Neuroprotective Effects of Diazepam, Carbamazepine, Phenytoin and Ketamine after Pilocarpine‐induced Status Epilepticus

Abstract

Cell damage and spatial localization deficits are often reported as long-term consequences of pilocarpine-induced status epilepticus. In this study, we investigated the neuroprotective effects of repeated drug administration after longlasting status epilepticus. Groups of six to eight Wistar rats received microinjections of pilocarpine (2.4 mg/µl, 1 µl) in the right dorsal hippocampus to induce a status epilepticus, which was attenuated by thiopental injection (35 mg/kg, i.p.) 3 hrs after onset. Treatments consisted of i.p. administration of diazepam, ketamine, carbamazepine, or phenytoin at 4, 28, 52, and 76 hr after the onset of status epilepticus. Two days after the treatments, rats were tested in the Morris water maze and 1 week after the cognitive tests, their brains were submitted to histology to perform haematoxylin and eosin staining and glial fibrillary acidic protein (GFAP) immunofluorescence detection. Post-status epilepticus rats exhibited extensive gliosis and cell loss in the hippocampal CA1, CA3 (70% cell loss for both areas) and dentate gyrus (60%). Administration of all drugs reduced cell loss in the hippocampus, with best effects observed in brains slices of diazepam-treated animals, which showed less than 30% of loss in the three areas and decreased GFAP immunolabelling. Treatments improved spatial navigation during training trials and probe trial, with exception of ketamine. Interestingly, in the probe trial, only diazepam-treated animals showed preference for the goal quadrant. Our data point to significant neuroprotective effects of repeated administration of diazepam against status epilepticus-induced cell damage and cognitive disturbances.

Rapid Throughput Analysis Demonstrates that Chemicals with Distinct Seizurogenic Mechanisms Differentially Alter Ca2+ Dynamics in Networks Formed by Hippocampal Neurons in Culture

“…Furthermore, we also demonstrate that the clinically used anticonvulsant lamotrigine antagonizes both kainate-and pilocarpine-induced Ca 21 responses at therapeutic concentrations. This is consistent with previous studies demonstrating that the low-affinity Na 1 channel antagonist carbamazepine antagonized pilocarpine-induced status epilepticus (Morrisett et al, 1987) and neuronal cell death (Cunha et al, 2009). Both carbamazepine and LTG also suppress KA-triggered status epilepticus (Czuczwar et al, 1982;Wang et al, 2000) and neuronal cell death (Das et al, 2010;Halbsgut et al, 2013;Park et al, 2013).…”

Modeling epileptogenesis and temporal lobe epilepsy in a non-human primate

“…In the pilocarpine and kainate models of epilepsy in rodents, a severe episode of SE is essential for the subsequent development of SRS (Goffin et al, 2007;Lemos and Cavalheiro, 1996). By managing the severity of the SE, injecting sub-therapeutic doses of diazepam after the SE onset, one can decrease mortality without decreasing the development of epilepsy (Cunha et al, 2009;Gao et al, 2007;Hellier et al, 1998;Mello et al, 1993;Treiman et al, 1998;Walton and Treiman, 1988). The immediate seizures following pilocarpine injection in marmosets were similar to those described in pilocarpine-treated rodents (Racine et al, 1972;Turski et al, 1983).…”

Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

“…The impact of SE induction and severity on neuroprotection or antiepileptogenesis was also demonstrated by Cunha et al (2009), who used intrahippocampal injection of pilocarpine to induce SE. SE was interrupted after 3 h by thiopental, followed 1 h later by treatment with different AEDs (diazepam, carbamazepine, phenytoin) or the NMDA antagonist ketamine.…”

“…Convulsive versus Nonconvulsive Status Epilepticus. Except for the study by Cunha et al (2009), which involved focal intrahippocampal injection of pilocarpine, all antiepileptogenesis studies have used systemic administration of either pilocarpine or kainate, which induces a severe generalized convulsive SE (summarized in Tables 2 and 3). Furthermore, the different electrical stimulation-based SE models have typically used stimulation protocols that induce a self-sustained convulsive SE that continues for hours after termination of stimulation.…”

“…SE was interrupted after 3 h by thiopental, followed 1 h later by treatment with different AEDs (diazepam, carbamazepine, phenytoin) or the NMDA antagonist ketamine. All drugs reduced cell loss in the hippocampal formation, including the hilus, and reduced SE-induced impairment of learning and memory (Cunha et al, 2009). These effects were clearly more marked than respective effects found after systemic administration of chemoconvulsants (Tables 2 and 3), substantiating the idea that the SE model used has a striking effect on the outcome of antiepileptogenesis studies.…”