Up-regulation of cPLA(2) gene expression in astrocytes by all three conventional anti-bipolar drugs is drug-specific and enzyme-specific

Abstract

Rationale: Common biological effects by all three conventional anti-bipolar drugs, the lithium ion (Li(+)), carbamazepine, and valproic acid, are important because identical effects may provide information about the pathophysiology of affective disorders. It has been reported that chronic treatment with either drug in vivo down-regulates the turnover of arachidonic acid in brain. This reaction is catalyzed by Ca(2+)-dependent phospholipase A(2) (cPLA(2)), the expression of which was down-regulated by Li(+) or carbamazepine but not by valproic acid; expression of two other PLA subtypes, iPLA(2) and sPLA(2) was unaffected. cPLA(2) is amply expressed in astrocytes, and in the present study, effects of 1-4 weeks of treatment with clinically relevant concentrations of each of the three anti-bipolar drugs on cPLA(2), iPLA(2), and sPLA(2) mRNA and protein expression were determined in primary cultures of mouse astrocytes by reverse transcription polymerase chain reaction (RT-PCR) and immunoblotting.

Results: Two or more weeks treatment with Li(+) concentrations below 2 mM, carbamazepine or valproic acid up-regulated mRNA and protein expression of cPLA(2), but had no effect on iPLA(2) and sPLA(2), showing enzyme specificity. The effect occurred more rapidly at higher than lower concentrations but also tended to end after 4 weeks at the higher concentrations. Two millimolar Li(+) caused an initial increase of cPLA(2) followed by a decrease after 3 and 4 weeks. Topiramate had no effect, indicating specificity for anti-bipolar drugs.

Conclusions: Both up- and down-regulation of cPLA(2) gene expression are involved in the mechanisms of action of anti-bipolar drugs; astrocytes are a target for these drugs.