RESUMO
The critical involvement of dopamine in cognitive processes has been well established, suggesting that therapies targeting dopamine metabolism may alleviate cognitive dysfunction. Catechol-O-methyl transferase (COMT) is a catecholamine-degrading enzyme, the substrates of which include dopamine, epinephrine, and norepinephrine. The present work illustrates the potential therapeutic efficacy of COMT inhibition in alleviating cognitive impairment. A brain-penetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine-treated rats and COMT-Val transgenic mice. In a novel object recognition procedure, tolcapone counteracted a 24-h-dependent forgetting of a familiar object as well as phencyclidine-induced recognition deficits in the rats at doses ranging from 7.5 to 30 mg/kg. In contrast, entacapone, a COMT inhibitor that does not readily cross the blood-brain barrier, failed to show efficacy at doses up to 30 mg/kg. Tolcapone at a dose of 30 mg/kg also improved novel object recognition performance in transgenic mice, which showed clear recognition deficits. Complementing earlier studies, our results indicate that central inhibition of COMT positively impacts recognition memory processes and might constitute an appealing treatment for cognitive dysfunction related to neuropsychiatric disorders.
Assuntos
Benzofenonas/farmacologia , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Nitrofenóis/farmacologia , Animais , Benzofenonas/administração & dosagem , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Catecol O-Metiltransferase/genética , Inibidores de Catecol O-Metiltransferase/administração & dosagem , Catecóis/farmacologia , Transtornos Cognitivos/fisiopatologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Masculino , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Nitrilas/farmacologia , Nitrofenóis/administração & dosagem , Fenciclidina/administração & dosagem , Fenciclidina/toxicidade , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , TolcaponaRESUMO
In the present article, we describe a new protocol for the inhibitory avoidance test, with a dual purpose: (1) to provide a less variable and more reliable assessment of the efficacy of potential cognitive enhancers in antagonizing scopolamine-induced long-term-memory deficits, and (2) to secure a high throughput for pharmacological screening of cognitive enhancers. The new protocol consists of two acquisition trials that are followed 24 h later by a single retention trial. In the present study, this protocol clearly dissociated the frequency distributions of retention latencies between scopolamine- and vehicle-treated groups and allowed validation by means of two acetylcholinesterase inhibitors-tacrine and donepezil-that proved to be active in counteracting the scopolamine-induced memory deficit. This protocol also produced stability of the behavioral response to pharmacological agents over a 3-year period. A statistical power analysis indicated that, depending on the efficacy of the drug/dose, a sample size of 5-12 mice was required in order to show a reversal of the scopolamine-induced memory deficit. The double-trial acquisition protocol is suitable for testing cognitive enhancers, while also providing a clearly enhanced throughput.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/instrumentação , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Donepezila , Interações Medicamentosas , Indanos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nootrópicos/farmacologia , Piperidinas/farmacologia , Escopolamina/farmacologia , Tacrina/farmacologiaRESUMO
Birth defects (congenital anomalies) are the leading cause of death in babies under 1 year of age. Neural tube defects (NTD), with a birth incidence of approximately 1/1000 in American Caucasians, are the second most common type of birth defect after congenital heart defects. The most common presentations of NTD are spina bifida and anencephaly. The etiologies of NTDs are complex, with both genetic and environmental factors implicated. In this manuscript, we review the evidence for genetic etiology and for environmental influences, and we present current views on the developmental processes involved in human neural tube closure.
Assuntos
Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/patologia , Animais , Meio Ambiente , Feminino , Humanos , Camundongos , Sistema Nervoso/embriologia , Defeitos do Tubo Neural/epidemiologia , GravidezRESUMO
Modern cell biologists typically use reporter genes either alone or co-expressed with a protein of interest to facilitate the localization or quantification of protein expression. Our work demonstrates that reporter genes should be used cautiously, as several common reporter gene products are toxic to primary cortical neuronal cultures. We used the herpes simplex virus-based viral amplicon vector to transduce cortical neurons with three different reporter genes and assessed whether any reporter gene products were toxic over time, by monitoring neurite disintegration and apoptosis. Toxicity varied as a function of the reporter gene, the gene product localization, and the level of reporter gene expression. Transduction of enhanced green fluorescent protein or nuclear-localized beta-galactosidase was more toxic than non-nuclear localized beta-galactosidase. This work underscores the need for careful design of gene expression constructs. Moreover, in studies where cell injury or toxicity is being evaluated, their use should be carefully considered.