gamma, IL-1beta, TNF, IL-6 and IL-10. These data indicate that interference with GRP pathway is a potential new strategy for the treatment of RA that needs further investigational studies.
Assuntos
Artrite Experimental/tratamento farmacológico , Bombesina/análogos & derivados , Fragmentos de Peptídeos/uso terapêutico , Receptores da Bombesina/antagonistas & inibidores , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Bombesina/uso terapêutico , Adjuvante de Freund/imunologia , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Placebos , Distribuição Aleatória , Ratos , Ratos Wistar , Tarso Animal/imunologia , Tarso Animal/patologia , Fator de Necrose Tumoral alfa/sangueRESUMO
Although the gastrin-releasing peptide-preferring bombesin receptor (GRPR) has been implicated in memory formation, the underlying molecular events are poorly understood. In the present study, we examined interactions between the GRPR and cellular signaling pathways in influencing memory consolidation in the hippocampus. Male Wistar rats received bilateral infusions of bombesin (BB) into the dorsal hippocampus immediately after inhibitory avoidance (IA) training. Intermediate doses of BB enhanced, whereas a higher dose impaired, 24-h IA memory retention. The BB-induced memory enhancement was prevented by pretraining infusions of a GRPR antagonist or inhibitors of protein kinase C (PKC), mitogen-activated protein kinase (MAPK) kinase and protein kinase A (PKA), but not by a neuromedin B receptor (NMBR) antagonist. We next further investigated the interactions between the GRPR and the PKA pathway. BB-induced enhancement of consolidation was potentiated by coinfusion of activators of the dopamine D1/D5 receptor (D1R)/cAMP/PKA pathway and prevented by a PKA inhibitor. We conclude that memory modulation by hippocampal GRPRs is mediated by the PKC, MAPK, and PKA pathways. Furthermore, pretraining infusion of BB prevented beta-amyloid peptide (25-35)-induced memory impairment, supporting the view that the GRPR is a target for the development of cognitive enhancers for dementia.
Assuntos
Hipocampo/fisiologia , Memória , Receptores da Bombesina/fisiologia , Peptídeos beta-Amiloides/farmacologia , Animais , Bombesina/farmacologia , AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Hipocampo/efeitos dos fármacos , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/fisiologia , Fragmentos de Peptídeos/farmacologia , Proteína Quinase C/fisiologia , Ratos , Ratos Wistar , Receptores da Bombesina/agonistas , Receptores de Dopamina D5/agonistas , Transdução de SinaisRESUMO
Apomorphine is a dopamine receptor agonist proposed to be a neuroprotective agent in the treatment of patients with Parkinson's disease. Both in vivo and in vitro studies have shown that apomorphine displays both antioxidant and pro-oxidant actions, and might have either neuroprotective or neurotoxic effects on the central nervous system. Some of the neurotoxic effects of apomorphine are mediated by its oxidation derivatives. In the present review, we discuss recent studies from our laboratory in which the molecular, cellular and neurobehavioral effects of apomorphine and its oxidized derivative, 8-oxo-apomorphine-semiquinone (8-OASQ), were evaluated in different experimental models, i.e., in vitro genotoxicity in Salmonella/microsome assay and WP2 Mutoxitest, sensitivity assay in Saccharomyces cerevisiae, neurobehavioral procedures (inhibition avoidance task, open field behavior, and habituation) in rats, stereotyped behavior in mice, and Comet assay and oxidative stress analyses in mouse brain. Our results show that apomorphine and 8-OASQ induce differential mutagenic, neurochemical and neurobehavioral effects. 8-OASQ displays cytotoxic effects and oxidative and frameshift mutagenic activities, while apomorphine shows antimutagenic and antioxidant effects in vitro. 8-OASQ induces a significant increase of DNA damage in mouse brain tissue. Both apomorphine and 8-OASQ impair memory for aversive training in rats, although the two drugs showed a different dose-response pattern. 8-OASQ fails to induce stereotyped behaviors in mice. The implications of these findings are discussed in the light of evidence from studies by other groups. We propose that the neuroprotective and neurotoxic effects of dopamine agonists might be mediated, in part, by their oxidized metabolites.
