Anxiety and Oxidative Distress

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Accepted Manuscript

Title: Oxidative stress in anxiety and comorbid disorders

Authors: Iiris Hovatta, Juuso Juhila, Jonas Donner

PII: S0168-0102(10)02779-3DOI: doi:10.1016/j.neures.2010.08.007

Reference: NSR 3191

To appear in: Neuroscience Research

Received date: 15-7-2010

Revised date: 20-8-2010

Accepted date: 23-8-2010

Please cite this article as: Hovatta, I., Juhila, J., Donner, J., Oxidative stress in anxiety and

comorbid disorders, Neuroscience Research (2010), doi:10.1016/j.neures.2010.08.007

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Review article

Oxidative stress in anxiety and comorbid disorders

Iiris Hovattaa, b, c

, Juuso Juhilaa, b

, and Jonas Donnera, b, c

aResearch Program of Molecular Neurology, Faculty of Medicine, Biomedicum PO box 63, FIN-00014

University of Helsinki, Finland (emails: [email protected], [email protected],

[email protected])

b Department of Medical Genetics, Haartman Institute, Biomedicum PO box 63, FIN-00014 University of

Helsinki, Finland

cDepartment of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, PO

box 30, FIN-00271 Helsinki, Finland

Manuscript


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ABSTRACT

Anxiety disorders, depression, and alcohol use disorder are common neuropsychiatric diseases that often

occur together. Oxidative stress has been suggested to contribute to their etiology. Oxidative stress is a

consequence of either increased generation of reactive oxygen species or impaired enzymatic or non-

enzymatic defense against it. When excessive it leads to damage of all major classes of macromolecules,

and therefore affects several fundamentally important cellular functions. Consequences that are especially

detrimental to the proper functioning of the brain include mitochondrial dysfunction, altered neuronal

signaling, and inhibition of neurogenesis. Each of these can further contribute to increased oxidative stress,

leading to additional burden to the brain. In this review, we will provide an overview of recent work on

oxidative stress markers in human patients with anxiety, depressive, or alcohol use disorders, and in

relevant animal models. In addition, putative oxidative stress-related mechanisms important for

neuropsychiatric diseases are discussed. Despite the considerable interest this field has obtained, the


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1. IntroductionOxidative phosphorylation, which takes place in mitochondria of the cell, is the major source of ATP in

aerobic organisms. The downside of this important process is that as a byproduct, it may produce free

radicals, such as some reactive oxygen species (ROS) and reactive nitrogen species (RNS). They have both

beneficial and harmful roles in the cell. At low or moderate concentrations, they take part in normal

physiological processes such as cellular response to injury or infection, signaling, and mitosis (Valko et al.,

2007). However, when the pro-oxidant/antioxidant balance is disturbed towards higher concentrations of

ROS/RNS, cells exhibit harmful conditions of oxidative and nitrosative stress. On one hand, oxidative stress

arises when generation of ROS/RNS is increased and exceeds the cellular detoxification and damage repair

capacity. On the other hand, oxidative stress results from impaired oxidative defense mechanisms, such as

depletion of enzymatic (e.g., superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase

[GPX]) and non-enzymatic (e.g., glutathione [GSH], vitamins A, C, and E, and selenium) antioxidants (Figure

1) Either way the consequence of oxidative stress is increased damage to all major groups of cellular


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Reynolds et al., 2007), in psychiatric disorders in general (Ng et al., 2008), and in anxiety (Bouayed et al.,

2009) has been discussed in recent reviews.

Anxiety, depressive, and alcohol use disorders are highly comorbid mental disorders, as shown by

epidemiological studies (Kessler et al., 2008, Pirkola et al., 2005). In particular, anxiety and depression have

co-occurring and related symptoms that may be due to an underlying shared genetic basis (Hettema, 2008).

In the Finnish population-wide Health 2000 Survey, the annual prevalences of anxiety-, depressive-, and

alcohol use disorders were 4.1 %, 6.5 %, and 4.5 %, respectively (Pirkola et al., 2005). In the same study,

35.9 % of the anxiety disorder patients had a comorbid depressive disorder (major depressive disorder

and/or dysthymia), and 22.4 % a comorbid alcohol use disorder (alcohol abuse and/or dependence). These

disorders are commonly diagnosed and classified for research purposes according to the Diagnostic and

Statistical Manual of Mental Disorders (American Psychiatric Association, 2000). The core feature of anxiety

disorders is exaggerated anxiety that causes distress, disability and loss of quality of life. Anxiety disorders

can further be divided into diagnostic subcategories based on specific features regarding the focus course


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The direct measurement of free radical concentrations is difficult due to their short half-lives and low

concentrations, and therefore measurements of metabolites of reactive species, antioxidant levels,

antioxidant enzyme activities, and markers of oxidative damage (lipid peroxidation, protein carbonylation,

and DNA damage) are commonly used to quantify levels of oxidative stress (Berk et al., 2008). In humans,

these parameters have been evaluated in a number of studies that establish a link between oxidative stress

and anxiety, depressive, and alcohol use disorders (Table 1). Results are mainly based on studies of plasma,

serum, and blood cells investigating oxidative stress on a systemic level, while fewer post mortem studies

of specific brain regions exist.

