deoxycholic-acid and Epilepsy

Focal epilepsy often develops following traumatic, ischemic, or infectious brain injury. While the electrical activity of the epileptic brain is well characterized, the mechanisms underlying epileptogenesis are poorly understood. We have recently shown that in the rat neocortex, long-lasting breakdown of the blood-brain barrier (BBB) or direct exposure of the neocortex to serum-derived albumin leads to rapid upregulation of the astrocytic marker GFAP (glial fibrillary acidic protein), followed by delayed (within 4-7 d) development of an epileptic focus. We investigated the role of astrocytes in epileptogenesis in the BBB-breakdown and albumin models of epileptogenesis. We found similar, robust changes in astrocytic gene expression in the neocortex within hours following treatment with deoxycholic acid (BBB breakdown) or albumin. These changes predict reduced clearance capacity for both extracellular glutamate and potassium. Electrophysiological recordings in vitro confirmed the reduced clearance of activity-dependent accumulation of both potassium and glutamate 24 h following exposure to albumin. We used a NEURON model to simulate the consequences of reduced astrocytic uptake of potassium and glutamate on EPSPs. The model predicted that the accumulation of glutamate is associated with frequency-dependent (>100 Hz) decreased facilitation of EPSPs, while potassium accumulation leads to frequency-dependent (10-50 Hz) and NMDA-dependent synaptic facilitation. In vitro electrophysiological recordings during epileptogenesis confirmed frequency-dependent synaptic facilitation leading to seizure-like activity. Our data indicate a transcription-mediated astrocytic transformation early during epileptogenesis. We suggest that the resulting reduction in the clearance of extracellular potassium underlies frequency-dependent neuronal hyperexcitability and network synchronization.

Topics: Albumins; Animals; Astrocytes; Computer Simulation; Deoxycholic Acid; Disease Models, Animal; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Glutamic Acid; In Vitro Techniques; Male; Models, Neurological; Neocortex; Oligonucleotide Array Sequence Analysis; Patch-Clamp Techniques; Potassium; Rats; Rats, Wistar

Disruption of the blood-brain barrier (BBB) is a characteristic finding in common neurological disorders. Human data suggest BBB disruption may underlie cerebral dysfunction. Animal experiments show the development of epileptiform activity following BBB breakdown. In the present study we investigated the neurophysiological, structural and functional consequences of BBB disruption. Adult rats underwent focal BBB disruption in the rat sensory-motor cortex using the bile salt sodium deoxycholate (DOC). Magnetic resonance imaging in-vivo showed an early BBB disruption with delayed reduction in cortical volume. This was associated with a reduced number of neurons and an increased number of astrocytes. In-vitro experiments showed that the threshold for spreading depression and the propagation velocity of the evoked epileptic potentials were increased 1 month after treatment. Furthermore, animals' motor functions deteriorated during the first few weeks following BBB disruption. Treatment with serum albumin resulted in a similar cell loss confirming that the effect of DOC was due to opening of the BBB. Our findings suggest that delayed neurodegeneration and functional impairment occur following the development of the epileptic focus in the BBB-permeable cerebral cortex.

Topics: Animals; Astrocytes; Atrophy; Blood-Brain Barrier; Cerebral Arteries; Cerebrovascular Circulation; Cortical Spreading Depression; Deoxycholic Acid; Dyskinesia, Drug-Induced; Epilepsy; Gliosis; Magnetic Resonance Imaging; Male; Neocortex; Nerve Degeneration; Neural Conduction; Organ Culture Techniques; Rats; Rats, Wistar; Serum Albumin; Time Factors