title: Co-administration of subtherapeutic diazepam enhances neuroprotective effect of COX-2 inhibitor, NS-398, after lithium pilocarpine-induced status epilepticus.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108, United States.
authors.forename: C C
authors.initials: CC
authors.lastname: Trandafir
authors.affiliation: Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108, United States.
authors.forename: W A
authors.initials: WA
authors.lastname: Pouliot
authors.affiliation: Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108, United States.
authors.forename: F E
authors.initials: FE
authors.lastname: Dudek
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84108, United States. Electronic address: jeffrey.ekstrand@hsc.utah.edu.
authors.forename: J J
authors.initials: JJ
authors.lastname: Ekstrand
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D003975:Diazepam / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D004567:Electrodes, Implanted; D004569:Electroencephalography; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D018020:Lithium Compounds; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009578:Nitrobenzenes / Q000008:administration & dosage*; D010862:Pilocarpine; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013449:Sulfonamides / Q000008:administration & dosage*; D014741:Video Recording
chemical_list: D000927:Anticonvulsants; D052246:Cyclooxygenase 2 Inhibitors; D018020:Lithium Compounds; D018696:Neuroprotective Agents; D009578:Nitrobenzenes; D013449:Sulfonamides; D010862:Pilocarpine; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D003975:Diazepam
keywords: cyclooxygenase-2 (COX-2); inflammation; neuroprotection