Abstracts

Levetiracetam is an anticonvulsant whose action is reported to be through the selective and high affinity binding to a protein called SV2A, which is involved in synaptic vesicle function (PNAS 2004, 101:9861-9866). SV2 is a glycoprotein present in all neural cells and occurs in 3 isoforms -- SV2A, SV2B and SV2C. The SV2 synaptic vesicle proteins are structurally similar to vesicular transporters for neurotransmitters. Levetiracetam is of mixed effectiveness in the treatment of temporal lobe epilepsy (TLE). This study looks at the expression of the synaptic vesicle protein SV2 genes and well as genes for several other proteins involved in the synaptic vesicle cycle (Annu.Rev. Neurosci. 2004, 27: 509-47) to assess the potential effectiveness of this drug at hippocampal seizure foci in TLE patients Hippocampi surgically removed from patients for the control of medically intractable seizures were used in this study. Hippocampi with mesial sclerosis (MTLE) were compared to those without sclerosis from patients with extrahippocampal temporal mass lesions (MaTLE) and with no clear etiology (PTLE). Gene expression patterns in the two groups were compared for hippocampal area CA2/CA1 using DNA microarray analysis and the Affymetrix platform with GeneChip U133A. The expression patterns of the SV2 proteins (A.B. and C) as well as synaptic cycle proteins Synapsins, Synaptogyrins, Synaptogamins, Synaptobrevins, Synaptophysins, Rab proteins, RIM proteins, SCAMPs and SVOP were comared among others. The comparisons showed that there were significantly reduced expression levels of SV2A and SV2B in the sclerotic hippocampi of the MTLE group compared non-sclerotic hippocampi. The levels of SV2C were undetectable as expected of this minor isoform in the brain. The majority of the other proteins were also reduced or undetectable. The reduction of the SV2 and other synaptic vesicle cycle proteins in area CA1 of MTLE hippocampi may reflect the significant neuronal loss in this region of this patient group. Hippocampal sclerosis is the hallmark of the pathology of this patient group, and in the absence of the necessary mechanism for the action of this drug, may suggest that it may be of limited efficacy for this subtype of TLE. However, for PTLE and MaTLE patients, where synaptic vesicle proteins are unaffected, Levetiracetam may be expected to be useful. (Supported by NS048434.)