Article

Oxidative stress parameters in unmediated and treated bipolar subjects during initial manic episode: A possible role for lithium antioxidant effects

Institute of Psychiatry, University of São Paulo, San Paulo, São Paulo, Brazil
Neuroscience Letters (Impact Factor: 2.03). 07/2007; 421(1):33-6. DOI: 10.1016/j.neulet.2007.05.016
Source: PubMed
ABSTRACT
Studies have proposed the involvement of oxidative stress and neuronal energy dysfunctions in the pathophysiology of bipolar disorder (BD). This study evaluates plasma levels of the oxidative/energy metabolism markers, thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and neuron-specific enolase (NSE) during initial episodes of mania compared to controls in 75 subjects. Two groups of manic subjects (unmedicated n=30, and lithium-treated n=15) were age/gender matched with healthy controls (n=30). TBARS and antioxidant enzymes activity (SOD and CAT) were increased in unmedicated manic patients compared to controls. Conversely, plasma NSE levels were lower during mania than in the controls. In contrast, acute treatment with lithium showed a significant reduction in both SOD/CAT ratio and TBARS levels. These results suggest that initial manic episodes are associated with both increased oxidative stress parameters and activated antioxidant defenses, which may be related to dysfunctions on energy metabolism and neuroplasticity pathways. Antioxidant effects using lithium in mania were shown, and further studies are necessary to evaluate the potential role of these effects in the pathophysiology and therapeutics of BD.

Full-text

Available from: Rodrigo Machado-Vieira, May 13, 2014
Neuroscience Letters 421 (2007) 33–36
Oxidative stress parameters in unmedicated and treated bipolar subjects
during initial manic episode: A possible role for lithium antioxidant effects
Rodrigo Machado-Vieira
a,
, Ana Cristina Andreazza
b
, Carlos Ivan Viale
a
, Vanessa Zanatto
b
,
Victor Cereser Jr.
b
, Rafael da Silva Vargas
b
,Fl
´
avio Kapczinski
b
, Luiz V. Portela
b
,
Diogo O. Souza
b
, Mirian Salvador
c
, Valentim Gentil
d
a
Mood Disorders Program, HMIPV, Fundacao Faculdade Federal Ciencias Medicas de Porto Alegre and Bipolar Disorder Research Program,
Espirita Hospital of Porto Alegre, Porto Alegre, Brazil
b
Department of Psychiatry and Biochemistry, Federal University of Rio Grande do Sul, Brazil
c
Institute of Biotechnology and Department of Biomedical Sciences, University of Caxias do Sul, Brazil
d
Department and Institute of Psychiatry, University of Sao Paulo Medical School, Sao Paulo, Brazil
Received 22 February 2007; received in revised form 7 May 2007; accepted 9 May 2007
Abstract
Studies have proposed the involvement of oxidative stress and neuronal energy dysfunctions in the pathophysiology of bipolar disorder (BD).
This study evaluates plasma levels of the oxidative/energy metabolism markers, thiobarbituric acid reactive substances (TBARS), superoxide
dismutase (SOD), catalase (CAT), and neuron-specific enolase (NSE) during initial episodes of mania compared to controls in 75 subjects. Two
groups of manic subjects (unmedicated n = 30, and lithium-treated n = 15) were age/gender matched with healthy controls (n = 30). TBARS and
antioxidant enzymes activity (SOD and CAT) were increased in unmedicated manic patients compared to controls. Conversely, plasma NSE levels
were lower during mania than in the controls. In contrast, acute treatment with lithium showed a significant reduction in both SOD/CAT ratio
and TBARS levels. These results suggest that initial manic episodes are associated with both increased oxidative stress parameters and activated
antioxidant defenses, which may be related to dysfunctions on energy metabolism and neuroplasticity pathways. Antioxidant effects using lithium
in mania were shown, and further studies are necessary to evaluate the potential role of these effects in the pathophysiology and therapeutics of
BD.
© 2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Bipolar disorder; Mania; Oxidative stress; Stress; Brain; Mitochondria; Energy metabolism; Psychiatry; Lithium; Neurobiology
Bipolar disorder (BD) is a chronic and severe debilitating men-
tal disorder which affects about 1.2% of the population [31].
