Abstracts

Epileptogenesis precipitated by status epilepticus (SE) is believed to evolve during a latent period which intervenes between SE and the emergence of spontaneous seizures. Vascular pathologies have been observed in several limbic structures in chronically epileptic animals following SE, including upregulated vascular endothelial growth factor (VEGF) among reactive astrocytes, angiogenesis, and increases in neovascular permeability. Here we have investigated the temporal evolution of these vascular pathologies following SE in the rat., SE was induced in male wistar rats (250g [ndash] 350 g) by systemic kainic acid injection (10 mg/kg, i.v.), and was terminated four hours after onset by injection of pentobarbital (20 mg/kg, i.p.). The control group received vehicle injections and did not develop SE. Bromodeoxyuridine (BrdU) injections (50 mg/kg, i.p.) were administered daily for seven consecutive days to separate cohorts beginning 1, 7, 14, 21, 28, 35, 42, or 49 days post-SE. Animals in each cohort were sacrificed 14 days after completing the BrdU injection series, and angiogenesis was subsequently assayed by double-label immunohistochemistry for BrdU and von Willebrand factor. Prior to sacrifice, vascular permeability was assayed serially at 7, 14, 21, 24 and 56 days post-SE, using gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-enhanced magnetic resonance imaging (MRI). Gd-DTPA was administered using a stepped down infusion protocol that maintained a relatively constant blood Gd-DTPA level during 20 min of imaging. Pre-contrast T1-weighted images (T1WI) were subtracted from post-contrast T1WI to identify enhancing areas., Endothelial proliferation was significantly increased (p [lt] 0.05) during the first two weeks (day 1 and day 7 cohorts) post-SE, spanning the duration of the average latent period. At sacrifice, coincidently labeled cells were commonly found in abnormal neovessels within regions damaged by SE. MRI image subtraction indicated that vascular permeability increased toward the end of the latent period, coinciding with the formation of abnormal neovascular complexes within regions of epileptogenesis., The evolution of vascular pathologies following kainic acid-induced SE occurred primarily during the latent period which preceded the onset of spontaneous seizures. These were observed exclusively in regions of the brain damaged by SE and consist of abnormally permeable neovascular complexes formed via angiogenesis. The timing of events in relation to SE suggests that the resultant increase in vascular permeability may bias the adjoining neuropil toward hyperexcitability and promote the emergence of spontaneous seizures., (Supported by Henry Ford Health Sciences Center: Mentored Scientist Grant #A10222)