Abstracts

The neuropeptide, corticotrophin releasing hormone (CRH) may play an important role in seizure disorders as high concentrations of CRH can directly depolarize hippocampal pyramidal neurons and the peptide has been shown to produce both epileptiform activity and neuronal loss. In contrast, antagonists of CRH have been shown to exert neuroprotective effects in a variety of neurodegenerative models. Therefore, we examined the neuroprotective efficacy of an antagonist of CRH against kainate-induced status epilepticus (SE).
Adult male (C57BL/6X129/SvJ)F2 mice were intraperitoneally injected with CRH antagonist either 15 minutes before and 45 minutes following systemic kainate administration (25 mg/kg, s.c.), or following 45 minutes of continuous kainate-induced SE. Mice were monitored continuously for 4 hours for the onset and extent of seizure activity following KA administration. After 3 days of recovery, mice were assessed for histopathological outcome using selective silver stains and the fluorescent marker, Fluoro-Jade, to identify the presence of degenerative debris, and a Nissl stain to assess neuronal loss and lesion size.
Administration of kainic acid (KA) alone induced SE in all F2 mice, while administration of CRH antagonist before and following KA administration, significantly reduced the duration of severe seizures and diminished behavioral seizure scores. Administration of CRH antagonist following 45 minutes of kainate-induced SE was without effect on modulating behavioral seizure score or duration of severe seizures. While KA administration alone induced extensive cell death of CA3 hippocampal neurons in F2 mice, F2 animals administered the CRH antagonist before and following kainate administration displayed little to no cell death throughout area CA3. In contrast, when CRH antagonist was administered 45 minutes following KA-induced status epilepticus, F2 mice exhibited cell death throughout area CA3.
This study suggests that the neuroprotective effects of the CRH antagonist against KA-induced SE may be the result of its anticonvulsant effects, as administration of the CRH antagonist decreased the intensity of epileptic seizures as compared to controls and reduced histologic injury. The ability of CRH antagonists to decrease necrotic damage combined with the induction of CRH mRNA in vulnerable tissue following such insults, as demonstrated by some investigators, suggests that endogenous CRH may contribute to neuronal injury induced by excitotoxin administration. However, additional data are required to support this hypothesis.
[Supported by: [Supported by The James D. and Delia B. Baxter Foundation and NIH grant NS38696 to PES.]]