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Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate
Abstract
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.
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“In addition, consistent evidences are showing that the inhibition of oxidative damaging processes provoked by injuries to rat cerebral cortical cells by the chronic treatment with lithium is remarkably efficient [259].”
From Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches (2016) · cites this paper as [259]
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Metadata
- Authors
- Cui, J., Shao, L., Young, L. T., & Wang, J.-F.
- Affiliations
- Centre for Addiction and Mental Health (CA)
- Corresponding author
- Wang, J.-F.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 144
- Issue
- 4
- Pages
- 1447-1453
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2085156996
- Cited by
- 160
- References
- 54
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 7 · 2017: 7 · 2016: 5 · 2015: 11 · 2014: 13 · 2013: 9 · 2012: 20
- FWCI
- 7.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Keywords
- glutathione, neuroprotection, mood stabilizers, lithium, valproic acid, bipolar disorder, oxidative stress, gamma-glutamylcysteine synthetase, buthionine sulfoximine, hydrogen peroxide-induced cell death, SH-SY5Y cells, lamotrigine, carbamazepine, glutathione synthesis
- MeSH terms
- Lamotrigine, Animals, Brain, Carbamazepine, Cells, Cultured, Cerebral Cortex, Enzyme Inhibitors, Glutamate-Cysteine Ligase, Glutathione, Humans, Lithium, Nerve Degeneration, Neurons, Triazines, Valproic Acid, Cell Death, Rats, Sprague-Dawley, Reactive Oxygen Species, Oxidative Stress, Antimanic Agents, Neuroprotective Agents, Cell Line, Tumor, Rats
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