ABSTRACT
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.
Subject(s)
Interleukin-6/pharmacology , Neurons/drug effects , Receptor, Adenosine A1/metabolism , Synaptic Transmission/drug effects , Up-Regulation/drug effects , Analysis of Variance , Animals , Autoradiography/methods , Cell Survival/drug effects , Cells, Cultured , Cerebral Cortex/cytology , Embryo, Mammalian , Enzyme Inhibitors/pharmacology , Excitatory Amino Acid Agents/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/radiation effects , Hippocampus/drug effects , Hippocampus/physiology , Interleukin-6/deficiency , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pentylenetetrazole/pharmacology , Radioligand Assay/methods , Receptor, Adenosine A1/genetics , Seizures/chemically induced , Seizures/drug therapy , Seizures/genetics , Time FactorsABSTRACT
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.
