The antiepileptic drug levetiracetam selectively modifies kindling‐induced alterations in gene expression in the temporal lobe of rats

Abstract

Gene expression profiling by microarrays is a powerful tool for identification of genes that may encode key proteins involved in molecular mechanisms underlying epileptogenesis. Using the Affymetrix oligonucleotide microarray, we have surveyed the expression levels of more than 26,000 genes and expressed sequence tags (ESTs) in the amygdala-kindling model of temporal lobe epilepsy. Furthermore, the effect of the antiepileptic drug levetiracetam (LEV) on kindling-induced alterations of gene expression was studied. Treatment of rats with LEV during kindling acquisition significantly suppressed kindling development. For gene expression profiling, six groups of rats were included in the present study: (i) and (ii) sham-operated rats treated with saline or LEV; (iii) and (iv) electrode-implanted but non-kindled rats treated with saline or LEV; (v) and (vi) kindled rats treated with saline or LEV. Treatment was terminated after 11 or 12 daily amygdala stimulations, when all vehicle-treated rats had reached kindling criterion, i.e. a stage 5 seizure. Twenty-four hours later, the ipsilateral temporal lobe was dissected for mRNA preparation. Six temporal lobe preparations from each group were analysed for differential gene expression. In control (non-kindled) rats, LEV treatment was devoid of any significant effect on gene expression. In saline-treated kindled rats, a large number of genes were observed to display mRNA expression alterations compared with non-kindled rats. LEV treatment induced marked effects on gene expression from kindled rats. Previously described epilepsy-related genes, such as neuropeptide Y (NPY), thyrotropin-releasing hormone (TRH) and glial fibrillary acidic protein (GFAP) were confirmed to be up-regulated by kindling and partially normalized by LEV treatment. Real-time quantitative polymerase chain reaction confirmed NPY, TRH and GFAP expression data from chip experiments. Furthermore, a number of novel genes were identified from the gene chip experiments. A subgroup of these genes demonstrated correlation between expression changes and kindled phenotype measurements. In summary, this study identified many genes with potentially important roles in epileptogenesis and highlighted several important issues in using the gene chip technology for the study of animal models of CNS disorders.

Curcumin: The Molecular Mechanisms of Action in Inflammation and Cell Death during Kainate-Induced Epileptogenesis

“…Generally, the number of genes significantly regulated by KA seizure induction was lesser as compared with previous studies using rat model of epileptogenesis, either by kindling 17,22 or post-SE methods. 15,23,24 This comparison difference could be attributed to different study designs in microarray platforms, time points, epileptogenesis models, tissue sampling sites and animal factors that have been employed in different studies.…”

A New Frontier in Epilepsy: Novel Antiepileptogenic Drugs

“…Rather, the findings suggest that LEV can inhibit epileptogenesis, viz., inhibiting the formation of epileptic foci and / or suppressing the development of seizures by inducing certain inhibitory factors through promotion of gene expression. LEV has been reported to prevent changes in levels of BDNF neuropeptide Y mRNA (61) and selectively modify gene expression including neuropeptide Y, TRH, and glial fibrillary acidic protein in kindling rats (62). It is highly possible that long-term treatments with LEV may normalize up-regulation of relevant gene expression induced during the kindling process.…”

Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

“…It is noteworthy that unlike any other currently available AED, treatment with levetiracetam during kindling resulted in a persistent reduction of electrographic seizure activity in kindled brain, even long after the termination of treatment Stratton et al, 2003). After our initial observation of an antiepileptogenic or disease-modifying potential of levetiracetam in the kindling model , we used gene expression analysis to identify the mechanisms responsible for these effects (Gu et al, 2004). Previously described epilepsy-related genes, such as neuropeptide Y (NPY), thyrotropin-releasing hormone, and glial fibrillary acidic protein were up-regulated by kindling and partially normalized by levetiracetam treatment.…”