Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate.
Mood stabilizing drugs lithium and valproate are the most commonly used treatments for bipolar disorder. Previous studies in our laboratory indicate that chronic treatment with lithium and valproate inhibits oxidative damage in primary cultured rat cerebral cortical cells. Glutathione, as the major antioxidant in the brain, plays a key role in defending against oxidative damage. The purpose of this study was to determine the role of glutathione in the neuroprotective effects of lithium and valproate against oxidative damage. We found that chronic treatment with lithium and valproate inhibited reactive oxygen metabolite H(2)O(2)-induced cell death in primary cultured rat cerebral cortical cells, while buthionine sulfoximine, an inhibitor of glutathione rate-limiting synthesis enzyme glutamate-cysteine ligase, reduced the neuroprotective effect of lithium and valproate against H(2)O(2)-induced cell death. Further, we found that chronic treatment with lithium and valproate increased glutathione levels in primary cultured rat cerebral cortical cells and that the effects of lithium and valproate on glutathione levels were dose-dependent in human neuroblastoma SH-SY5Y cells. Chronic treatment with lithium and valproate also increased the expression of glutamate-cysteine ligase in both rat cerebral cortical cells and SH-SY5Y cells. In addition, chronic treatment with other mood stabilizing drugs lamotrigine and carbamazepine, but not antidepressants desipramine and fluoxetine, increased both glutathione levels and the expression of glutamate-cysteine ligase in SH-SY5Y cells. These results suggest that glutathione plays an important role in the neuroprotective effects of lithium and valproate, and that glutathione may be a common target for mood stabilizing drugs.
Cui
J
J
The Vivian Rakoff Mood Disorders Laboratory, Centre for Addiction and Mental Health, 250 College Street, 11th floor, Toronto, Ontario, Canada M5T 1R8.
Shao
L
L
Young
L T
LT
Wang
J-F
JF
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D002220:Carbamazepine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D000077213:Lamotrigine; D008094:Lithium / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000633:toxicity; D014227:Triazines / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology*
D018692:Antimanic Agents; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D014227:Triazines; D002220:Carbamazepine; D014635:Valproic Acid; D008094:Lithium; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D000077213:Lamotrigine