Effect of levetiracetam on hippocampal protein expression and cell proliferation in rats.
OBJECTIVE
Levetiracetam (LEV) is a broad-spectrum antiepileptic drug (AED) with possibly also antiepileptogenic properties. LEV has a specific binding site in the central nervous system and reduces brain excitability; however, the precise mechanism of action (MOA) of LEV remains unclear. To further unravel the potential MOA pathways of LEV we investigated altered protein expression and cell proliferation in rat hippocampal tissue during LEV administration.


METHODS
On day 1 of the experiment, rats 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 bromodeoxyuridine (50 mg/kg, i.p., BID). After 7 days of treatment rats were killed and their brains removed. The right hemisphere was processed for histochemistry. 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 LEV did not influence hippocampal cell proliferation. Multivariate analysis of differential protein expression, determined by proteomic analysis, revealed a significant clustering of control and treatment groups. The proteins which most contribute to the difference between groups were identified with mass spectrometry. The identified proteins were either involved in cytoskeleton, energy metabolism, neurotransmission, signal transduction, myelinization or stress response.


CONCLUSIONS
LEV does not affect hippocampal cell proliferation but has significant effects on the expression of proteins involved in a variety of physiological processes involved in physiological processes that play an important role in the currently identified MOAs of AEDs such as neurotransmission and signal transduction.
Paulson
Linda
L
Center for Brain Repair and Rehabilitation, University of Gothenburg, Gothenburg, Sweden. Linda.paulson@rr-research.no
Persson
Asa
A
Vonck
Kristl
K
Van Dycke
Annelies
A
Kuhn
H Georg
HG
Boon
Paul
P
Ben-Menachem
Elinor
E
Raedt
Robrecht
R
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D030562:Databases, Protein / Q000706:statistics & numerical data; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000077287:Levetiracetam; D013058:Mass Spectrometry / Q000379:methods; D015999:Multivariate Analysis; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D000927:Anticonvulsants; D000077287:Levetiracetam; D001973:Bromodeoxyuridine; D010889:Piracetam