One of the few specific free radicals measured in several studies is nitric oxide (NO), which interestingly is

both a ROS and a neuronal second messenger involved in modulation of, among other physiological

functions, noradrenaline and dopamine release, learning and memory, wakefulness, and food intake and

drinking (Herken et al., 2006). However, increased, decreased, and unaltered levels of NO in the studied

disorders have been reported (Table 1) suggesting that it might be involved in oxidative stress through


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In general, activities of antioxidant enzymes appear increased in anxiety, depression, and alcohol use

disorder (Table 1). Some discrepant and negative results exist both across and within phenotypes, possibly

due to many studies carried out with limited sample sizes or due to heterogeneity of study samples and

conditions. The strongest and most consistent support exists for increased activity of SOD, possibly

reflecting its crucial role as the first enzyme of the superoxide radical detoxification pathway, although SOD

is also the most intensively studied antioxidant enzyme. Several studies have detected increased activities

of the other enzymes involved in superoxide radical detoxification, including CAT, glutathione reductase

(GSR), and GPX, but decreased activity of GPX has also been reported. Notably, most of the studies

measuring CAT found no change in its activity. This observation may reflect the fact that disposition of H2O2

occurs more readily by the GPX system at low concentrations, and by CAT at higher concentrations

(Halliwell, 2007). In a complementary approach, peripheral blood gene expression profiling of PTSD

patients revealed differential expression of enzymes related to ROS-metabolism, including downregulation

of thioredoxin reductase and SOD (Zieker et al., 2007). Interestingly, the same study also reported


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antioxidant status were observed in OCD and PD (Ersoy et al., 2008, Selek et al., 2008). Similarly, discrepant

results from studies evaluating general total oxidant status or oxidative stress index (total oxidant

status/total antioxidant status) in blood exist.It was hypothesized that increased total antioxidant capacity

could reflect reactive increase in defense mechanisms, as rebound decreases in total oxidant levels were

also observed (Selek et al., 2008). Such rebound phenomena only in certain studied patient groups could

explain some of the discrepancies between phenotypes.

Taken together, findings from human studies clearly support involvement of altered oxidative stress-related

mechanisms in anxiety disorders, major depression, and alcohol use disorder, but to what extent and how

these represent state or trait markers has not yet been conclusively resolved. Some studies have addressed

the effect of antidepressant treatment on oxidative stress markers in patients with anxiety or depressive

disorders (Atmaca et al., 2004, Bilici et al., 2001, Ersoy et al., 2008, Herken et al., 2006, Herken et al., 2007).

In several of these studies, oxidative stress was diminished in patients after drug treatment. However, in

the absence of healthy controls receiving treatment or patient groups receiving placebo interpretation of


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rodent models to measure anxiety-like and depression-like behavior, such as the elevated plus maze,

light/dark box, open field, forced swim, and the tail suspension tests exist. Both psychological distress (e.g.,

communication box paradigm (Matsumoto et al., 1999)) and physical stress (e.g., immobilization stress

(Zafir and Banu, 2009)) modulate antioxidant defenses and increase oxidative damage in the brain (Table

2). Studies of markers of oxidative stress-related cellular damage in animals strongly suggest that not only is

there increased damage to lipids, proteins, and DNA in the brain after stress but also after ethanol

treatment (Table 2). Notably, these effects seem to be brain region-specific. The effect of stress on specific

free radicals has not been evaluated as extensively as oxidative stress damage. Increased generation of O2-

was observed in submitochondrial particles of rat hippocampus, prefrontal cortex and cortex after chronic

mild stress treatment (Lucca et al., 2009), whereas increased NO levels were found in mouse whole brain

(Matsumoto et al., 1999), rat hippocampus (Harvey et al., 2004), and rat serum after different stress

paradigms (Kamper et al., 2009). Outbred Swiss albino mice show positive correlation between trait anxiety

and intracellular ROS levels in cerebellum and hippocampus (Rammal et al., 2008a), and in peripheral blood


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restraint stress, chronic mild stress, olfactory bulbectomy, and ethanol treatment. Depleted GSH levels may

explain the decreased enzyme activities of GPX and GSR observed in some studies (Atif et al., 2008, Zafir

and Banu, 2009).

