RESUMEN
BACKGROUND: There is evidence of increased systemic expression of active GSK3B in Alzheimer's disease patients, which apparently is associated with the formation of senile plaques and neurofibrillary tangles. Due to its central role in the pathogenesis of AD, GSK3B is currently a promising target of the pharmaceutical industry. Whilst trials with specific GSK inhibitors in AD are under way, major attention has been focused on the neuroprotective effects of lithium. Whereas the direct and indirect inhibitory effects of lithium over GSK3 activity have been documented by several groups, its effects over Gsk3 transcription have not yet been addressed. METHODS: We used quantitative PCR to evaluate the transcriptional regulation of Gsk3a and Gsk3b in lithium-treated primary cultures of rat cortical and hippocampal neurons. RESULTS: We found a significant and dose-dependent reduction in the expression of Gsk3b, which was specific to hippocampal cells. This same effect was further confirmed in vivo by measuring Gsk3 expression in different brain regions and in peripheral leukocytes of adult rats treated with lithium. CONCLUSION: Our studies show that LiCl can modulate Gsk3b transcription in vitro and in vivo. This observation suggest new regulatory effects of lithium over Gsk3b, contributing to the better understanding of its mechanisms of action, offering a new and complementary explanation for Gsk3b modulation and reinforcing its potential for the inhibition of key pathological pathways in Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Glucógeno Sintasa Quinasa 3/metabolismo , Leucocitos/metabolismo , Litio/farmacología , Neuronas/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Leucocitos/efectos de los fármacos , Neuronas/efectos de los fármacos , Reacción en Cadena de la Polimerasa , Embarazo , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
Leprosy is the major cause of non-traumatic neuropathy. Herein, we investigated the role of ninjurin 1, an adhesion molecule involved in nerve regeneration in leprosy. Our results demonstrated that M. leprae stimulates in vitro up-regulation of ninjurin mRNA in cultured Schwann and blood cells as well as in vivo mRNA and protein expression in leprosy nerve biopsies. A polymorphism (asp110ala) was investigated in a case-control study (1123 individuals) and no association was found with leprosy per se or with disseminated forms. Nevertheless, ala110 was associated with functional nerve impairment (OR=2.42; p=0.02 for ala/ala) and with lower mRNA levels. Our data suggests that asp110ala could be a valuable genetic marker of nerve damage in leprosy.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Lepra/complicaciones , Lepra/genética , Factores de Crecimiento Nervioso/genética , Nervios Periféricos/metabolismo , Enfermedades del Sistema Nervioso Periférico/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Alanina/genética , Sustitución de Aminoácidos/genética , Ácido Aspártico/genética , Moléculas de Adhesión Celular Neuronal/química , Análisis Mutacional de ADN , Femenino , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Genotipo , Humanos , Inmunidad Innata/genética , Lepra/fisiopatología , Masculino , Persona de Mediana Edad , Factores de Crecimiento Nervioso/química , Nervios Periféricos/patología , Nervios Periféricos/fisiopatología , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/fisiopatología , ARN Mensajero/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
Estudos recentes tem sugerido a participacao da galanina na fisiopatologia de algumas doencas neuropsiquiatricas, tais como a doenca de Alzheimer, a esquizofrenia e a anorexia nervosa. A galanina e um neuropeptideo largamente distribuido nos sistemas nervoso central e periferico, presente de forma expressiva no prosencefalo de varios mamiferos. Modelos animais ...