The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS

Differential display of mRNA was used to identify concordant changes in gen e expression induced by two mood-stabilizing agents, lithium and valproate (VPA). Both treatments, on chronic administration, increased mRNA levers of the transcription factor polyomavirus enhancer-binding protein (PEBP) 2 be ta in frontal cortex (FCx). Both treatments also increased the DNA binding activity of PEBP2 alpha beta and robustly increased the levels of bcl-2 (kn own to be transcriptionally regulated by PEBP2) in FCx. Immunohistochemical studies revealed a marked increase in the number of bcl-2-immunoreactive c ells in layers 2 and 3 of FCx. These novel findings represent the first rep ort of medication-induced increases in CNS bcl-2 levels and may have implic ations not only for mood disorders, but also for long-term treatment of var ious neurodegenerative disorders.