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Title: A kainic acid-induced status epilepticus model of epileptogenesis in the C57BL/6J mouse : interventions targeting nitric oxide and NMDA receptor-mediated pathophysiology
Author: Beamer, Edward
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2012
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In this thesis, the behavioral, electrographic and neurobiological effects of a period of kainic acid-induced status epilepticus (SE) on the C57BL/6J inbred mouse strain are characterised. The severity of epileptic behaviour was scored, used immunohistochemistry to investigate the anatomical distribution of c-Fos expression in the hippocampal formation following SE and recorded EEG during and after SE using an implantable, wireless telemetry device. Further to assessing the severity of SE, changes subsequent to seizures related to the emergence of chronic epilepsy were investigated, including reactive gliosis and synaptogenesis and epileptiform discharges in the EEG trace. I investigated the potential of a range of pharmacological agents for modulating the severity of induced seizures and disease progression. These included drugs targetting the NR2B subunit of the NMDA receptor (RO 25-6981), neuronal nitric oxide synthase (L-NPA), The post synaptic density protein 95 (Tat-NR2B9a) and inducible nitric oxide synthase (1400W). L-NPA, when administered prior to the induction of SE was found to profoundly suppress the emergence of epileptiform activity, including behavioural, electrographic and neurobiological indicators. Further, L-NPA’s modulation of the precipitating event lead to a decrease in neurobiological changes associated with epileptogenesis, such as reactive gliosis in the CA3 region of the hippocampus and 5 elevated synaptogenesis in th molecular layer of the hippocampus. This correlated with a marked decrease in epileptiform discharges in the EEG trace. A novel method of kainic acid administration was trialed, involving multiple small doses of the drug, titrated by the severity of behaviour. This method led to a decrease in mortality and an increase in the severity and inter-individual uniformity of SE, assessed by the analysis of behaviour, EEG and c-Fos expression in the hippocampus. Furthermore, this method induced neurobiological changes associated with epileptogenesis 3 days following SE and was associated with an increased frequency of epileptiform discharges for 7 days post SE.
Supervisor: Thippeswamy, T.; Sills, G. J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry ; RM Therapeutics. Pharmacology ; SF Animal culture