Lithium (Li) represents a first choice mood stabilizer for bipolar disorder (BD). Despite extensive clinical use, questions regarding its mechanism of action and pathological mechanism of renal function impairment by Li remain open. The present study aimed to improve our knowledge in this area paying special attention to the relationship between the length of Li action, lipid peroxidation (LP), and Na+/K+-ATPase properties. The effects of therapeutic Li doses, administered daily to male Wistar rats for 1 (acute), 7 (short term) and 28 days (chronic), were studied. For this purpose, Na+/K+-ATPase activity measurements, [3H]ouabain binding and immunoblot analysis of α-Na+/K+-ATPase were performed. Li-induced LP was evaluated by determining the malondialdehyde concentration by HPLC. Sleep deprivation (SD) was used as an experimental approach to model the manic phase of BD. Results obtained from the kidney were compared to those obtained from erythrocytes and different brain regions in the same tested animals. Whereas treatment with therapeutic Li concentration did not bring any LP damage nor significant changes of Na+/K+-ATPase expression and [3H]ouabain binding in the kidney, it conferred strong protection against this type of damage in the forebrain cortex. Importantly, the observed changes in erythrocytes indicated changes in forebrain cortices. Thus, different resistance to SD-induced changes of LP and Na+/K+-ATPase was detected in the kidney, erythrocytes and the brain of Li-treated rats. Our study revealed the tissue-specific protective properties of Li against LP and Na+/K+-ATPase regulation.

• Keywords
• Lithium, Malondialdehyde, Na+/K+-ATPase, Rat tissues, Sleep deprivation,
• MeSH
• Antimanic Agents administration & dosage   pharmacology   MeSH
• Bipolar Disorder drug therapy   MeSH
• Time Factors MeSH
• Erythrocytes drug effects   metabolism   MeSH
• Rats MeSH
• Kidney drug effects   metabolism   MeSH
• Lithium Carbonate administration & dosage   pharmacology   MeSH
• Disease Models, Animal MeSH
• Brain drug effects   metabolism   MeSH
• Lipid Peroxidation drug effects   MeSH
• Rats, Wistar MeSH
• Sodium-Potassium-Exchanging ATPase metabolism   MeSH
• Sleep Deprivation psychology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antimanic Agents MeSH
• Lithium Carbonate MeSH
• Sodium-Potassium-Exchanging ATPase MeSH

Regulation of Na+/K+-ATPase in bipolar disorder and lithium therapy has been investigated for more than 40 years. Contradictory results in this area may be caused by the difference between acute and long-term Li effects on cell metabolism and variance in responsiveness of different cell types. We compared the time-course of Li action focusing on Na+/K+-ATPase and lipid peroxidation in two widely different cell models-Jurkat and HEK293. Na+/K+-ATPase expression level was determined in cells cultivated in the absence or presence of 1 mM Li for different time spans (1, 7, and 28 days) using [3H] ouabain binding and immunoblot assay of α-subunit. In parallel samples, the formation of malondialdehyde (MDA) was quantified by HPLC, and 4-hydroxy-2-nonenal (4-HNE) protein adducts were determined by immunoblot. Cultivation of Jurkat cells in 1 mM Li medium resulted in downregulation of Na+/K+-ATPase (decrease of [3H] ouabain-biding sites and intensity of immunoblot signals) in all Li-groups. In HEK293 cells, the decrease of Na+/K+-ATPase was observed after the acute, 1-day exposure only. The long-term treatment with Li resulted in Na+/K+-ATPase upregulation. MDA and 4-HNE modified proteins were decreased in Jurkat cells in all Li-groups. On the other hand, in HEK293 cells, MDA concentration was decreased after the acute, 1-day Li exposure only; the long-term cultivations, for 7 or 28 days, resulted in a significant increase of lipid peroxidation products. The Li-induced decrease of lipid peroxidation products was associated with the decrease of Na+/K+-ATPase level and vice versa.

• Keywords
• HEK293 cells, Jurkat cells, Lipid peroxidation products, Lithium, Na+/K+-ATPase,
• MeSH
• Bipolar Disorder drug therapy   metabolism   MeSH
• Time Factors MeSH
• HEK293 Cells MeSH
• Jurkat Cells MeSH
• Humans MeSH
• Lipid Peroxides metabolism   MeSH
• Lipid Peroxidation drug effects   MeSH
• Gene Expression Regulation drug effects   MeSH
• Lithium Compounds administration & dosage   metabolism   pharmacology   MeSH
• Sodium-Potassium-Exchanging ATPase genetics   metabolism   MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Lipid Peroxides MeSH
• Lithium Compounds MeSH
• Sodium-Potassium-Exchanging ATPase MeSH