The neurobiological basis of BD may involve dysfunctions on
neurotrophic pathways and energy metabolism [13,15,24,20].
Increased neuronal oxidative stress (OxS) levels generate dele-
terious effects on signal transduction, structural plasticity and
cellular resilience, mostly by inducing lipid peroxidation in
membranes, proteins and genes [21,32]. Such changes in diverse
oxidative stress parameters have been reported in BD and
schizophrenia [22,43,28]. Thiobarbituric acid reactive sub-
stances (TBARS) levels is considered a direct index of cell
Corresponding author at: Quintino Bocaiuva 1495/1202, 90440-051, Porto
Alegre-RS, Brazil.
E-mail address: machadovieirar@terra.com.br (R. Machado-Vieira).
lipid peroxidation and the primary antioxidant system involves
coordinated effects induced by superoxide dismutase (SOD),
catalase (CAT) and glutathione peroxidase (GPx) [29,40]. Ele-
vated SOD/CAT ratio results in increased OxS, which is mostly
represented by elevation in cell hydrogen peroxide concentration
[9]. Regarding pharmacological treatment, lithium has shown
to exert antioxidant and neuroprotective effects by increasing
tolerance to OxS [32,44]. Similarly [33], showed that lithium
treatment prevents excitotoxicity by inhibition of oxidative
stress [33].
The neuronal glycolytic enzyme neuron-specific eno-
lase (NSE) has been shown to present direct effects on
energy metabolism, neuroplastic pathways and cell survival
[14,39,3,12]. Peripherally determined NSE is mainly derived
from neurons and its non-neuronal origin accounts for about 1/50
of its total levels [35]. Several studies have described altered NSE
0304-3940/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.neulet.2007.05.016
Page 1
34 R. Machado-Vieira et al. / Neuroscience Letters 421 (2007) 33–36
peripheral levels in diverse neurological disorders [14,37]. Oth-
erwise, few studies evaluated NSE levels in psychiatric disorders
and these findings are conflicting [6,10].
Despite recent data describing increased oxidative stress in
neurological and psychiatric disorders, we found no study mea-
suring oxidative stress parameters during manic episodes in
unmedicated or lithium-treated subjects. We now report differ-
ences in the peripheral markers TBARS, SOD, CAT and NSE
during manic episode compared to healthy controls.
Thirty unmedicated adult inpatients (7 men, 23 women;
mean age = 26 ± 4 years) and 15 lithium-treated (4 men, 11
women; mean age = 26.2 ± 6 years) meeting criteria for a manic
episode (Structured Clinical Interview for Axis I DSM-IV
Disorders-SCID-P) [7] were included. Subjects included in the
unmedicated group were evaluated in the admission unit of
Espirita Hospital of POA (HEPA). Regarding the past history,
patient sample included 36 never-treated (21 subjects in the
unmedicated group and 14 in the lithium-treated group) and 9
medication-free subjects presenting their second manic episode
(without psychopharmacological treatment for at least 5 weeks
prior to admission; unmedicated group = 9, lithium-treated = 1).
Young Mania Rating Scale (YMRS) score of 25 was con-
sidered inclusion criterion. YMRS scores did not significantly
differ between groups. Subjects were free of comorbid substance
abuse or dependency (lifetime) and had no acute medical or psy-
chiatric comorbidities. Patients presenting rapid cycling course
or mixed episode or using antioxidant vitamins were excluded.
Lithium-treated patients were evaluated from 1 to 3 weeks after
admission (mean = 14.5 ± 5days) and before clinical improve-
ment. Except for two patients who were hospitalized for fewer
than 10 days, all lithium-treated patients presented therapeutic
serum levels (0.85 ± 0.22 mM, mean dose = 970 ± 125 mg/day).
(The control group included 30 healthy subjects (according to
SCID-I non-patient), age and gender-matched (±2 years) with
manic patients. Controls were selected among health profes-
sionals (nurses, researchers, fellows and medical students). This
study was approved by the HEPA Ethics Committee, and all
patients or family members provided written informed consent
before study entry.
