RESUMEN
The immunological response in the brain is crucial to overcome neuropathological events. Some inflammatory mediators, such as the immunoregulatory cytokine interleukin-6 (IL-6) affect neuromodulation and may also play protective roles against various noxious conditions. However, the fundamental mechanisms underlying the long-term effects of IL-6 in the brain remain unclear. We now report that IL-6 increases the expression and function of the neuronal adenosine A1 receptor, with relevant consequences to synaptic transmission and neuroprotection. IL-6-induced amplification of A1 receptor function enhances the responses to readily released adenosine during hypoxia, enables neuronal rescue from glutamate-induced death, and protects animals from chemically induced convulsing seizures. Taken together, these results suggest that IL-6 minimizes the consequences of excitotoxic episodes on brain function through the enhancement of endogenous adenosinergic signaling.
Asunto(s)
Interleucina-6/farmacología , Neuronas/efectos de los fármacos , Receptor de Adenosina A1/metabolismo , Transmisión Sináptica/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Análisis de Varianza , Animales , Autorradiografía/métodos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/citología , Embrión de Mamíferos , Inhibidores Enzimáticos/farmacología , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/efectos de la radiación , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Interleucina-6/deficiencia , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Pentilenotetrazol/farmacología , Ensayo de Unión Radioligante/métodos , Receptor de Adenosina A1/genética , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/genética , Factores de TiempoRESUMEN
Amyloid beta peptide (Abeta) is a neurotoxic metabolic product of the amyloid precursor protein (APP). Abeta is strongly implicated in the pathology of Alzheimer's disease (AD) and can be formed intracellularly. In this study, we show that the addition of Abeta to isolated mouse brain mitochondria can directly induce cytochrome c (Cyt c) release and mitochondrial swelling, which were partially inhibited by cyclosporin A (CsA). These results suggest that the Abetaaccumulated intracellularly by APP processing might exert neurotoxicity by interacting with mitochondria and inducing mitochondrial swelling and release of Cyt c, which activates caspase-3 and finally can lead to apoptosis in neuronal cells and to neurodegeneration in AD.