Rat transcriptome biomarkers for the prediction of temporal lobe epilepsy

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DESCRIPTION (provided by applicant): Status epilepticus (SE) is a common cause of hippocampal neurodegeneration and synaptic reorganization that ultimately may, or may not lead to the development of temporal lobe epilepsy (TLE). While the role of SE as a possible cause of TLE has been recognized, no effective prognostic tools exist that would reliably predict whether chronic epilepsy would indeed develop in post-SE patients. Hence it is not known whether post- SE patients should undergo antiepileptogenic preventive therapy, and in which case, the effectiveness of such therapy is difficult to assess. The goal of this proposal is to identify novel and prognostic peripheral biomarkers of TLE applying a microarray-based approach for the analysis of expression changes in the blood of rat models of temporal lobe epilepsy. This will be achieved through comparison and identification of genomic changes in peripheral blood of experimental animals that are common despite animal strain, age, sex, and SE model. Male and female Wistar and Sprague-Dawley rats will be subjected to SE induced by either systemic pilocarpine or intrahippocampal kainic acid during either childhood (postnatal day 35) or adulthood (postnatal day 90). Samples of peripheral blood collected one, three and seven days after SE, will undergo genomic assay. After SE, animals will be continuously monitored using both EEG and video for the occurrence, frequency and severity of spontaneous recurrent limbic seizures for a period of six weeks. Seizure syndrome will be retrospectively correlated with the changes in blood genomic profile. If successful, our study would allow a large-scale parallel, cost-effective expression analysis of genes whose expression is altered in a specific fashion prior to the development of TLE. The project will generate a custom TLE prognostic biomarker chip that can be used both to screen and diagnose potential TLE patients, and to prospectively evaluate the effectiveness of antiepileptogenic therapy. Project narrative: by either systemic pilocarpine or intrahippocampal kainic acid is an acute neurological condition that consists of an episode of long-lasting continuous seizure. After SE, significant portion of patients develop chronic epilepsy. Currently no diagnostic tools exist that would allow predicting whether post-SE patient would develop epilepsy. The current project proposes the development of a simple diagnostic blood test method that would allow predicting the development of epilepsy in post-SE patients. The test will be based on the detection of characteristic gene expression changes in the peripheral blood that precede the progression of epilepsy. This will provide an important diagnostic tool and could indicate the necessity of prophylactic treatment to prevent the development and progression of chronic epilepsy. Such a test would also be useful in prognostic assessment of the effectiveness of antiepileptic therapy.