Assuntos
Antiparkinsonianos/farmacologia , Apomorfina/análogos & derivados , Apomorfina/farmacologia , Comportamento Animal/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Quinonas/farmacologia , Animais , Antiparkinsonianos/toxicidade , Apomorfina/toxicidade , Dano ao DNA/efeitos dos fármacos , Agonistas de Dopamina/toxicidade , Relação Dose-Resposta a Droga , Memória/efeitos dos fármacos , Camundongos , Testes de Mutagenicidade , Oxirredução/efeitos dos fármacos , Quinonas/toxicidade , Ratos , Saccharomyces cerevisiae/efeitos dos fármacos , Salmonella typhimurium/efeitos dos fármacosRESUMO
We studied the effects of infusion of nerve growth factor (NGF) into the hippocampus and entorhinal cortex of male Wistar rats (250-300 g, N = 11-13 per group) on inhibitory avoidance retention. In order to evaluate the modulation of entorhinal and hippocampal NGF in short- and long-term memory, animals were implanted with cannulae in the CA1 area of the dorsal hippocampus or entorhinal cortex and trained in one-trial step-down inhibitory avoidance (foot shock, 0.4 mA). Retention tests were carried out 1.5 h or 24 h after training to measure short- and long-term memory, respectively. Immediately after training, rats received 5 microl NGF (0.05, 0.5 or 5.0 ng) or saline per side into the CA1 area and entorhinal cortex. The correct position of the cannulae was confirmed by histological analysis. The highest dose of NGF (5.0 ng) into the hippocampus blocked short-term memory (P < 0.05), whereas the doses of 0.5 (P < 0.05) and 5.0 ng (P < 0.01) NGF enhanced long-term memory. NGF administration into the entorhinal cortex improved long-term memory at the dose of 5.0 ng (P < 0.05) and did not alter short-term memory. Taken as a whole, our results suggest a differential modulation by entorhinal and hippocampal NGF of short- and long-term memory.
Assuntos
Córtex Entorrinal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Fator de Crescimento Neural/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Córtex Entorrinal/fisiologia , Hipocampo/fisiologia , Masculino , Memória/fisiologia , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Ratos , Ratos Wistar , Retenção Psicológica/efeitos dos fármacosRESUMO
Prions are the causative agents of transmissible spongiform encephalopathies. The transmissible agent (PrP(Sc)) is an abnormal form of PrP(C), a normal neuronal protein. The physiological role of PrP(C) remains unclear. In the present report, we evaluated behavioral parameters in Prnp(0/0) mice devoid of PrP(C). Prnp(0/0) mice showed normal short- and long-term retention of a step-down inhibitory avoidance task and normal behavior in an elevated plus maze test of anxiety. During a 5-min exploration of an open field, Prnp(0/0) mice showed normal number of rearings, defecation, and latency to initiate locomotion, but a significant increase in the number of crossings. The results suggest that Prnp(0/0) mice show normal fear-motivated memory, anxiety and exploratory behavior, and a slight increase in locomotor activity during exploration of a novel environment.
Assuntos
Ansiedade , Aprendizagem da Esquiva/fisiologia , Locomoção/fisiologia , Proteínas PrPC/fisiologia , Animais , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos KnockoutRESUMO
Laminin (LN) plays a major role in neuronal differentiation, migration and survival. Here, we show that the cellular prion protein (PrPc) is a saturable, specific, high-affinity receptor for LN. The PrPc-LN interaction is involved in the neuritogenesis induced by NGF plus LN in the PC-12 cell line and the binding site resides in a carboxy-terminal decapeptide from the gamma-1 LN chain. Neuritogenesis induced by LN or its gamma-1-derived peptide in primary cultures from rat or either wild type or PrP null mice hippocampal neurons, indicated that PrPc is the main cellular receptor for that particular LN domain. These results point out to the importance of the PrPc-LN interaction for the neuronal plasticity mechanism.
