C C Trandafir1, W A Pouliot1, F E Dudek1, J J Ekstrand2. 1. Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108, United States. 2. Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84108, United States. Electronic address: jeffrey.ekstrand@hsc.utah.edu.
Abstract
RATIONALE: Seizures during status epilepticus (SE) cause neuronal death and induce cyclooxygenase-2 (COX-2). Pilocarpine-induced SE was used to determine if COX-2 inhibition with NS-398, when administered alone or with diazepam, decreases the duration and/or intensity of SE and/or reduces neuronal injury in the rat hippocampus. METHODS: Electroencephalogram (EEG) electrodes were implanted in male Sprague-Dawley rats. SE was induced with lithium-pilocarpine, and continuous EEG and video monitoring were performed for 24 h. Rats were divided into four groups (n=8-14 rats/group) and received NS-398, diazepam, NS-398 and diazepam, or vehicle 30 min after the first motor seizure. Six hours later, NS-398 injection was repeated in the NS-398 and in the NS-398+diazepam groups. The duration of SE (continuous spiking) and the EEG power in the γ-band were analyzed. FluoroJade B staining in the dorsal hippocampus at 24h after SE was analyzed semi-quantitatively in the CA1, CA3 and hilus. RESULTS: The duration and intensity of electrographic SE was not significantly different across the four groups. In rats treated with NS-398 alone, compared to vehicle-treated rats, neuronal damage was significantly lower compared to vehicle-treated rats in the CA3 (27%) and hilus (27%), but neuroprotection was not detected in the CA1. When NS-398 was administered with diazepam, decreased neuronal damage was further obtained in all areas investigated (CA1: 61%, CA3: 63%, hilus: 60%). CONCLUSIONS: NS-398, when administered 30 min after the onset of SE with a repeat dose at 6h, decreased neuronal damage in the hippocampus. Administration of diazepam with NS-398 potentiates the neuroprotective effect of the COX-2 inhibitor. These neuroprotective effects occurred with no detectable effect on electrographic SE.
RATIONALE: Seizures during status epilepticus (SE) cause neuronal death and induce cyclooxygenase-2 (COX-2). Pilocarpine-induced SE was used to determine if COX-2 inhibition with NS-398, when administered alone or with diazepam, decreases the duration and/or intensity of SE and/or reduces neuronal injury in the rat hippocampus. METHODS: Electroencephalogram (EEG) electrodes were implanted in male Sprague-Dawley rats. SE was induced with lithium-pilocarpine, and continuous EEG and video monitoring were performed for 24 h. Rats were divided into four groups (n=8-14 rats/group) and received NS-398, diazepam, NS-398 and diazepam, or vehicle 30 min after the first motor seizure. Six hours later, NS-398 injection was repeated in the NS-398 and in the NS-398+diazepam groups. The duration of SE (continuous spiking) and the EEG power in the γ-band were analyzed. FluoroJade B staining in the dorsal hippocampus at 24h after SE was analyzed semi-quantitatively in the CA1, CA3 and hilus. RESULTS: The duration and intensity of electrographic SE was not significantly different across the four groups. In rats treated with NS-398 alone, compared to vehicle-treated rats, neuronal damage was significantly lower compared to vehicle-treated rats in the CA3 (27%) and hilus (27%), but neuroprotection was not detected in the CA1. When NS-398 was administered with diazepam, decreased neuronal damage was further obtained in all areas investigated (CA1: 61%, CA3: 63%, hilus: 60%). CONCLUSIONS:NS-398, when administered 30 min after the onset of SE with a repeat dose at 6h, decreased neuronal damage in the hippocampus. Administration of diazepam with NS-398 potentiates the neuroprotective effect of the COX-2 inhibitor. These neuroprotective effects occurred with no detectable effect on electrographic SE.