Glutathione S-transferase is a novel target for mood stabilizing drugs in primary cultured neurons.
Oligonucleotide microarray technology was used to analyze gene expression profiles after chronic treatment with the mood stabilizing drug valproate at a therapeutically relevant concentration in primary cultured rat cerebral cortical cells. We discovered that valproate regulates expression of 28 genes, including three isoenzymes (M1, A3 and A4) of glutathione S-transferase (GST), an important protective factor against oxidative stress. Because previous studies in our laboratory found that chronic valproate treatment protected cultured neurons against oxidative stress, further experiments on the regulation of GST were performed. Regulation of GST M1, GST A3 and GST A4 was verified using northern blotting hybridization. Chronic valproate treatment increased mRNA levels of M1 and A4, but decreased the A3 mRNA level dose-dependently, indicating further complexities in the regulation of GST by valproate. The level of GST M1 protein and GST activity were also increased by chronic valproate treatment. In addition, chronic treatment with lithium, another commonly prescribed mood stabilizer, also increased levels of GST M1 mRNA and protein. The present findings suggest that regulation of GST M1, and possibly GST A4, may mediate the anti-oxidative effects of valproate treatment, and regulation of GST may be involved in the mood stabilizing effect of valproate and lithium.
Wang
Jun-Feng
JF
Centre for Addiction and Mental Health, and Department of Psychiatry, University of Toronto, Ontario, Canada. jun-feng_wang@camh.net
Shao
Li
L
Sun
Xiujun
X
Young
L Trevor
LT
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D015152:Blotting, Northern; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D005982:Glutathione Transferase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014635:Valproic Acid / Q000494:pharmacology*
D018692:Antimanic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D012333:RNA, Messenger; D014635:Valproic Acid; D008094:Lithium; D005982:Glutathione Transferase