Abstracts

Rationale: The sequelae of status epilepticus (SE) include a pattern of selective, hierarchical vulnerability of hippocampal neurons. Evidence suggests that nitric oxide (NO) may be involved in seizure-induced neuronal death, but its role has not been characterized fully. Available data suggest that low concentrations of NO may be neuroprotective, but that high concntrations are neurotoxic. In order to better understand the effect of SE on NO synthesizing hippocampal neurons, we studied the temporal profile of their vulnerability to injury following electrogenic limbic SE. Methods: SE was induced for 140 minutes in adult male Wistar rats via unilateral dorsal hippocampal stimulation. Control rats had electrodes implanted only. After a survival period of 1 hr, 24 hrs or 5 days, serial 50mm hippocampal sections were processed for neuronal nitric oxide synthase (NOS) immunohistochemistry using a standard ABC method with nickel enhanced DAB as the chromagen. Results: A consistent distribution of NOS-immunoreactive (NOS-IR) neurons was observed in all control animals. NOS-IR neurons were scattered throughout the hippocampus with the highest concentration in the dentage gyrus where a band of neurons was seen along the border of the hilus and dentate granule cells. One hr and 24 hrs after SE there was a reduction in NOS-IR neurons in a pattern suggesting vulnerability of hilar polymorphic neurons> CA1/CA3 neurons hilar neurons bordering granule cells. Five days after SE there was a striking loss of NOS-IR neurons in all hippocampal regions. NOS-IR loss was greatest in dorsal hippocampus, with a dorsal to ventral gradient of preserved immunoreactivity. Discussion: NOS-IR neurons are highly vulnerable to delayed neuronal death following SE, and hilar polymorphic neurons appear more vulnerable than the NOS-IR neurons bordering granule cells. These findings suggest a neurotoxic role for NO in SE. The temporal profile of neuronal loss suggests that NOS inhibitors could have a therapeutic role.