title: N (w) -propyl-L-arginine (L-NPA) reduces status epilepticus and early epileptogenic events in a mouse model of epilepsy: behavioural, EEG and immunohistochemical analyses.
abstract: We investigated the anticonvulsant and neurobiological effects of a highly selective neuronal nitric oxide synthase (nNOS) inhibitor, N (w) -propyl-l-arginine (L-NPA), on kainic acid (KA)-induced status epilepticus (SE) and early epileptogenesis in C57BL/6J mice. SE was induced with 20 mg/kg KA (i.p.) and seizures terminated after 2 h with diazepam (10 mg/kg, i.p). L-NPA (20 mg/kg, i.p.) or vehicle was administered 30 min before KA. Behavioural seizure severity was scored using a modified Racine score and electrographic seizure was recorded using an implantable telemetry device. Neuronal activity, activity-dependent synaptogenesis and reactive gliosis were quantified immunohistochemically, using c-Fos, synaptophysin and microglial and astrocytic markers. L-NPA treatment reduced the severity and duration of convulsive motor seizures, the power of electroencephalogram in the gamma band, and the frequency of epileptiform spikes during SE. It also reduced c-Fos expression in dentate granule cells at 2 h post-KA, and reduced the overall rate of epileptiform spiking (by 2- to 2.5-fold) in the first 7 days after KA administration. Furthermore, treatment with L-NPA suppressed both hippocampal gliosis and activity-dependent synaptogenesis in the outer and middle molecular layers of the dentate gyrus in the early phase of epileptogenesis (72 h post-KA). These results suggest that nNOS facilitates seizure generation during SE and may be important for the neurobiological changes associated with the development of chronic epilepsy, especially in the early stages of epileptogenesis. As such, it might represent a novel target for disease modification in epilepsy.
authors.affiliation: Institute of Ageing and Chronic Disease, Faculty of Health and Life Sciences, University of Liverpool, 4th floor Room 4.306, UCD Duncan Building, Daulby Street, Liverpool L69 3GA, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Beamer
authors.forename: Jakub
authors.initials: J
authors.lastname: Otahal
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Sills
authors.forename: Thimmasettappa
authors.initials: T
authors.lastname: Thippeswamy
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058256:Brain Waves / Q000187:drug effects*; D018891:Dentate Gyrus / Q000737:chemistry / Q000166:cytology / Q000503:physiopathology; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D005911:Gliosis / Q000188:drug therapy; D007150:Immunohistochemistry; D007608:Kainic Acid; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects; D016708:Synaptophysin / Q000032:analysis; D013686:Telemetry
chemical_list: C109599:N(omega)-propylarginine; D016760:Proto-Oncogene Proteins c-fos; D016708:Synaptophysin; D001120:Arginine; D003975:Diazepam; D007608:Kainic Acid