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Research regarding child outcome following in utero exposure to antiepileptic drugs, has documented increased risks for later developmental delay, cognitive impairment and associated language difficulties. Research regarding malformation data has utilised pregnancy and epilepsy registers in order to document the relative risks associated with individual antiepileptic drug exposure, yet pregnancy and epilepsy registers have not been widely utilised in the investigation of child cognitive development. The current research aims to document the developmental abilities of children born to women with epilepsy exposed to the novel antiepileptic drug Levetiracetam (n=110) and the established antiepileptic drug Sodium Valproate (n=86), utilising the U.K.Epilepsy and Pregnancy Register. A control group of children born to women without epilepsy, not taking medication during pregnancy, previously assessed by the Liverpool and Manchester Neurodevelopment Group-was also utilised for comparison (n=232). Children were assessed at either 0-24 months of age or 36-54 months of age. Tests of child development and language abilities, as well as parental report questionnaires pertaining to neurodevelopmental disorders, were administered. Children exposed in utero to Levetiracetam were not found to differ from control children on any measures administered. Linear regression analysis revealed Sodium Valproate exposure to be predictive of poorer overall developmental abilities for children between 0-24 months of age. Further, for children 36-54 months of age, linear regression analysis revealed Sodium Valproate exposure to be predictive of poorer gross locomotor skills, comprehension oflanguage abilities and expressive language abilities. No significant differences were found between any of the groups in regards to parental report pertaining to features of neurodevelopmental disorder. Pregnancy guidelines and preconception counselling information for women with epilepsy should take into account the findings of the current thesis, when deciding upon anti epileptic drug treatment, so that informed decisions can be made by women with epilepsy in conjunction with their healthcare professionals. The current research was sponsored by UCR

Epilepsy affects approximately 1% of the world population and is the most serious neurological conditions. In the UK, 30-35,000 new cases of epilepsy are diagnosed each year, resulting in a prevalence of 300,000 nationwide. There is significant need for new drug treatments. Yet we have a poor understanding of how many of these drugs mediate their antiepileptic effect, and how and where they are distributed within the brain. This thesis sought to investigate the pharmacokinetic and neuropharmacokinetic inter-relationship and the neuropharmacology of two new antiepileptic drugs, vigabatrin and levetiracetam two drugs with distinct mechanisms of action. Firstly, a freely moving and freely behaving rat model was used to determine the pharmacokinetics of vigabatrin and levetiracetam simultaneously in serum, cerebrospinal fluid (CSF) and brain frontal cortex and hippocampal extracellular fluid (ECF). Secondly, amino acid neurotransmitter concentrations were monitored in CSF (by direct CSF sampling) and brain ECF (by microdialysis) after vigabatrin and levetiracetam administration. Thirdly, the effects of vigabatrin and levetiracetam on paired-pulse inhibition recorded in the dentate gyrus evoked by perforant path stimulation were established. Vigabatrin rapidly entered the blood (serum), CSF and ECF (frontal cortex and hippocampus) compartments with concentrations increasing linearly and dose- dependently. Time to maximum concentration (rmax) was achieved at a mean value of 0.4 0.06 minutes in the blood compartment, 0.9 0.1 minutes in the CSF compartment and 0.8 0.1 minutes in both the frontal cortex and hippocampal ECF compartments. Although the CSF kinetics of vigabatrin paralleled that seen in serum, CSF vigabatrin concentrations represented only 2% of serum vigabatrin concentrations and did not reflect free drug concentrations in serum. Vigabatrin was not protein bound in serum. Furthermore, the efflux of vigabatrin from the CSF compartment was significantly slower (mean terminal half life {1/2} values, 2.2-3.3 h) than that suggested by serum values (mean tm values, 1.1-1.4 h). Distribution in the brain ECF was brain region specific vigabatrin concentrations achieved in the frontal cortex were 2-fold greater than concentrations achieved in the hippocampus. However, the efflux of vigabatrin from the two brain regions was essentially identical (mean t a values, 2.4-3.6 h) and indeed was similar to values seen in the CSF compartment. The findings are consistent with an active uptake and elimination of vigabatrin from the CSF and ECF. Levetiracetam rapidly entered the blood (serum) and ECF (frontal cortex and hippocampus) compartments with concentrations increasing linearly and dose- dependently. Mean rmax values were 0.4 - 0.7 minutes in the blood compartment and 1.8 - 2.5 minutes in both the frontal cortex and hippocampal ECF compartments. Levetiracetam was not protein bound in serum. In contrast to vigabatrin, levetiracetam did not exhibit brain region specificity in that its neuropharmacokinetic profiles in frontal cortex and hippocampal ECF were essentially identical. However, the efflux of levetiracetam from the two brain regions was slower (mean t a values, 3.1 - 3.3 h) compared to that which occurred in the blood compartment (mean tm values, 2.2 h). In the CSF compartment, vigabatrin administration was associated with changes in 5 of the 16 amino acid neurotransmitter concentrations measured over time. Thus whilst arginine and tyrosine concentrations decreased, homocarnosine, glycine and taurine concentrations increased. Although gamma-aminobutyric acid (GABA) was not measured in CSF, the fact that homocarnosine (a GABA conjugate) concentrations increased is consistent with a GABAergic action for vigabatrin. In the frontal cortex and hippocampal ECF compartments, vigabatrin administration was associated with significant changes in various amino acid concentrations but the changes did not parallel those seen in CSF. The most profound change was that with GABA. However, whilst ECF GABA concentrations increased 6-fold in the frontal cortex, concentrations in the hippocampus were unaffected. These GABA changes did not parallel the concentration versus time profile of ECF vigabatrin nevertheless vigabatrin concentrations in the frontal cortex were 2-fold higher than those achieved in the hippocampus. These findings indicate that CSF amino acid measurements may be a poor reflection of ECF amino acid changes and that changes in ECF amino acids is regionally specific. That vigabatrin reduced paired pulse inhibition in the dentate gyrus evoked by perforant path stimulation at 20 ms interpulse interval but not at 50 ms and 100 ms intervals would suggest that vigabatrin by increasing extracellular GABA may either desensistise synaptic GABAA receptors or inhibit GABA release through an action on GABAB receptors. In the brain ECF compartment, levetiracetam administration was associated with changes in only two (taurine and glutamate) of the 20 amino acid neurotransmitter concentrations measured over time. The significance of these changes in relation to the mechanism of action of levetiracetam is unknown.

