Abstracts

Rationale: Symptomatic epilepsy is a neurological disorder characterized by status epilepticus (SE) induced by a brain insult, a latent period, and occurrence of spontaneous recurrent seizures (SRS). Seizures lead directly to damage in the CNS and are accompanied by other alterations, including neurogenesis in the hippocampal dentate gyrus (DG). Methods: This study investigated the epileptogenic process in an organophosphorous (OP) nerve agent soman (GD) exposure model of epilepsy using electrographic seizure-detecting techniques, FluoroJade B staining for neuropathology and doublecortin immunostaining for neurogenesis. The following groups were evaluated: 1) Control group (na ve animals); 2) No SE group (animals without SE); 3) No DZP group (animals with no diazepam (DZP) treatment); 4) DZP group (animals with DZP treatment 30 min after SE onset); and 5) DZP/VPA group (animals with DZP and valproic acid (VPA, 50 mg/kg) combined treatment 30 min after SE onset and two more doses of VPA 60 and 180 min after SE onset).Results: Animals from No DZP, DZP and DZP/VPA groups showed signs of SRS 7 days after GD exposure accompanied by severe neuropathology in the hippocampus and amygdala and increased levels of neurogenesis in the DG. Frequency of SRS from 7 to 15 days after SE onset (9.33 2.31; No DZP group) decreased in the animals that received only DZP (2.33 1.11) or DZP/VPA treatments (1.5 1.02). This treatment s antiepileptogenic effects were correlated with reduced neuronal damage in the hippocampus as seen 15 days after exposure (r = 0.559; p = 0.008). DZP alone treatment protected hippocampus and amygdala and when combined with VPA increased neuroprotection over that of DZP alone, but only in the hippocampus (Fig 1B and E). All of the hippocampal nuclei were protected after DZP and VPA combined therapy as seen by the image of the dentate gyrus which shows no damage (Fig 1C and E). In the amygdala, the only nuclei protected by this combination therapy were the basomedial and the basolateral nuclei (Fig. 1D and E), and there was no difference between the DZP and DZP/VPA groups. Only animals that presented SRS 7 days after GD-exposure (no DZP, DZP and DZP/VPA groups), presented a statistically significant increase in new neurons in the DG relative to the control group. However, neurogenesis in the DG increased after both treatments (r = -0.454; p=0.04). Conclusions: The combination of DZP/VPA and DZP alone treatments proved to be quite reliable in causing anticonvulsant and neuroprotective effects during SE that lead to a reduction in SRS and neuronal damage, mainly in hippocampus, but with continuing enhanced neurogenesis above normal levels. These results support the idea that in this model, the increased levels of neurogenesis may serve as signal that the hippocampus is trying to repair itself against the first brain insult, reducing excitability in the DG and consequent seizure discharges and neuronal damage. Financial Support: The Defense Threat Reduction Agency (Grant I.E0042-08-WR-C)