¹Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

Correspondence: Dr JS Rao, Brain Physiology and Metabolism Section, 9000 Rockville Pike, Bldg 9, IS 128, BPMS, National Institute on Aging, NIH, Bethesda, MD 20892, USA. Tel: +1 301 594 3134; Fax: +1 301 402 0074; E-mail: jrao@mail.nih.gov

Received 5 October 2004; Revised 7 March 2005; Accepted 8 March 2005; Published online 13 April 2005.

Abstract

Lithium chloride (LiCl), when fed to rats for 6 weeks, has been reported to decrease brain mRNA, protein, and activity levels of arachidonic acid (AA)-selective cytosolic phospholipase A₂ (cPLA₂), without affecting secretory sPLA₂ or Ca²⁺-independent iPLA₂. We investigated whether transcription factors known to regulate cPLA₂ gene expression are modulated by chronic lithium treatment. Male Fischer-344 rats were fed a LiCl-containing diet for 6 weeks to produce a therapeutically relevant brain lithium concentration. Control animals were fed a LiCl-free diet. Using a gelshift assay, we found that LiCl significantly decreased activating protein 2 (AP-2)-binding activity, and protein levels of the AP-2 and AP-2 but not of the AP-2 subunits in the frontal cortex. Activating protein 1 (AP-1)-binding activity was increased, whereas glucocorticoid response element, polyoma enhancer activator 3, and nuclear factor kappa B DNA-binding activities were not changed significantly. Since both cPLA₂ and AP-2 can be activated by protein kinase C (PKC), we examined the frontal cortex protein levels of PKC and PKC , as well as AA-dependent PKC activity. The protein levels of PKC and PKC were decreased significantly, as was AA-dependent PKC activity, in the lithium-treated compared to control rats. Our results suggest that the reported decrease in brain gene expression of cPLA₂ by chronic lithium may be mediated by reduced AP-2 transcriptional activity, and that decreased expression of PKC and PKC contributes to lowering the AP-2 activity.