Abstract
This study examined the effects of lithium on gene expression and activity of the antioxidant enzymes copper zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) in the hippocampus of chronically stressed rats. In addition, we examined the effects of lithium on anxiety behaviors, hippocampal concentrations of dopamine (DA) and malondialdehyde (MDA), protein levels of brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), dopamine transporter (DAT), and catechol-O-methyltransferase (COMT), as well as activity of monoamine oxidase (MAO) in chronically stressed rats. The investigated parameters were quantified by real-time RT-PCR, Western blot analyses, and assays of enzyme activities. We found that lithium did not change gene expression of SOD1, CAT, GPx, and GR but decreased gene expression of SOD2 in chronically stressed rats. A very important result in this study was that lithium treatment decreased the enzyme activities of SOD1 and SOD2 but increased the enzyme activities of GPx and GR in stress condition, which indicates the control of redox balance. The reduced concentration of MDA confirms this. In addition, we found that lithium treatment decreased high protein levels of BDNF and DAT in chronically stressed rats to the level found in unstressed animals. Also, lithium treatment increased the expression of TH but decreased the enzyme activity of MAO B, which contributed to the increase of hippocampal concentration of DA in chronically stressed rats to the level of unstressed animals. Finally, lithium treatment in animals exposed to chronic stress increased the time spent in open arms. Lithium-induced modulation of hippocampal antioxidant status and attenuation of oxidative stress stabilized behavior in animals with high anxiety index. In addition, reduced oxidative stress was followed by the changes of both turnover of DA and levels of BDNF protein in chronically stressed rats treated with lithium. These findings may be important in preclinical research of the effects of lithium on oxidative stress level in pathological conditions.
Highlights
Molecular interactions in the neuroendocrine system under stress condition can lead to homeostatic disorders [1, 2]
We found that chronic restraint stress (CRS) induced significant decrease of both hippocampal dopamine (DA) concentration [6] and protein levels of tyrosine hydroxylase (TH), a “rate-limiting” enzyme of dopamine biosynthesis [7], which confirmed that the hippocampus was sensitive to chronic stress [8, 9]
We found that lithium treatment in animals exposed to CRS significantly increased levels of TH protein by 26% (p < 0 001, t-test, Figure 1(a)) and increased the concentration of DA by 125% (p < 0 001, t-test, Figure 1(b)) compared with CRS animals
Summary
Molecular interactions in the neuroendocrine system under stress condition can lead to homeostatic disorders [1, 2]. Chronic stress induces overactivation and dysfunction of stress-activated systems, resulting in further brain damage and mood disorders [3, 4]. It is known that brain-derived neurotrophic factor (BDNF) modulates the activity of monoaminergic systems in the rat brain [5]. Our earlier research confirmed that chronic restraint stress (CRS) influenced anxiety-like behavior in rats [6]. We found that CRS induced increased activity of superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), and catalase (CAT) in the hippocampus [17]. The increased activity of antioxidant enzymes may be an important adaptive phenomenon of the antioxidant defense system in chronically stressed rats [17]. Very little is known about the antioxidant defense system and turnover of DA in animals with high anxiety index treated with lithium
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