Cannabis sativa has been used for symptomatic relief of seizures for thousands of years. The constituents responsible for such effects, their mechanisms and any involvement of the endocannabinoid system remain speculative. This work focussed on actions of the phytocannabinoid [delta]9-THCV on excitatory neurotransmission in in vitro cerebellar acute brain slices, an in vitro piriform cortical {PC} brain slice model of epileptiform activity and three in vivo rodent models of seizure. The functional effects of synthetic cannabinoids WIN55 (CBl/2R agonist) and AM251 (CBlR antagonist) and [delta]9-THCV on network level neurotransmission in the cerebellum were investigated using MEA extracellular electrophysiological recording methods. Significant increases from control level spontaneous spike firing rates recorded from Purkinje cells were seen upon addition of WIN 55 (5μM) and reversed by [delta]9-THCV {5 μML whilst significant spike firing rate reductions from control levels were induced by [delta]9-THCV (5 μM) or AM251 (2 μM). Functional effects of [delta]9-THCV and AM251 upon epileptiform activity in the Mg2+-free model of PC epileptiform activity were investigated using extracellular electrophysiological MEA recording techniques. Both [delta]9-THCV (>20μ M) and AM251 (>2 μM) significantly reduced burst complex incidence, paroxysmal depolarising shift (PDS) amplitude, PDS frequency and propagation rate across slices, effects which were reproduced following brain slice pre-incubation with [delta]9-THCV (10 μM) . Based on these results, potential anticonvulsant effects ; of [delta]9-THCV were investigated using pentylenetetrazole {PTZh pilocarpine (PIL)- and penicillin (PEN)- induced models of seizure. [delta]9-THCV was found to be significantly anticonvulsant in the PTZ-induced model. Results from other models demonstrated no significant anticonvulsant effect, but non- significant trends towards reduced percentage mortality, median severity and duration of seizures were seen. These results suggest that [delta]9-THCV has less anticonvulsant effect in a system with complete excitatory and inhibitory input. Further investigation is warranted to determine the cause of apparently conflicting results between in vitro and in vivo investigations.

Levetiracetam (LEV) is a prominent antiepileptic drug (AED) with an unknown mechanism of action. Within this thesis, electrophysiological, biochemical and imaging approaches were combined to investigate potential effects of LEV on action potential (AP) -dependent synaptic transmission and presynaptic voltage-dependent Ca2+ channel (VDCC) activity in superior cervical ganglion neurons (SCGNs). The putative role of LEV's molecular target, synaptic vesicle protein 2A (SV2A) in mediating LEV effects was investigated using the R-enantiomer, UCB L060, which exerts a lOOO-fold lower SV2A binding affinity than LEV. In these experiments, LEV inhibited synaptic transmission in SCG model synapses in a time-dependent manner, significantly reducing excitatory postsynaptic potential (EPSP) amplitudes and surface areas when applied for 2:30 min in comparison to UCB L060. In isolated SCGNs and recombinantly expressed Cav2.2 channels in HEK293 cells, LEV pretreatment (2:1 h), but not acute external application, significantly inhibited whole-cell IBa- Antibody labelling of SV2A in SCGNs revealed that the protein was predominantly expressed in close proximity to the plasma membrane and did not appear to redistribute or change its total expression in response to LEV pretreatment. Intracellular LEV application significantly inhibited IBa rapidly after establishing the whole-cell configuration to an extent comparable to that following LEV pretreatment; however, neither pretreatment nor intracellular application of UCB L060 produced any inhibitory effects in these experiments, which indicates an intracellular site of action. Under physiological conditions, LEV reduced both, fast and slow AP after- hyperpolarisations in a Ca2+ -dependent manner but did not affect the AP waveform or resting membrane potential. Additionally, LEV increased AP latency and slowed the repolarisation rates in a Ca2+-independent manner, suggesting further mechanisms associated with reduced excitability . Taken together, the presented results identify presynaptic VDCCs as targets for the archetypal SV2A ligand, LEV, potentially acting via an SV2A-dependent, intracellular pathway to inhibit presynaptic Ca2+ influx.

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