Assuntos
Laminina/metabolismo , Neuritos/fisiologia , Proteínas PrPC/metabolismo , Animais , Células Cultivadas , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Camundongos , Neurônios/metabolismo , Neurônios/ultraestrutura , Fragmentos de Peptídeos/metabolismo , Proteínas PrPSc/genética , Ligação Proteica , Ratos , Células Tumorais CultivadasRESUMO
The nucleoside guanosine, previously found to exert trophic and neuroprotective effects, was found to impair retention of inhibitory avoidance responses, with a complete effect at 7.5 mg/kg i.p. pretraining. Treated animals, when retrained 1 week later, showed normal learning ability. Guanosine injected immediately after training or pretest did not alter retention latency. Combined pretraining and pretest treatments with guanosine failed to reverse its amnestic effect, excluding the contribution of state dependency. Open field parameters and shock sensitivity were mostly unaltered by guanosine. These results suggest an amnestic effect of guanosine on inhibitory avoidance in rats, in a pattern compatible with inhibition of glutamatergic activity. However, the mechanism for the amnestic effect of guanosine is yet to be elucidated.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Guanosina/farmacologia , Animais , Aprendizagem da Esquiva/fisiologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Wistar , Receptores de Glutamato/efeitos dos fármacos , Receptores de Glutamato/metabolismoRESUMO
Two experiments investigated the effects of Fe(2+), administered postnatally to rat pups on days 10-12, upon tests of memory performance and motor behaviour. In experiment I, Wistar rat pups were administered Fe(2+) at doses of either 2.5, 7.5, 15.0 or 30.0 mg/kg, or vehicle, postnatally, and tested in the open-field at 3 months of age, followed 6 weeks later by testing in the radial arm maze. In the open-field test, only the 30.0 mg/kg Fe(2+) group showed a significantly decreased number of ambulations, but not rearings. In the radial arm maze, all four dose groups, demonstrated deficits in acquisition performance from test days 3 to 5. Retention quotients confirmed the cognitive deficits over all four Fe(2+) groups. In experiment II, rats were administered either 2.5, 7.5 or 22.5 mg Fe(2+) per kg, or vehicle, postnatally, and tested in the inhibitory avoidance (IA) conditioning and retention test at 3 months of age. In the IA conditioning test, groups were either given five 10-min preexposures to the test chamber (preexposed) or simply moved to another cage (non-preexposed). IA retention was blocked in non-preexposed rats administered 7.5 and 22.5 mg Fe(2+) per kg whereas in preexposed rats the 7.5 mg/kg group did not differ from the control (vehicle) group, although the preexposed control group showed significantly better retention than the non-preexposed control group. Postnatal iron administration appears to induce long-lasting detrimental effects upon performance of both appetitively and negatively reinforced tests of memory. Analysis of iron content indicated significant increases in the substantia nigra of the 7.5, 15.0 and 30.0 mg/kg dose groups, but not in the 2.5 mg/kg dose group. Postnatal iron administration appears to induce far-reaching effects upon the performance of certain learned behaviours.
Assuntos
Encéfalo/efeitos dos fármacos , Compostos Ferrosos/toxicidade , Rememoração Mental/efeitos dos fármacos , Administração Oral , Fatores Etários , Animais , Animais Recém-Nascidos , Relação Dose-Resposta a Droga , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacosRESUMO
Extensive evidence suggests that N-methyl-D-aspartate (NMDA) glutamate receptor channels in the amygdala are involved in fear-motivated learning, and infusion of NMDA receptor antagonists into the amygdala blocks memory of fear-motivated tasks. Recent studies have shown that previous training can prevent the amnestic effects of NMDA receptor antagonists on spatial learning. In the present study, we evaluated whether infusion of the NMDA antagonist D,L-2-amino-5-phosphonopentanoic acid (AP5) into the basolateral nucleus of the amygdala (BLA) impairs reinforcement of inhibitory avoidance learning in rats given previous training. Adult male Wistar rats (220-310 g) were bilaterally implanted under thionembutal anesthesia (30 mg/kg, i.p.) with 9.0-mm guide cannulae aimed 1.0 mm above the BLA. Infusion of AP5 (5.0 microg) 10 min prior to training in a step-down inhibitory avoidance task (0.4 mA footshock) blocked retention measured 24 h after training. When infused 10 min prior to a second training session in animals given previous training (0.2 mA footshock), AP5 blocked the enhancement of retention induced by the second training. Control experiments showed that the effects were not due to alterations in motor activity or footshock sensitivity. The results suggest that NMDA receptors in the basolateral amygdala are involved in both formation of memory for inhibitory avoidance and enhancement of retention in rats given previous training.
