Neuroprotective effects of diazepam, carbamazepine, phenytoin and ketamine after pilocarpine-induced status epilepticus.
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 long-lasting status epilepticus. Groups of six to eight Wistar rats received microinjections of pilocarpine (2.4 mg/microl, 1 microl) 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.
Cunha
Alexandra Olimpio Siqueira
AO
Neurobiology and Venoms Laboratory, Department of Biology, University of São Paulo, Ribeirão Preto, SP, Brazil.
Mortari
Márcia Renata
MR
Liberato
José Luiz
JL
dos Santos
Wagner Ferreira
WF
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology*; D018891:Dentate Gyrus / Q000187:drug effects / Q000473:pathology; D003975:Diazepam / Q000494:pharmacology*; D004334:Drug Administration Schedule; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010672:Phenytoin / Q000494:pharmacology*; D010862:Pilocarpine; D051381:Rats; D017208:Rats, Wistar; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology
D000927:Anticonvulsants; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D010862:Pilocarpine; D002220:Carbamazepine; D010672:Phenytoin; D007649:Ketamine; D003975:Diazepam