Nw-Propyl-l-arginine (L-NPA) reduces status epilepticus and early epileptogenic events in a mouse model of epilepsy: behavioural, EEG and immunohistochemical analyses

Authors

  • Edward Beamer,

    1. 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
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  • Jakub Otahal,

    1. Department of Developmental Epileptology, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska, Czech Republic
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  • Graeme J. Sills,

    1. Institute of Translational Medicine, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
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  • Thimmasettappa Thippeswamy

    1. 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
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Dr T. Thippeswamy, as above.
E-mail: tswamy@liv.ac.uk

Abstract

We investigated the anticonvulsant and neurobiological effects of a highly selective neuronal nitric oxide synthase (nNOS) inhibitor, Nw-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.

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