title: Orphenadrine-induced convulsive status epilepticus in rats responds to the NMDA antagonist dizocilpine.
abstract: BACKGROUND
  Identification of new molecular targets as well as the new models recapitulating different aspects of pathophysiology of status epilepticus (SE) in humans might prove essential for the breakthrough in the efforts against pharmacoresistance in epilepsy. Recently, we described a new model of generalized convulsive SE induced with orphenadrine (ORPH) in rats with unique characteristics [5]. The current study was aimed at assessing the efficacy of a new generation antiepileptic drugs (AEDs) and some of the experimental agents in suppressing ORPH-evoked seizures in rats.
  
  
  METHODS
  ORPH was administered intraperitoneally (ip) in the dose of 80 mg/kg in male Wistar rats. The latency to first seizure, the number of seizure episodes and the duration of overt SE, as well as the incidence of deaths was scored with simultaneous electroencephalographic (EEG) recordings.
  
  
  RESULTS
  ORPH induced seizures in 100% of animals at a dose of 80 mg/kg, associated with low mortality and good behavioural outcome. Among new generation AEDs: felbamate, levetiracetam, topiramate, lamotrigine and progabide did not affect the seizure incidence. Among the experimental drugs, only dizocilpine, the non-competitive NMDA antagonist, dose-dependently affected the occurrence of the SE (p<0.001). However, CGP-39551 competitive NMDA antagonist, the same as scopolamine and mecamylamine (muscarinic and nicotinic receptors antagonists, respectively) showed no effect.
  
  
  CONCLUSIONS
  Based on the above findings, one may speculate that NMDA activation is partly involved in the proconvulsant activity of orphenadrine but may not be the primary pathomechanism. ORPH-induced seizures may provide an interesting option for studying novel targets for pharmacological interventions in status epilepticus.
authors.affiliation: Department of Neurology, Medical University of Lublin, Lublin, Poland. Electronic address: krejdak@europe.com.
authors.forename: Konrad
authors.initials: K
authors.lastname: Rejdak
authors.affiliation: Department of Animal Physiology, Institute of Biology and Biochemistry, Maria Curie-Skłodowska University, Lublin, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Nieoczym
authors.affiliation: 2(nd) Department of Anesthesiology and Intensive Care, Medical University of Lublin, Lublin, Poland.
authors.forename: Mirosław
authors.initials: M
authors.lastname: Czuczwar
authors.affiliation: Department of Human Anatomy, Medical University of Lublin, Lublin, Poland; Department of Urology and Urological Oncology, Medical University of Lublin, Lublin, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Kiś
authors.affiliation: Department of Animal Physiology, Institute of Biology and Biochemistry, Maria Curie-Skłodowska University, Lublin, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Wlaź
authors.affiliation: Department of Toxicology, Institute of Agricultural Medicine, Lublin, Poland; Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Lublin, Poland.
authors.forename: Waldemar A
authors.initials: WA
authors.lastname: Turski
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004569:Electroencephalography / Q000379:methods; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009966:Orphenadrine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; C064540:CGP 39551; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D009966:Orphenadrine
keywords: Dizocilpine; Orphenadrine; Rats; Refractory status epilepticus model