Assuntos
2-Amino-5-fosfonovalerato/metabolismo , Tonsila do Cerebelo/metabolismo , Aprendizagem da Esquiva/fisiologia , Antagonistas de Aminoácidos Excitatórios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Eletrochoque , Medo/fisiologia , Inibição Psicológica , Locomoção , Masculino , Microinjeções , Plasticidade Neuronal , Ratos , Ratos WistarRESUMO
Mitogen-activated protein kinase (MAPK) is a serine/threonine protein kinase abundantly expressed in postmitotic neurons of the developed nervous system. MAPK is activated in and required for both the induction of long-term potentiation (LTP) in hippocampal slices and the acquisition of fear conditioning training in rats. The present work was performed in order to test the effect of the specific inhibitor of MAPK kinase (MAPKK), PD 098059, on retention of a step-down inhibitory avoidance (IA). Adult male Wistar rats were bilaterally injected (0.5 microl/side) with PD 098059 (at 0.5, 5, or 50 microM) or vehicle into the entorhinal cortex or into the parietal cortex immediately after IA training using a 0.4 mA footshock. Retention testing was carried out 24 h after training. PD 098059 impaired retention when injected into the entorhinal cortex at the dose of 50 microM, but not at the doses of 5 or 0.5 microM. When infused into the parietal cortex, PD 098059 was amnestic at the doses of 5 and 50 microM. The drug had no effect when infused at the highest dose in either structure 6 h after training. Our results suggest that the MAPKK inhibitor impairs IA retention memory in a dose-dependent manner when injected immediately after training into entorhinal cortex or parietal cortex. The effective dose is variable according to the neocortical structure studied.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Córtex Cerebral/fisiologia , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Memória/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Animais , Depressão Química , Relação Dose-Resposta a Droga , Córtex Entorrinal/fisiologia , Inibidores Enzimáticos/administração & dosagem , Medo/psicologia , Flavonoides/administração & dosagem , Injeções , Masculino , Lobo Parietal/fisiologia , Ratos , Ratos WistarRESUMO
Considering the involvement of extracellular ATP in the memory formation, we analyzed the effect of inhibitory avoidance training on ectonucleotidase activities in synaptosomes from hippocampus, entorhinal cortex and parietal cortex. ATP diphosphohydrolase activity presented a decrease (33%) in hippocampal synaptosomes of rats sacrificed 180 min after training. Our results also showed a decrease in synaptosomal ATP diphosphohydrolase (30% and 42% for ATP and ADP, respectively) in entorhinal cortex immediately after training. These findings suggest an integrated action of ATP diphosphohydrolase from hippocampus and entorhinal cortex in the formation of inhibitory avoidance memory.
Assuntos
Apirase/metabolismo , Aprendizagem da Esquiva/fisiologia , Córtex Entorrinal/enzimologia , Hipocampo/enzimologia , Sinaptossomos/enzimologia , Animais , Masculino , Ratos , Ratos WistarRESUMO
The amygdala is important for memory processes of emotionally motivated learning and the amygdala glutamatergic system may play a key role in this process. In this study we assessed the effect of the infusion of (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG), a metabotropic glutamate receptor (mGluR) antagonist, into the basolateral complex of the amygdala (BLA) on the learning and retention of an emotionally motivated task. Rats received either vehicle or three different doses of MCPG (0.2, or 1.0, or 5.0 microg/0.2 microl/side, respectively) bilaterally into the BLA, 5 min before they were trained in a continuous multiple-trial inhibitory avoidance (CMIA) task. Response latencies during the training were recorded. Retention was assessed 8 days later. MCPG in the doses given did not significantly affect the acquisition of the CMIA task. However, MCPG at a dose of 5.0 microg/0.2 microl/side impaired the long-term retention test performance. Additionally, a nociception test indicated that dose of MCPG infused into the BLA did not affect the footshock sensitivity. Our results indicate that MCPG, when infused into the BLA of rats prior to the training, impaired long-term memory of aversive training without affecting acquisition.