Chronic treatment of rats with sodium valproate downregulates frontal cortex NF-kappaB DNA binding activity and COX-2 mRNA.
OBJECTIVE
Valproic acid (VPA) is used to treat bipolar disorder, but its mechanism of action is not clear. VPA shares many cellular and molecular targets with lithium, including reducing arachidonic acid turnover in rat brain phospholipids and cyclooxygenase-2 (COX-2) protein level and activity in rat brain.


METHODS
We examined the effect of chronic VPA administration (200 mg/kg body weight for 30 days) to produce therapeutically relevant plasma concentrations, on transcription factors (NF-kappaB, AP-1, AP-2, C/EBP, CREB, and ETS) that are known to regulate the COX-2 gene.


RESULTS
Chronic VPA significantly increased AP-1 DNA binding activity and decreased NF-kappaB DNA binding activity, p50 subunit protein and mRNA expression of COX-2 in frontal cortex compared with untreated control rats. It did not alter AP-2, C/EBP, ETS or CREB DNA binding activity.


CONCLUSIONS
VPA downregulates NF-kappaB DNA binding activity, likely by decreasing the p50 protein levels. This effect may explain its downregulation of COX-2 mRNA. The decrease in NF-kappaB activity by chronic VPA may affect other NF-kappaB-regulated genes and may be related to VPA's action in bipolar disorder. Chronic VPA may decrease the reported increased brain NF-kappaB components in bipolar patients.
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. jrao@mail.nih.gov
Jagadeesh S
JS
Rao
Richard P
RP
Bazinet
Stanley I
SI
Rapoport
Ho-Joo
HJ
Lee
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D004334:Drug Administration Schedule; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000187:drug effects* / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D014635:Valproic Acid; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat