Abstracts

Rationale: Traumatic brain injury is a common cause of epileptogenesis. The involvement of inflammation in the pathogenesis of epilepsy and its underlying mechanisms are still poorly understood. Thus, it is also unknown how epileptogenesis can be prevented. Here we investigated the possible involvement of the COX-2 dependent inflammatory pathway in the progression from injury to seizure activity. Methods: The short term effects of PGE-2 were studied by directly applying low concentration of PGE-2 to both cultured and acute neocortical slices. To study long term effects, the organotypic slice preparation was used to simulate an inflammation of the brain tissue for 48 hours by incubating the slices in PGE2. Results: In acute slices (n=6), PGE-2 decreased the amplitude of evoked excitatory postsynaptic potentials (EPSP) by 32.59 ± 17.01 % compared to controls. The specific PGE-2 receptor (EP-3) agonist sulprostone mimicked the effect of PGE-2 and reduced the amplitude of EPSPs by 29.52 ± 10.07 % in acute slices (n=5). Acute application of PGE-2 reversibly suppressed spontaneous network activity and spontaneously occurring upstates (amplitude: 13.95 ± 4.46 mV) in slices cultured in normal media. Chronic treatment with PGE-2 for 48 hours dramatically altered the network behavior of organotypic slice cultures. In PGE-2 treated slices, upstates showed paroxysmal depolarization shifts (PDSs) that were characterized by significantly larger depolarization amplitudes (36.65 ± 9.11 mV;n=11). Conclusions: Development of PDSs during the upstates in the cultured slices after prolonged exposure to PGE2 suggests a possible mechanism for epileptogenesis. We propose that the prolonged activity deprivation caused by PGE2 incubation evokes a homeostatic response that increases synaptic excitatory transmission and provokes high-amplitude paroxysmal depolarization shifts at the network level.