In addition to investigations focusing on specific markers of oxidative stress, more global brain proteomic

and gene expression studies also support a connection between oxidative stress and anxiety. Glyoxalase 1

(GLO1), a detoxification enzyme, is downregulated in the brain of two separate mouse strains selectively

bred for high anxiety behavior compared to their respective low-anxiety strains (Kromer et al., 2005, Szego

et al., 2010). In addition, several other proteins related to oxidative stress metabolism are either

upregulated (glutathione S-transferase M1, and sirtuin 2) or downregulated (glutaredoxin 3, peroxiredoxin

6, and quinoid dihydropteridine reductase) in one of the anxious mouse strains (Szego et al., 2010).

Contrary to these findings, brain gene expression levels and enzyme activities of GLO1 and GSR correlate

positively with anxiety-related behavior across six inbred mouse strains (Hovatta et al., 2005). Furthermore,

local overexpression of Glo1 and Gsr in the cingulate cortex of inbred mice increases anxiety-related


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levels and oxidative stress markers, and also show decreased anxiety-like behavior (Berry et al., 2007). Mice

lacking the phospholipid transfer protein (PLTP), a transfer factor for the antioxidant vitamin E, have

depleted brain vitamin E levels, and increased levels of oxidative stress markers and show increased

anxiety-like behavior (Desrumaux et al., 2005). Oxidative stress can also be induced by administration of

compounds, such as L-buthionine-(S,R)-sulfoximine (BSO), which depletes cellular GSH levels by inhibiting

its synthesis. Interestingly, treatment of mice or rats with BSO induces oxidative stress and increases

anxiety-like behavior (Masood et al., 2009, Salim et al., 2010). The oxidative stress-induced anxiety is

reduced by inhibition of NADPH oxidase pathway via PDE2 inhibition (Masood et al., 2009) or with

moderate treadmill exercise (Salim et al., 2010). In rats, intake of a highly palatable diet causes increased

oxidative damage in the frontal cortex and induces anxiety-like behavior (Souza et al., 2007).

To summarize, rodent models suggest that psychological and physical stress are associated with increased

levels of free radicals, depleted antioxidant levels, and altered antioxidant enzyme activities, which may

lead to the observed oxidative damage to the brain Also gene expression and proteomic studies in various


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diseases, including cardiovascular diseases, diabetes, inflammatory diseases, schizophrenia, mood

disorders, and anxiety disorders. Mechanisms that contribute to accelerated telomere shortening in vivo

remain largely unknown. Oxidative stress shortens telomeres in vitro, as shown by mild stress induced in

various ways, including chronic hyperoxia, treatment with homocysteine, low doses oftert-

butylhydroperoxide or hydrogen peroxide (Dumont et al., 2000, Dumont et al., 2001, Lorenz et al., 2001,

Vaziri et al., 1997, von Zglinicki et al., 1995, von Zglinicki et al., 2000, von Zglinicki, 2002, Xu et al., 2000).

Importantly, antioxidant vitamin C and the free radical scavenger -phenyl-t-butylnitrone reverses the

oxidative stress-induced telomere shortening in vitro (Furumoto et al., 1998, von Zglinicki et al., 2000). It

has been hypothesized that DNA damage caused by mild oxidative stress might lead to the presence of

unrepaired nucleotide or base damage, which interferes with the replication fork at telomeres and

therefore leads to shortened telomeres (von Zglinicki, 2002).

Epel et al. associated self-perceived stress to shorter leukocyte telomere length and increased oxidative


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Mitochondria are the main intracellular sites of ROS generation and are also targets for oxidative damage.

Several genetic studies both in humans and in rodents have provided evidence for the involvement of

mitochondrial dysfunction in neuropsychiatric diseases. Patients with some mitochondrial diseases, such as

progressive external ophtalmoplegia (PEO) and mitochondrial recessive ataxia syndrome (MIRAS), have

psychiatric symptoms, including anxiety and depression(Hakonen et al., 2005, Suomalainen et al., 1992).

