Abstracts

Different types of cortical injury such as trauma, ischemia and infection are often accompanied by increased permeability of the blood-brain barrier (BBB). We have recently shown that perturbations in the blood-brain barrier (BBB) may lead to epileptiform activity in the neocortex. We also demonstrated that serum albumin acts as the epileptogenic factor. Our recent data suggest that the action of serum albumin is mediated via its interactions with transforming growth factor-beta (TGF-[beta]) receptors in astrocytes. Following albumin uptake into astrocytes we show that the glial inward rectifying potassium channel, Kir 4.1, was down regulated which results in reduced buffering of extracellular potassium. This, in turn, leads to activity-dependent accumulation of extracellular potassium, resulting in N-methyl-D-asparate (NMDA)-receptor-mediated neuronal hyperexcitability and epileptiform activity., In order to elucidate the cascade of transcriptional effects following albumin uptake and the consequent TGF-[beta] receptor activation we evaluated expression levels at different time points following induced permeation of BBB, exposure to albumin, or exposure to TGF-[beta]. Genome scale evaluations using DNA microarrays were carried out in conjunction with gene-specific quantitative RT-PCR of pre-selected genes., All three treatments resulted in down regulation of both Kir 4.1 and the glial protein, glutamine synthetase as well as up regulation of the glial fibrillary acidic protein albeit with different time courses. All genes were normalized to [beta]-Actin which showed no change in expression across all treatments and time points. Analysis of the genome scale expression levels present transcriptional signatures common to all three treatments, revealing the molecular pathway underlying the process of epileptogenesis., Here, we highlight a novel cascade of events following common brain insults leading to brain dysfunction and eventually epilepsy, suggesting possible therapeutic targets., (Supported by the Mary Elizabeth Rennie Epilepsy Foundation.)