Genetic or pharmacological superoxide-hydrogen peroxide imbalances modulate the in vitro effects of lithium on glycogen synthase kinase-3β

Abstract

Introduction: Lithium (Li), a mood stabilizer used to treat bipolar disorder (BP) symptoms has important anti-inflammatory effects by downregulation of glycogen synthase kinase-3 beta (GSK-3β). However, sometime Li effect is not efficient in some patients suggesting genetic interference. Previous investigations described association between a genetic superoxide‑hydrogen (S-HP) imbalance caused by a superoxide dismutase manganese dependent gene polymorphism (Val16Ala-SOD2 SNP, rs4880) and differential anti-inflammatory response of some drugs and bioactive molecules. Therefore, we postulated here that S-HP imbalance could present some effect on GSK-3β modulation by Li.

Methods: to test this hypothesis, a genetic and a pharmacological S-HP imbalance protocols were performed. In the two protocols, immune cells were activated by phythohemaglutin (PHA). The first one, used peripheral blood mononuclear cells (PBMCs) cultures carrying different Val16Ala-SOD2 genotypes, and the second used a commercial macrophage cell line RAW 264.7. Macrophages were exposed to paraquat to induce high S levels (VV-like cells) or porphyrin, that is a SOD2-like molecule that increase dismutation of S into HP (AA-like cells). In both protocols the Li effects on GSK-3β gene and protein modulation as evaluated in 24 h cultures. The inflammatory activation was also analyzed by cellular proliferation in 72 h cell cultures.

Results: as expected PHA exposure triggered a strong upregulation of GSK-3β gene expression (p ≤ 0.001), and Li exposure showed GSK-3β gene downregulation from 0.7 mEq/L concentrations. However, Li modulatory effects on GSk-3β gene and protein expression was directly influenced by basal S-HP balance. Presence of high S-basal levels (VV genotype and VV-like cells) induced attenuated Li anti-inflammatory effects in comparison with balanced and AA and AA-like cells (p < 0.001). Despite methodological limitations related to in vitro assays, the whole of results suggested that Li anti-inflammatory effects is influenced by S-HP basal state and is plausible that its influence could contributes to resistance of some patients to Li treatment or to increase of intensity of some side effects Li-associated.

Keywords: Genotype; Inflammation; PBMC; SOD2, bipolar disorder, oxidative metabolism.