CHANGES IN GENE EXPRESSION SUGGEST NEW MECHANISMS OF CHRONIC VALPROATE TREATMENT
Abstract number :
F.01
Submission category :
Year :
2003
Submission ID :
3594
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Bjornar Hassel, Ray Dingledine, Vidar Beisv[aring]g, Erik Tauboll, Leif Gjerstad Division for Environmental Toxicology, Norwegian Defence Research Establishment, Kjeller, Norway; Department of Pharmacology, Emory University, Atlanta, GA; Department of Can
Valproate (VPA) has a variety of biological effects, some may be important for its anti-epileptic and anti-manic efficacy, others may relate to its anti-tumour activity. We have investigated possible new mechanisms by the use of microarray technology.
Six male Wistar rats received VPA, 400 mg/kg, while 6 rats received vehicle perorally twice per day for 90 days. Total RNA was isolated from hippocampi samples. cDNA was made by reverse transcription and labelled with Cy3 and Cy5 coupled dendrimers (3DNA method, Genisphere) and applied to cDNA microarrays by The Norwegian Microarray Consortium, Trondheim, Norway.
Two mRNAs were over-represented: succinyl[sim]CoA-oxoacid transferase (SCOT) and interferon regulatory factor-3 (IRF-3). Two mRNAs were under-represented: branched-chain ketoacid dehydrogenase kinase (BCKD-K) and squalene synthase (SqS). BCKD-K, SCOT and SqS are related to leucine metabolism. Hippocampal leucine content was reduced by 56%. Branched-chain aminoacid transferase activity was reduced by 20%.[beta]-OH-butyrate dehydrogenase was reduced by 30%. SCOT protein level was unchanged.
Reduced leucine levels could be anti-epileptic, since leucine administration lowers absence seizure threshold in GAERS rats. Down-regulation of SqS is of interest with respect to mania, since metamphetamine causes SqS gene activation. Up-regulation of IRF-3 may contribute to the anti-tumour activity, since loss of IRF-3 is oncogenic. The microarray approach may suggest novel pharmacological targets for VPA, but discrepancy between mRNA changes and protein levels must be accounted for.