Both PEO and MIRAS can be caused by mutations in the nuclear encoded mitochondrial polymerase gamma

(POLG) gene. Mutations in POLG, which is responsible for mitochondrial DNA replication, result in randomly

distributed mtDNA point mutations. Interestingly, transgenic mice expressing mutant POLG specifically in

forebrain neurons have accumulation of mitochondrial DNA mutations and show a mood disorder-like

phenotype (Kasahara et al., 2006). Studies of another transgenic model with the Y955C POLG mutation

causing PEO have suggested that one of the pathological mechanisms may be oxidative damage to mtDNA

(Graziewicz et al., 2007). The effect of mtDNA damage to the forebrain neurons of mice and its

consequences on behavioral phenotypes has also been studied in a transgenic mouse model that has been


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mitochondria-focused microarrays found that the majority of the differentially expressed transcripts were

related to mitochondrial dysfunction and oxidative phosphorylation (Su et al., 2008), conditions which may

be associated with excessive ROS production.

Another approach to study the specific mechanisms relating mitochondrial function to anxiety has been

behavioral studies of knockout mice of mitochondria-located proteins. BCL2 is a mitochondrial membrane

protein involved in apoptosis and Ca2+

homeostasis. Mice over-expressing Bcl2 in neurons have decreased

anxiety-like behavior (Rondi-Reig et al., 1997) while mice with a targeted mutation ofBcl2 show increased

anxiety-like behavior (Einat et al., 2005). In a human genetic association analysis one SNP in BCL2 was

associated with generalized anxiety disorder (Sipila et al., 2010). Interestingly, glucocorticoid receptors

form a complex with BCL2 followed by translocation to mitochondria in response to corticosterone which

leads to modulation of mitochondrial oxidation, membrane potential, and mitochondrial calcium holding

capacity (Du et al., 2009).


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In summary, genetic defects or environmental factors, such as stress or diet, can cause mitochondrial

dysfunction, which leads to increased oxidative stress or altered Ca

2+

homeostasis (Figure 2). This in turn

might alter neuronal signaling and further increase oxidative stress through accelerated ROS production.

Genetic studies in human patients with mitochondrial disorders and mouse genetic studies using transgenic

models have been especially useful to show that mechanisms related to mitochondrial dysfunction are

involved in the pathogenesis of neuropsychiatric diseases.

6. The effect of oxidative stress on neuronal signaling and excitotoxicity

Excitotoxicity is the pathological process by which nerve cells are damaged and eventually killed by

endogenous substances, and therefore it is one of the mechanisms contributing to neuronal degeneration.

Excitotoxic neuronal damage may occur when the excitatory signaling (glutamate or other excitatory

transmitters or peptides) outweighs the inhibitory (mainly aminobutyric acid, GABA) signaling. Excessive

excitatory signaling leads to modulation of glutamate receptors and increased cellular Ca2+

influx. This in
http://en.wikipedia.org/wiki/Neuronhttp://en.wikipedia.org/wiki/Neuron


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studies with NMDA or -amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonists

or calcium channel blockers have failed to prevent NMDA receptor-mediated toxicity especially in brain

damage caused by chronic ethanol. These studies indicate that NMDA glutamate receptor-related

excitotoxicity by itself cannot fully explain the neurodegeneration induced by ethanol exposure (Crews et

al., 2004).NO-producing pathways and NO-mediated signaling are also linked to modulation of anxiety-like

behavior, although results from different models have been contradictory as inhibition of NOS increased

anxiety-like behavior in one study (Masood et al., 2009) and decreased it in another (Zhang et al., 2010).

To conclude, while it is evident that glutamatergic and GABAergic systems modulate neuronal Ca2+

influx

putatively stimulating NO production and leading to oxidative stress, additional work on specific

mechanisms concerning the effect of oxidative stress on excitotoxic neuronal degeneration is needed.

7. Oxidative stress and inflammation

Increased levels of pro-inflammatory cytokines have been detected in patients with major depression,


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and additional pro-inflammatory signaling molecules, such as eicosanoids, that further promote

inflammation and degeneration in the brain (Sun et al., 2004). AA may also have direct apoptotic effects

(Caro and Cederbaum, 2006, Fang et al., 2008, Sun et al., 2004). Conversely, anti-inflammatory agent

docosahexaenoic acid (DHA), a major component of brain membrane phospholipids, prevents neuronal

apoptosis and plays an important role as an anti-oxidant agent (Bazan, 2007, Suganuma et al., 2010).

Furthermore, brain concentrations of DHA are reduced after chronic ethanol exposure in cats and monkeys

(Pawlosky and Salem, 1995, Pawlosky et al., 2001). Subchronic ethanol induces damage to neurons in rat

brain slice culture. This effect can be prevented by the PLA2 pan-inhibitor mepacrine and is ameliorated by

DHA supplementation (Brown et al., 2009). Taken together, there is evidence that enhanced pro-

inflammatory cytokine signaling may promote ROS generation and lead to oxidative damage, and this might

be one mechanism that links inflammation to neuropsychiatric diseases.

