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Kainic Acid-induced F-344 Rat model of Mesial Temporal Lobe Epilepsy: Gene Expression and Canonical Pathways

¹ Department of Pathology, Covance Laboratories Inc., Madison, WI 53704, USA
² Department of Pathology, Covance Laboratories Inc., Greenfield, IN 46140, USA
³ Lilly Research Laboratories, Division of Eli Lilly and Co., Indianapolis, IN 46285, USA
⁴ Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA

Correspondence: Alok K. Sharma, Department of Pathology, Covance Laboratories Inc., 3301 Kinsman Blvd, Madison, WI, 53704-2523, USA; e-mail:Alok.Sharma{at}covance.com.

Mesial temporal lobe epilepsy (MTLE) is a severe neurological condition of unknown pathogenesis for which several animal models have been developed. To obtain a better understanding of the underlying molecular mechanisms and identify potential biomarkers of lesion progression, we used a rat kainic acid (KA) treatment model of MTLE coupled with global gene expression analysis to examine temporal (four hours, days 3, 14, or 28) gene regulation relative to hippocampal histopathological changes. The authors recommend reviewing the companion histopathology paper (Sharma et al. 2008) to get a better understanding of the work presented here. Analysis of filtered gene expression data using Ingenuity Pathways Analysis (Ingenuity Systems, http://www.ingenuity.com) revealed that a number of genes pertaining to neuronal plasticity (RhoA, Rac1, Cdc42, BDNF, and Trk), neurodegeneration (Caspase3, Calpain 1, Bax, a Cytochrome c, and Smac/Diablo), and inflammation/immune-response pathways (TNF-, CCL2, Cox2) were modulated in a temporal fashion after KA treatment. Expression changes for selected genes known to have a role in neuronal plasticity were subsequently validated by quantitative polymerase chain reaction (qPCR). Notably, canonical pathway analysis revealed that a number of genes within the axon guidance signaling canonical pathway were up-regulated from Days 3 to 28, which correlated with aberrant mossy fiber (MF) sprouting observed histologically beginning at Day 6. Importantly, analysis of the gene expression data also identified potential biomarkers for monitoring neurodegeneration (Cox2) and neuronal/synaptic plasticity (Kalrn).

Key Words: animal models • toxicologic pathology • toxicogenomics • mesial temporal lobe epilepsy • kainic acid

Abbreviations: DRG, differentially regulated gene • IPA, Ingenuity Pathway Analysis • KA, kainic acid • MF, mossy fiber • MTLE, mesial temporal lobe epilepsy • QPCR, quantitative polymerase chain reaction • SE, status epilepticus

This version was published on October 1, 2009

Toxicologic Pathology, Vol. 37, No. 6, 776-789 (2009)
DOI: 10.1177/0192623309344202


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