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Series GSE2880 Query DataSets for GSE2880
Status Public on Jul 06, 2005
Title dingl-affy-rat-50847
Organism Rattus norvegicus
Experiment type Expression profiling by array
Summary Epilepsy is a major neurological disorder that affects approximately 1% of the population. The processes that lead to the development of epilepsy (epileptogenesis) are largely unknown. Levetiracetam is a novel antiepileptic drug (AED) that in the kindling model inhibits epileptogenesis in addition to being effective in controlling established epilepsy. The mechanisms of action of levetiracetam as an AED and an antiepileptogenic drug are unknown. By identifying the effect of chronic levetiracetam therapy on gene expression in the brain we hope to be able to identify genes that are involved in epileptogenesis. By comparing the gene expression profiles of levetiracetam and phenytoin treatments, we hope to be able to distinguish between genes that are important for the antiepileptic (anti-seizure) effect and genes that are important for the antiepileptogenic effect of levetiracetam. Phenytoin is a well-established AED; its mechanism of action involves inhibition of sodium channels. In contrast to levetiracetam, available data suggest that phenytoin in certain situations may enhance rather than inhibit the development of epilepsy.
We will identify changes in gene expression in the hippocampus, frontal cortex, and brain stem caused by chronic treatment (3 months) with levetiracetam or phenytoin. We will search for differences in the gene expression profiles after chronic treatment with the two drugs, to explain the different clinical effects of the two drugs.
We hypothesize that chronic treatment with levetiracetam leads to changes in the expression of genes that are involved in both the antiepileptogenetic and antiepileptic effect of the drug, whereas chronic treatment with phenytoin affects genes that may be related to pro-epileptogenetic as well as antiepileptic effects of that drug. We further hypothesize that i) regional differences in the effects of levetiracetam and phenytoin may reflect important functional differences in the actions of these two drugs, and ii) there may be different mechanisms involved in their anti-seizure effect.
Male Wistar rats receive levetiracetam (150 mg/kg x 2), phenytoin (75 mg/kg x 2) or control solution (N=7 in each group) through a gastric tube twice daily for 90 days. Experimental animals and controls are housed together in the same cages in groups of three, facilitating paired comparisons among the three groups in animals that have experienced the same environment throughout the 3 month experimental period. Four hrs after the last dose animals are anesthetized, decapitated, and total RNA is extracted from brain stem, frontal cortex, and hippocampus. RNA will be sent to the TGEN facility for hybridization to the rat U230A chips. The number of chips needed is (2 drugs + 1 control) * (3 brain regions) * (7 animals per group) = 63 chips. We will initially select those genes for analysis that are called “present” by the Affymetrix software in 4 or more animals for at least one of the 6 experimental groups. Then t-tests with Benjamini & Hochberg correction for protection against multiple comparisons will be used to identify genes that are differentially expressed at a false discovery rate of .05 among any of the six groups. We will be primarily interested in the following expression profiles, analyzed as paired comparisons by the Affymetrix software:

1. phenytoin vs control in hippocampus
2. phenytoin vs control in brain stem
3. levetiracetam vs control in hippocampus
4. levetiracetam vs control in brain stem

We will then compare the profiles of both drugs in each brain region (e.g., phenytoin vs levetiracetam in hippocampus) to select genes that are drug-specific. We will also take a Venn diagram approach to identify genes that are drug-specific across both brain regions tested.
Keywords: other
 
Overall design as above
 
Contributor(s) Dingledine R
Citation(s) 20345932
Submission date Jul 05, 2005
Last update date Jul 31, 2017
Contact name Winnie Liang
E-mail(s) wliang@tgen.org
Organization name Translational Genomics
Street address 445 N. Fifth Street
City Phoenix
State/province AZ
ZIP/Postal code 85012
Country USA
 
Platforms (1)
GPL1355 [Rat230_2] Affymetrix Rat Genome 230 2.0 Array
Samples (62)
GSM53412 brain, brainstem: PB1_e1_le1
GSM53413 brain, brainstem: PB2_e1_le1
GSM53414 brain, brainstem: PB3_e1_le1
Relations
BioProject PRJNA92561

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE2880_RAW.tar 150.0 Mb (http)(custom) TAR (of CEL)

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