Nuclear factor B (NFB) is a transcription factor associated with the induction of pro-inflammatory

cytokines It is activated by ROS cytokines and glutamate and thought to be a mediator of oxidative stress


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The role ofNFB activation in relation to oxidative stress has also been extensively studied in alcoholic

neuropathy (Crews et al., 2006, Crews and Nixon, 2009). Ethanol exposure increases NFBDNA binding in

rat brain (Crews et al., 2006) and in brain slice cultures in vitro (Zou and Crews, 2006, Zou and Crews, 2010).

In human astroglial cells, which normallyregulate extracellular glutamate concentrations, ethanol enhances

NFB-DNA binding and activation of inducible nitric oxide synthase (iNOS) (Davis and Syapin, 2004, Davis et

al., 2005). Induction of NOS may enhance NO production and oxidative stress, and modulate anxiety-

related behavior as discussed in the previous section.

cAMP response element-binding (CREB) family is another class of transcription factors linked to

inflammation. CREB promotes neuronal survival, protecting neurons from excitotoxicity and apoptosis

through transcriptional activation of pro-survival factors (Lonze and Ginty, 2002, Mantamadiotis et al.,

2002). In vivo, subchronic ethanol treatment decreases the expression of the phosphorylated form of CREB

in the brain (Bison and Crews, 2003). Interestingly hippocampal nNOS and CREB mediate some of the

anxiolytic effects of 5-HT1A serotonin receptor agonists and selective serotonin reuptake inhibitors (SSRIs)


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In summary, activation of inflammatory pathways has been observed in patients with anxiety disorders,

major depression, and alcoholism, and in experimental animal models for these disorders. On one hand,

increased levels of pro-inflammatory cytokines seem to be involved, and on the other hand activation of

inflammation-related transcription factors, such as NFB and CREB. These transcription factors in turn

regulate the expression level of several inflammation-related enzymes including NOS, COX2, and NADPH

oxidase that in turn enhance production of ROS. Of these, especially the NADPH oxidase pathway has been

associated with the regulation of anxiety-like behavior.

8. Inhibition of neurogenesis by oxidative stress

A growing body of evidence shows that impaired neurogenesis is involved in the pathogenesis of

neuropsychiatric illness. In preclinical studies enriched environment and exercise increase neurogenesis

and reduce anxiety- and depression-like behaviors (Kempermann et al., 1997, Salam et al., 2009, van Praag

et al., 1999, van Praag et al., 2005) and alcohol-induced brain damage (Leasure and Nixon, 2010). Also,


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oxidative events. Also chronic alcohol exposure decreases neurogenesis and increases cell death in the

dentate gyrus of hippocampus (Herrera et al., 2003), and similarly, the inhibition of neurogenesis was

prevented by an antioxidant, ebselen. Ebselen is an organoselenium GPX mimetic, and a poor oxidative

radical scavenger, but it inhibits lipid peroxidation and blocks the function of inflammatory enzymes, such

as COX2 (Nakamura et al., 2002). In addition, in cultured hepatocytes and in mouse skin ebselen

potentiates activities of phase II enzymes, including NAD(P)H:(quinone-acceptor) oxidoreductase 1 and

glutathione S-transferase (Nakamura et al., 2002).

Taken together, oxidative stress seems to impair neurogenesis, as exemplified by studies carried out on the

effects of ethanol in rodent models. However, it remains to be investigated how significantly oxidative

stress reduces neurogenesis in humans and what is the significance of this mechanism in neuropsychiatric

diseases.

9. Antioxidant-related clinical therapies


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symptoms observable after 9 weeks of active use (Grant et al., 2009). Case studies have further reported

symptom reduction by NAC in OCD (Lafleur et al., 2006), trichotillomania, and pathological nail biting and

skin picking (Berk et al., 2009, Odlaug and Grant, 2007). Depressive symptoms in bipolar disorder were

significantly reduced by 24 week adjunction of NAC to usual medication in another double-blind, placebo

controlled trial (Berk et al., 2008). The efficacy of natural remedies, most of which have antioxidant

properties, in treatment of anxiety disorders was recently reviewed, and the findings mainly suggested

beneficial effects of passionflower in GAD and inositol in PD and OCD (Kinrys et al., 2009). Taken together,

these findings suggest that targeting oxidative stress-related mechanisms may be beneficial in treatment of

anxiety, and an additional augmentation to conventional antidepressant and behavioral therapy. However,

understanding the detailed neurobiological mechanisms related to antioxidant supplementation and

perturbation of oxidative stress pathways is a key to the development of new and safe treatment practices.

