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Up-regulation of cPLA2 gene expression in astrocytes by all three conventional anti-bipolar drugs is drug-specific and enzyme-specific

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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 Ca2+-dependent phospholipase A2 (cPLA2), the expression of which was down-regulated by Li+ or carbamazepine but not by valproic acid; expression of two other PLA subtypes, iPLA2 and sPLA2 was unaffected. cPLA2 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 cPLA2, iPLA2, and sPLA2 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 cPLA2, but had no effect on iPLA2 and sPLA2, 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 cPLA2 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 cPLA2 gene expression are involved in the mechanisms of action of anti-bipolar drugs; astrocytes are a target for these drugs.

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Acknowledgements

This study was supported by Grant No. 30572180 and No. 30370451 from the National Natural Science Foundation of China. We thank Mrs. Xiaolin Yang for her valuable technical assistance.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, Shenyang, People’s Republic of China

    Baoman Li, Li Gu, Hongyan Zhang, Ye Chen, Leif Hertz & Liang Peng

  2. School of Medicine, University of Saskatchewan, Saskatoon, Canada

    Jingyang Huang

  3. College of Basic Medical Sciences, China Medical University, No. 92 Beier Road, Heping District, 110001, Shenyang, People’s Republic of China

    Liang Peng

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  1. Baoman Li
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  2. Li Gu
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  3. Hongyan Zhang
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Correspondence to Liang Peng.

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Li, B., Gu, L., Zhang, H. et al. Up-regulation of cPLA2 gene expression in astrocytes by all three conventional anti-bipolar drugs is drug-specific and enzyme-specific. Psychopharmacology 194, 333–345 (2007). https://doi.org/10.1007/s00213-007-0853-5

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