Abstracts

Rationale: Levetiracetam (LEV) is a broad-spectrum anti-epileptic drug (AED) with possibly also anti-epileptogenic properties. LEV has a specific binding site in the central nervous system and reduces brain excitability. The precise mechanism of action (MOA) of LEV remains unclarified. To further unrafel the potential MOA pathways of LEV this study investigated altered protein expression and cell proliferation in rat hippocampal tissue during LEV administration. Methods: On day 1 of the experiment, rats (n=20) were randomly assigned to a treatment group (LEV, 600 mg/kg/day, n=10) and a control group (saline, n=10). On days 2 and 3 rats were injected with BrDU (50mg/kg, i.p., BID). After 7 days of treatment rats were killed and their brains prelevated. The right hemisphere was processed for histochemistry and counting of BrdU-labelled cells. The left hippocampus was dissected and frozen for proteomic analysis. Proteins were extracted from the tissue and two-dimensional gel electrophoresis was performed. Results: Treatment with levetiracetam did not influence cell proliferation in the hippocampus. Multivariate analysis of differential protein expression, determined by proteomic analysis, revealed a significant clustering of the control and treatment groups. Twenty of the most up- and down-regulated proteins, correlating to the dependent variable, were identified by mass spectroscopy. The identified proteins were either involved in cytoskeleton, energy metabolism, endocytosis, neurotransmission, myelinisation, stress response or intracellular calcium buffering. Conclusions: Although levetiracetam does not influence hippocampal cell proliferation, it does have a significant effect on the expression of proteins involved in a variety of physiological processes. Further work needs to be done to identify which of these proteins are involved in the anti-epileptic effects of levetiracetam.