10.Summary and future directions


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oxidative stress. Various events including mitochondrial dysfunction, inflammation, alterations in glutamate

or GABA signaling, and inhibition of neurogenesis may each contribute individually to increased oxidative

stress which in turn impacts these very same factors leading to excessive oxidative stress, and resulting in

damage to cellular macromolecules. Eventually the consequences will be increased apoptosis, neuronal

degeneration, and brain damage, which contribute to the manifestation of neuropsychiatric illness in

susceptible individuals. The detailed mechanisms, however, remain largely unknown.

To distinguish pathogenetic mechanisms from adaptation and compensation, several approaches should be

combined. Functional genomics offer powerful tools to assess gene expression differences in tissue-specific

and temporal manner. At the same time, a large-scale biochemical approach should be taken to monitor

the oxidative stress status and resulting damage to various macromolecules. The recently developed

metabolomic technologies should be of great advantage allowing simultaneous investigation of a large

number of metabolites and signaling molecules. Considerable effort has been made in recent years to

develop accurate animal models for neuropsychiatric disorders and they will be instrumental to the


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References:

Aksenova, M. V., Aksenov, M. Y., Mactutus, C. F., and Booze, R. M., 2005. Cell culture models of oxidative

stress and injury in the central nervous system. Curr Neurovasc Res. 2, 73-89.

Andreazza, A. C., Frey, B. N., Erdtmann, B., Salvador, M., Rombaldi, F., Santin, A., Goncalves, C. A., and

Kapczinski, F., 2007. DNA damage in bipolar disorder. Psychiatry Res. 153, 27-32.

Arai, M., Yuzawa, H., Nohara, I., Ohnishi, T., Obata, N., Iwayama, Y., Haga, S., Toyota, T., Ujike, H., Ichikawa,

T., Nishida, A., Tanaka, Y., Furukawa, A., Aikawa, Y., Kuroda, O., Niizato, K., Izawa, R., Nakamura, K., Mori,

N., Matsuzawa, D., Hashimoto, K., Iyo, M., Sora, I., Matsushita, M., Okazaki, Y., Yoshikawa, T., Miyata, T.,

and Itokawa, M., 2010. Enhanced carbonyl stress in a subpopulation of schizophrenia. Arch Gen Psychiatry.

67, 589-597.


24/50

anuscript

Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S., and Baltimore, D., 1995. Embryonic lethality and liver

degeneration in mice lacking the RelA component of NF-kappa B. Nature. 376, 167-170.

Berk, M., Ng, F., Dean, O., Dodd, S., and Bush, A. I., 2008. Glutathione: a novel treatment target in

psychiatry. Trends Pharmacol Sci. 29, 346-351.

Berk, M., Jeavons, S., Dean, O. M., Dodd, S., Moss, K., Gama, C. S., and Malhi, G. S., 2009. Nail-biting stuff?

The effect of N-acetyl cysteine on nail-biting. CNS Spectr. 14, 357-360.

Berry, A., Capone, F., Giorgio, M., Pelicci, P. G., de Kloet, E. R., Alleva, E., Minghetti, L., and Cirulli, F., 2007.

Deletion of the life span determinant p66Shc prevents age-dependent increases in emotionality and pain

sensitivity in mice. Exp Gerontol. 42, 37-45.


25/50

anuscript

Bob, P., Raboch, J., Maes, M., Susta, M., Pavlat, J., Jasova, D., Vevera, J., Uhrova, J., Benakova, H., and Zima,

T., 2010. Depression, traumatic stress and interleukin-6. J Affect Disord. 120, 231-234.

Bouayed, J., Rammal, H., and Soulimani, R., 2009. Oxidative stress and anxiety: Relationship and cellular

pathways. Oxid Med Cell Longev. 2, 63-67.

Bourin, M. and Hascoet, M., 2003. The mouse light/dark box test. Eur J Pharmacol. 463, 55-65.

Brown, J., 3rd, Achille, N., Neafsey, E. J., and Collins, M. A., 2009. Binge ethanol-induced neurodegeneration

in rat organotypic brain slice cultures: effects of PLA2 inhibitor mepacrine and docosahexaenoic acid (DHA).

Neurochem Res. 34, 260-267.

Caro, A. A. and Cederbaum, A. I., 2006. Role of cytochrome P450 in phospholipase A2- and arachidonic acid-


26/50

anuscript

Crews, F. T., Collins, M. A., Dlugos, C., Littleton, J., Wilkins, L., Neafsey, E. J., Pentney, R., Snell, L. D.,

Tabakoff, B., Zou, J., and Noronha, A., 2004. Alcohol-induced neurodegeneration: when, where and why?