Samples were collected from 4 to 6 pm for unmedicated and
2–4 h after lithium intake in the treated group. Blood samples
were obtained using vacutainer tubes and kept on ice. Samples
were centrifuged at 3000 × g for 15 min and stored at 80
C for
less than 6 months. All samples and standards were assessed in
duplicate. SOD activity (U/g) was determined spectrophotomet-
rically by the inhibition in autocatalytic adrenochrome formation
rate at 480 nm, which was measured using 1 mmol/l adrenaline
(pH 2) and 50 mmol/l glycine (pH 10.2). The reaction was con-
duced at 30
C during 3 min [25]. CAT assay was carried out
according to [2]. Total protein levels were evaluated using the
Total Proteins Kit from Labtest
®
. Considering that SOD and
CAT act sequentially in a pathway of ROS elimination, we also
expressed results as SOD/CAT ratios. TBARS levels were mea-
sured on the production of MDA, which, by combining with
thiobarbituric acid, forms a pink chromogen compound [42].
Absorbance quantification at 530 nm was expressed as nmol/ml.
NSE levels were determined using a fluoroimmunoluminometric
assay (Sangtec Medical
®
). This direct sandwich technique using
two monoclonal antibodies identifies the antigen determinants
of NSE molecule. Standard control and samples containing NSE
reacted simultaneously with immobilized monoclonal antibod-
ies directed to a specific antigenic site for NSE. NSE levels were
expressed as g/l and the coefficient of variation was less than
5%.
Statistical analysis was performed using SPSS for Windows
12.0. Results and figure are presented as mean ± standard devi-
ation. Significance level was p < 0.05. Analysis of variance
was employed for comparison between patients and controls
(one-way ANOVA with Duncan post-hoc test). Possible associ-
ation between clinical variables and biochemical markers was
determined using the Pearson correlation analysis. Possible cor-
relation between age or gender with the peripheral markers was
evaluated using Spearman test.
Increased oxidative lipid peroxidation (TBARS) levels were
observed in unmedicated mania (5.1 ± 1.1) compared to con-
trol (2.7 ± 0.6) and lithium-treated (3.6 ± 0.3) groups (p < 0.001,
F = 62.4) (Fig. 1). The SOD/CAT ratio was significantly higher
in unmedicated mania (ratio = 0.83) than in the lithium-treated
group (ratio = 0.22, p < 0.001). SOD levels were higher in drug-
free mania (7.1 ± 3.5 U/g) compared to both lithium-treated
(2.65 ± 1.3) and controls (2.61 ± 1.4, F = 27.7, p < 0.001). CAT
was significantly increased in the lithium-treated and drug-
na
¨
ıve groups (11.8 ± 2.1 and 8.6 ± 4.0 mol/mg, respectively)
in comparison to controls (3.4 ± 1.8, F = 42.6, p < 0.001). NSE
levels were significantly lower in unmedicated (15.6 ± 6 g/l)
and lithium-treated (12.2 ± 7.4) subjects compared to the control
group (22.6 ± 9.4, F = 10, p = 0.002).
YMRS scores were similar in unmedicated (36.9 ± 5) and
lithium-treated (37.3 ± 4.9) patients (p = 0.8). There was no
significant correlation between the biochemical markers and
patients’ YMRS scores, age or gender in the total sample.
These increases in oxidative stress and antioxidant defenses
during manic episodes may derive from a compensatory mech-
anism to a previously increased cellular oxidative stress.
Interestingly, acute treatment with lithium decreased the
Fig. 1. Increased oxidative stress and antioxidant defenses were observed during
mania compared to controls, with enhanced antioxidant defenses in lithium-
treated BD patients compared to unmedicated mania. Decreased NSE was
observed in mania, without reversal effect by lithium. Data are presented as
mean ± S.D.; **P<0.001, *P<0.01.
Page 2
R. Machado-Vieira et al. / Neuroscience Letters 421 (2007) 33–36 35
SOD/CAT ratio and TBARS levels compared to unmedicated
mania. SOD catalyses the reduction of superoxide anion (O
2
•−
)
to hydrogen peroxide (H
2
O
2
) and oxygen, and CAT converts
H
2
O
2
to water and molecular oxygen. GPx can also act on
H
2
O
2
and others peroxides, like hydroperoxides. However, CAT
could became more important in removing H
2
O
2
than GPx,
mainly when there is a high concentrations of H
2
O
2
, since the
K
M
of catalase for H
2
O
2
is much higher than the GPx one.
