Levetiracetam prevents kindling-induced asymmetric accumulation of hippocampal 7S SNARE complexes.
OBJECTIVE
Understanding the molecular mechanisms underlying epilepsy is crucial to designing novel therapeutic regimens. This report focuses on alterations in the secretory machinery responsible for neurotransmitter (NT) release. Soluble N-ethylmaleimide sensitive factor (NSF) attachment protein receptor (SNARE) complexes mediate the fusion of synaptic vesicle and active zone membranes, thus mediating NT secretion. SNARE regulators control where and when SNARE complexes are formed. Previous studies showed an asymmetric accumulation of 7S SNARE complexes (7SC) in the ipsilateral hippocampus of kindled animals. The present studies probe the persistence of 7SC accumulation and the effect of the anticonvulsant, levetiracetam (LEV), on 7SC and SNARE regulators.


METHODS
Quantitative Western blotting was used to monitor levels of 7SC and SNARE regulators in hippocampal synaptosomes from kindled animals both before and after LEV treatment.


RESULTS
The asymmetric accumulation of 7SC is present 1-year postamygdalar kindling. The synaptic vesicle protein, synaptic vesicle protein 2 (SV2), a primary LEV-binding protein, and the SNARE regulator Tomosyn increase, whereas NSF decreases in association with this accumulation. Treatment with LEV prevented kindling-induced accumulation of SV2, but did not affect the transient increase of Tomosyn or the long-term decrease NSF. LEV treatment retarded the electrical and behavioral concomitants of amygdalar kindling coincident with a decrease in accumulation of 7SC.


CONCLUSIONS
The ipsilateral hippocampal accumulation of SNARE complexes is an altered molecular process associated with kindling that appears permanent. Kindling epileptogenesis alters synaptosomal levels of the SNARE regulators: NSF, SV2, and Tomosyn. Concomitant treatment with LEV reverses the kindling-induced 7SC accumulation and increase of SV2.
Matveeva
Elena A
EA
Department of Molecular & Cellular Biochemistry, University of Kentucky, Medical Center, Lexington, Kentucky, USA.
Vanaman
Thomas C
TC
Whiteheart
Sidney W
SW
Slevin
John T
JT
D000679:Amygdala / Q000528:radiation effects; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007696:Kindling, Neurologic; D000077287:Levetiracetam; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D050683:R-SNARE Proteins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050600:SNARE Proteins / Q000378:metabolism*; D012640:Seizures / Q000378:metabolism*; D013997:Time Factors
D000927:Anticonvulsants; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D050683:R-SNARE Proteins; D050600:SNARE Proteins; C484769:Stxbp5 protein, rat; C489618:Sv2a protein, rat; D000077287:Levetiracetam; D052066:N-Ethylmaleimide-Sensitive Proteins; C498737:Nsf protein, rat; D010889:Piracetam