Alcohol Clin Exp Res. 28, 350-364.

Crews, F. T. and Nixon, K., 2009. Mechanisms of neurodegeneration and regeneration in alcoholism.

Alcohol Alcohol. 44, 115-127.

Cui, J., Shao, L., Young, L. T., and Wang, J. F., 2007. Role of glutathione in neuroprotective effects of mood

stabilizing drugs lithium and valproate. Neuroscience. 144, 1447-1453.

Damjanovic, A. K., Yang, Y., Glaser, R., Kiecolt-Glaser, J. K., Nguyen, H., Laskowski, B., Zou, Y., Beversdorf, D.

Q., and Weng, N. P., 2007. Accelerated telomere erosion is associated with a declining immune function of

caregivers of Alzheimer's disease patients. J Immunol. 179, 4249-4254.


27/50

anuscript

Desrumaux, C., Risold, P. Y., Schroeder, H., Deckert, V., Masson, D., Athias, A., Laplanche, H., Le Guern, N.,

Blache, D., Jiang, X. C., Tall, A. R., Desor, D., and Lagrost, L., 2005. Phospholipid transfer protein (PLTP)

deficiency reduces brain vitamin E content and increases anxiety in mice. Faseb J. 19, 296-297.

Du, J., Wang, Y., Hunter, R., Wei, Y., Blumenthal, R., Falke, C., Khairova, R., Zhou, R., Yuan, P., Machado-

Vieira, R., McEwen, B. S., and Manji, H. K., 2009. Dynamic regulation of mitochondrial function by

glucocorticoids. Proc Natl Acad Sci U S A. 106, 3543-3548.

Dumont, P., Burton, M., Chen, Q. M., Gonos, E. S., Frippiat, C., Mazarati, J. B., Eliaers, F., Remacle, J., and

Toussaint, O., 2000. Induction of replicative senescence biomarkers by sublethal oxidative stresses in

normal human fibroblast. Free Radic Biol Med. 28, 361-373.

Dumont, P., Royer, V., Pascal, T., Dierick, J. F., Chainiaux, F., Frippiat, C., de Magalhaes, J. P., Eliaers, F.,


28/50

anuscript

Epel, E. S., Blackburn, E. H., Lin, J., Dhabhar, F. S., Adler, N. E., Morrow, J. D., and Cawthon, R. M., 2004.

Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A. 101, 17312-17315.

Erel, O., 2004. A novel automated direct measurement method for total antioxidant capacity using a new

generation, more stable ABTS radical cation. Clin Biochem. 37, 277-285.

Ersoy, M. A., Selek, S., Celik, H., Erel, O., Kaya, M. C., Savas, H. A., and Herken, H., 2008. Role of oxidative

and antioxidative parameters in etiopathogenesis and prognosis of panic disorder. Int J Neurosci. 118,

1025-1037.

Fang, K. M., Chang, W. L., Wang, S. M., Su, M. J., and Wu, M. L., 2008. Arachidonic acid induces both Na+

and Ca2+ entry resulting in apoptosis. J Neurochem. 104, 1177-1189.


29/50

anuscript

Fujimoto, M., Uchida, S., Watanuki, T., Wakabayashi, Y., Otsuki, K., Matsubara, T., Suetsugi, M., Funato, H.,

and Watanabe, Y., 2008. Reduced expression of glyoxalase-1 mRNA in mood disorder patients. Neurosci

Lett. 438, 196-199.

Furumoto, K., Inoue, E., Nagao, N., Hiyama, E., and Miwa, N., 1998. Age-dependent telomere shortening is

slowed down by enrichment of intracellular vitamin C via suppression of oxidative stress. Life Sci. 63, 935-

948.

Gardner, A., Johansson, A., Wibom, R., Nennesmo, I., von Dobeln, U., Hagenfeldt, L., and Hallstrom, T.,

2003. Alterations of mitochondrial function and correlations with personality traits in selected major

depressive disorder patients. J Affect Disord. 76, 55-68.

Gimsa, U., Kanitz, E., Otten, W., and Ibrahim, S. M., 2009. Behavior and stress reactivity in mouse strains


30/50

anuscript

A., and Suomalainen, A., 2005. Mitochondrial DNA polymerase W748S mutation: a common cause of

autosomal recessive ataxia with ancient European origin. Am J Hum Genet. 77, 430-441.

Halliwell, B., 2006. Oxidative stress and neurodegeneration: where are we now? J Neurochem. 97, 1634-

1658.