An imbalance in SOD/CAT ratio indicates the generation of
reactive species, which can be compensated or not [11].Itis
clear that diverse acute neurological disorders such as stroke
rapidly increase peripheral oxidative stress parameters showing
the potential association with central and peripheral levels. In
the present context, lithium activity on SOD/CAT turnover (by
increasing CAT and decreasing SOD levels) may result in antiox-
idant effects. Thus, considering the neurobiological basis of BD,
and in the absence of any clinical illness and other relevant risk
factors for increased oxidative stress here described, it is reason-
able to suggest that differences in oxidative stress parameters
may be associated, at least in part, with brain metabolism.
Accordingly, a decline in lipid peroxidation and a raise
in CAT levels were described in lithium-treated rats [38,33]
observed lower free radicals and elevated resistance to oxida-
tive stress (by inhibition of the proapoptotic protein GSK-3)
after lithium treatment. Similarly, risperidone and olanzapine
reduced lipid peroxidation and SOD activity during first-episode
of psychosis [41,45]. Interestingly [33], reported a significant
inhibition on the glutamate-induced increase of lipid peroxi-
dation and protein oxidation using lithium at therapeutically
relevant concentrations.
Altered oxidative stress parameters have been associated with
the pathophysiology of BD [30,18]. Increased TBARS levels
were previously observed in BD and schizophrenia, especially
during first psychotic episode [23,28]. Studies also demonstrated
an increase in SOD and decrease in CAT levels in BD [1,18].On
the other hand [28], described lower plasma levels of SOD in
BD and schizophrenia, suggesting the presence of dysfunctions
in reparative mechanisms on cell membrane [29]. Interestingly,
in mania, SOD activity after 30 days under treatment with anti-
manic agents showed to be negatively correlated to the number
of previous manic episodes [8].
The discrepancy observed in the literature concerning oxida-
tive stress parameters in BD patients is possibly due to the
disease itself, but is affected, also, by medications, comorbidi-
ties, diet and lifestyle [1,18,28].
This is the first study showing decreased NSE levels in
unmedicated manic subjects and absence of lithium effect on
this parameter. NSE modulates neuronal glycolysis [3] and BD
has been associated with dysfunctions on energy metabolism
and cell plasticity in neurons and glia [27,26,12] observed the
generation of neurotrophic effects induced by NSE. Similar to
our findings, studies have described lower central NSE lev-
els in patients presenting chronic neurological disorders, such
as Alzheimer and multi-infarct dementia [4,36]. Conversely,
increased central or peripheral NSE levels have been frequently
observed in acute neurological disorders [14,37,35,19,10],ina
postmortem study, found no difference on brain NSE expres-
sion in BD, depression or schizophrenia compared to controls.
Overall, conflicting results regarding NSE in psychiatric disor-
ders may limit the correct interpretation of these findings, but
improved neuronal integrity might be suggested.
Changes in mitochondrial and energy metabolism were
described in BD [15,17]. Mitochondria controls energy and
free radicals production in neurons, through regulatory effects
on cell redox and oxidative metabolism [44,26] proposed the
presence of dysfunctions on neuronal glucose metabolism in
mood disorders. In this context [5], observed an increase in
gray matter lactate levels in BD, possibly underlying a deficit
in neuronal glycolysis in BD. Thus, it is reasonable to sug-
gest that the altered oxidative stress parameters and decreased
NSE levels observed during manic episodes may play a role in
the energy metabolism dysfunctions associated with BD. Also,
lithium seems to exert antioxidant effects during mania. Limi-
tations of this study include the lack of information regarding
the specificity of the effects for mania and therapeutic effects of
lithium, as well as the extent to which these peripheral markers
are directly correlated to brain parameters. Also, lithium-treated
and unmedicated subjects were different people, which may
limit the interpretation in terms of direct lithium effects.
Further studies with larger samples may provide additional
data regarding the possible involvement of oxidative stress and
neuroplasticity in the pathophysiology of mania and in the ther-
apeutic effects of lithium.
Acknowledgements
Patients and Staff from Espirita Hospital of Porto Alegre,
Dr. Luciana Mesko, Luciane Wagner, CAPES, CNPq, Stanley
Medical Research Institute.
