Chronic treatment of rats with sodium valproate downregulates frontal cortex NF-κB DNA binding activity and COX-2 mRNA

Objectives: 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-kappa B, 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-kappa B 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-kappa B DNA binding activity, likely by decreasing the p50 protein levels. This effect may explain its downregulation of COX-2 mRNA. The decrease in NF-kappa B activity by chronic VPA may affect other NF-kappa B-regulated genes and may be related to VPA's action in bipolar disorder. Chronic VPA may decrease the reported increased brain NF-kappa B components in bipolar patients.