Levetiracetam attenuates hippocampal expression of synaptic plasticity-related immediate early and late response genes in amygdala-kindled rats.
BACKGROUND
The amygdala-kindled rat is a model for human temporal lobe epilepsy and activity-dependent synaptic plasticity. Hippocampal RNA isolated from amygdala-kindled rats at different kindling stages was analyzed to identify kindling-induced genes. Furthermore, effects of the anti-epileptic drug levetiracetam on kindling-induced gene expression were examined.


RESULTS
Cyclooxygenase-2 (Cox-2), Protocadherin-8 (Pcdh8) and TGF-beta-inducible early response gene-1 (TIEG1) were identified and verified as differentially expressed transcripts in the hippocampus of kindled rats by in situ hybridization and quantitative RT-PCR. In addition, we identified a panel of 16 additional transcripts which included Arc, Egr3/Pilot, Homer1a, Ania-3, MMP9, Narp, c-fos, NGF, BDNF, NT-3, Synaptopodin, Pim1 kinase, TNF-alpha, RGS2, Egr2/krox-20 and beta-A activin that were differentially expressed in the hippocampus of amygdala-kindled rats. The list consists of many synaptic plasticity-related immediate early genes (IEGs) as well as some late response genes encoding transcription factors, neurotrophic factors and proteins that are known to regulate synaptic remodelling. In the hippocampus, induction of IEG expression was dependent on the afterdischarge (AD) duration. Levetiracetam, 40 mg/kg, suppressed the development of kindling measured as severity of seizures and AD duration. In addition, single animal profiling also showed that levetiracetam attenuated the observed kindling-induced IEG expression; an effect that paralleled the anti-epileptic effect of the drug on AD duration.


CONCLUSIONS
The present study provides mRNA expression data that suggest that levetiracetam attenuates expression of genes known to regulate synaptic remodelling. In the kindled rat, levetiracetam does so by shortening the AD duration thereby reducing the seizure-induced changes in mRNA expression in the hippocampus.
Christensen
Kenneth V
KV
Dept. of Molecular Biology, Discovery Biology Research, H, Lundbeck A/S, DK-2500 Valby, Denmark. kvc@lundbeck.com
Leffers
Henrik
H
Watson
William P
WP
Sánchez
Connie
C
Kallunki
Pekka
P
Egebjerg
Jan
J
D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D015870:Gene Expression / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D000077287:Levetiracetam; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D010889:Piracetam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013997:Time Factors
D000927:Anticonvulsants; D012333:RNA, Messenger; D000077287:Levetiracetam; D010889:Piracetam