Chronic treatment with mood stabilizers lithium and valproate prevents excitotoxicity by inhibiting oxidative stress in rat cerebral cortical cells.
BACKGROUND
Recent studies indicate that chronic treatment with the mood-stabilizing drugs lithium and valproate produces a neuroprotective effect against excitotoxicity. In this study, we aimed to determine whether inhibiting oxidative damage plays a role in a neuroprotective effect of lithium and valproate against excitotoxicity.


METHODS
Intracellular free calcium concentration was measured with the fluorescent calcium ion indicator fluo-3. Malondialdehyde, an end product derived from peroxidation of polyunsaturated fatty acid, and protein carbonyls were used to assess oxidative damage to lipid and protein. Excitotoxicity was assayed by measuring cell viability with the MTT [3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide] method and by measuring deoxyribonucleic acid (DNA) fragmentation with TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling) staining.


RESULTS
We found that chronic treatment with lithium and valproate at their therapeutically relevant concentrations significantly inhibited the glutamate-induced increase of intracellular free calcium concentration, lipid peroxidation, protein oxidation, DNA fragmentation, and cell death in primary cultured rat cerebral cortical cells. This treatment had no effect on basal intracellular free calcium concentration, lipid peroxidation, protein oxidation, DNA fragmentation, and cell death.


CONCLUSIONS
Our results suggest that chronic treatment with lithium and valproate inhibits oxidative damage to lipid and protein and in turn produces a neuroprotective effect against excitotoxicity.
Shao
Li
L
The Vivian Rakoff Mood Disorders Laboratory, Centre for Addiction and Mental Health, and Department of Psychiatry, University of Toronto, Ontario, Canada.
Young
L Trevor
LT
Wang
Jun-Feng
JF
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D018846:Excitatory Amino Acids / Q000633:toxicity*; D018698:Glutamic Acid / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D015227:Lipid Peroxidation / Q000187:drug effects; D008094:Lithium / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000494:pharmacology*
D018692:Antimanic Agents; D018846:Excitatory Amino Acids; D009419:Nerve Tissue Proteins; D018698:Glutamic Acid; D014635:Valproic Acid; D008094:Lithium; D002118:Calcium