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Gene. 2018 May 20;655:48-55. doi: 10.1016/j.gene.2018.02.046. Epub 2018 Feb 18.

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

Author information

1
Postgraduate Program of Gerontology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
2
Postgraduate Program of Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
3
Biogenomic Laboratory, Federal University of Santa Maria, Santa Maria, RS, Brazil.
4
Lutheran University of Brazil, Santa Maria, RS, Brazil.
5
Federal University of Santa Catarina, Florianopólis, SC, Brazil.
6
Brain Institute, Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
7
Third Age Open University, University of Amazonas State, Manaus, AM, Brazil.
8
Postgraduate Program of Gerontology, Federal University of Santa Maria, Santa Maria, RS, Brazil; Postgraduate Program of Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil. Electronic address: ivana.cruz@ufsm.br.

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

PMID:
29466765
DOI:
10.1016/j.gene.2018.02.046
[Indexed for MEDLINE]

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