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Page 4
  • Source
    • "disorder (BD) (Clay et al. 2011; Machado-Vieira et al. 2013). Previous studies reported increased oxidative stress in postmortem brains and peripheral blood samples of BD subjects (Andreazza et al. 2008, 2010; Machado-Vieira et al. 2007), suggesting energy dysfunction at mitochondrial electron transport chain (ETC) complexes. A decrease in mitochondrial ETC complex I activity was observed in postmortem BD, associated with elevated oxidative stress parameters (Andreazza et al. 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: Different lines of evidence suggest that mitochondrial dysfunction may be implicated in bipolar disorder (BD) pathophysiology. Mitochondrial electron transport chain (ETC) is a key target to evaluate mitochondrial function, but its activity has never been assessed in unmedicated BD or during mood episodes. Also, lithium has been shown to increase ETC gene expression/activity in preclinical models and in postmortem brains of BD subjects, but to date, no study has evaluated lithium's direct effects on ETC activity in vivo.
    Full-text · Article · Jun 2014 · Psychopharmacology
  • Source
    • "Catalase and glutathione peroxidase levels are also elevated in patients with bipolar disorder during depressive episodes [32]. Treatment with the mood-stabilizer lithium reduces thiobarbituric acid reactive substances in those patients presenting for an initial manic episode as well as in those patients with episodes of hypomania (bipolar disorder type II) [32, 33]. Lithium administration in bipolar disorder patients has been noted to increase the activity of the Na+ K+ ATPase, a cellular event which is independently associated with reduction in lipid peroxidation [34]. "
    [Show abstract] [Hide abstract] ABSTRACT: The brain is known to be sensitive to oxidative stress and lipid peroxidation. While lipid peroxidation has been shown to contribute to many disease processes, its role in psychiatric illness has not been investigated until recently. In this paper, we provide an overview of lipid peroxidation in the central nervous system as well as clinical data supporting a link between lipid peroxidation and disorders such as schizophrenia, bipolar disorder, and major depressive disorder. These data support further investigation of lipid peroxidation in the effort to uncover therapeutic targets and biomarkers of psychiatric disease.
    Full-text · Article · Apr 2014 · Oxidative medicine and cellular longevity
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    • "Studies revealed that among other things, lithium toxicity can be connected with oxidative stress [6, 10, 13, 36], but contradicting outcomes were also reported [39, 40]. Furthermore, oxidative stress was also found to be involved into the pathophysiology of bipolar disorder [40, 41]. As long-term lithium therapy is used in the cure of this disease, the question of the influence of lithium on oxidative processes is an issue of great importance. "
    [Show abstract] [Hide abstract] ABSTRACT: Lithium is widely used in medicine, but its administration can cause numerous side effects. The present study aimed at the evaluation of the possible application of selenium, an essential and antioxidant element, as a protective agent against lithium toxicity. The experiment was performed on four groups of Wistar rats: I (control)-treated with saline, II (Li)-treated with lithium (Li2CO3), III (Se)-treated with selenium (Na2SeO3) and IV (Li + Se)-treated with lithium and selenium (Li2CO3 and Na2SeO3) in the form of water solutions by stomach tube for 6 weeks. The following biochemical parameters were measured: concentrations of sodium, potassium, calcium, magnesium, phosphorus, iron, urea, creatinine, cholesterol, glucose, total protein and albumin and activities of alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase in serum as well as whole blood superoxide dismutase and glutathione peroxidase. Morphological parameters such as red blood cells, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets, white blood cells, neutrophils as well as lymphocytes were determined. Lithium significantly increased serum calcium and glucose (2.65 ± 0.17 vs. 2.43 ± 0.11; 162 ± 31 vs. 121 ± 14, respectively), whereas magnesium and albumin were decreased (1.05 ± 0.08 vs. 1.21 ± 0.15; 3.85. ± 0.12 vs. 4.02 ± 0.08, respectively). Selenium given with lithium restored these parameters to values similar to those observed in the control (Ca-2.49 ± 0.08, glucose-113 ± 26, Mg-1.28 ± 0.09, albumin-4.07 ± 0.11). Se alone or co-administered with Li significantly increased aspartate aminotransferase and glutathione peroxidase. The obtained outcomes let us suggest that the continuation of research on the application of selenium as an adjuvant in lithium therapy seems warranted.
    Full-text · Article · Mar 2014 · Biological trace element research
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