Halliwell, B. a. G., J.M.C., 2007. Free radicals in biology and medicine, Oxford University Press, Oxford.

Harvey, B. H., Oosthuizen, F., Brand, L., Wegener, G., and Stein, D. J., 2004. Stress-restress evokes sustained

iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology (Berl).

175, 494-502.

He, J. and Crews, F. T., 2008. Increased MCP-1 and microglia in various regions of the human alcoholic


31/50

anuscript

Herken, H., Gurel, A., Selek, S., Armutcu, F., Ozen, M. E., Bulut, M., Kap, O., Yumru, M., Savas, H. A., and

Akyol, O., 2007. Adenosine deaminase, nitric oxide, superoxide dismutase, and xanthine oxidase in patients

with major depression: impact of antidepressant treatment. Arch Med Res. 38, 247-252.

Herrera, D. G., Yague, A. G., Johnsen-Soriano, S., Bosch-Morell, F., Collado-Morente, L., Muriach, M.,

Romero, F. J., and Garcia-Verdugo, J. M., 2003. Selective impairment of hippocampal neurogenesis by

chronic alcoholism: protective effects of an antioxidant. Proc Natl Acad Sci U S A. 100, 7919-7924.

Hettema, J. M., 2008. What is the genetic relationship between anxiety and depression? Am J Med Genet C

Semin Med Genet. 148, 140-146.

Hovatta, I., Tennant, R. S., Helton, R., Marr, R. A., Singer, O., Redwine, J. M., Ellison, J. A., Schadt, E. E.,

Verma, I. M., Lockhart, D. J., and Barlow, C., 2005. Glyoxalase 1 and glutathione reductase 1 regulate


32/50

anuscript

Jung, M. E., Agarwal, R., and Simpkins, J. W., 2007. Ethanol withdrawal posttranslationally decreases the

activity of cytochrome c oxidase in an estrogen reversible manner. Neurosci Lett. 416, 160-164.

Kaltschmidt, B., Uherek, M., Volk, B., Baeuerle, P. A., and Kaltschmidt, C., 1997. Transcription factor NF-

kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques

from patients with Alzheimer disease.

Proc Natl Acad Sci U S A. 94, 2642-2647.

Kamper, E. F., Chatzigeorgiou, A., Tsimpoukidi, O., Kamper, M., Dalla, C., Pitychoutis, P. M., and

Papadopoulou-Daifoti, Z., 2009. Sex differences in oxidant/antioxidant balance under a chronic mild stress

regime. Physiol Behav. 98, 215-222.

Kananen, L., Surakka, I., Pirkola, S., Suvisaari, J., Lonnqvist, J., Peltonen, L., Ripatti, S., and Hovatta, I., 2010.

Childhood adversities are associated with shorter telomere length at adult age both in individuals with an


33/50

anuscript

Kempermann, G., Kuhn, H. G., and Gage, F. H., 1997. More hippocampal neurons in adult mice living in an

enriched environment. Nature. 386, 493-495.

Kessler, R. C., Gruber, M., Hettema, J. M., Hwang, I., Sampson, N., and Yonkers, K. A., 2008. Co-morbid

major depression and generalized anxiety disorders in the National Comorbidity Survey follow-up. Psychol

Med. 38, 365-374.

Kinrys, G., Coleman, E., and Rothstein, E., 2009. Natural remedies for anxiety disorders: potential use and

clinical applications. Depress Anxiety. 26, 259-265.

Knapp, D. J. and Crews, F. T., 1999. Induction of cyclooxygenase-2 in brain during acute and chronic ethanol

treatment and ethanol withdrawal. Alcohol Clin Exp Res. 23, 633-643.


34/50

anuscript

Lauritzen, K. H., Moldestad, O., Eide, L., Carlsen, H., Nesse, G., Storm, J. F., Mansuy, I. M., Bergersen, L. H.,

and Klungland, A., 2010. Mitochondrial DNA toxicity in forebrain neurons causes apoptosis,

neurodegeneration, and impaired behavior. Mol Cell Biol. 30, 1357-1367.

Leasure, J. L. and Nixon, K., 2010. Exercise neuroprotection in a rat model of binge alcohol consumption.

Alcohol Clin Exp Res. 34, 404-414.

Liou, H. C. and Baltimore, D., 1993. Regulation of the NF-kappa B/rel transcription factor and I kappa B

inhibitor system. Curr Opin Cell Biol. 5, 477-487.

Lister, R. G., 1987. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology (Berl). 92,

180-185.


35/50

anuscript

Malberg, J. E., Eisch, A. J., Nestler, E. J., and Duman, R. S., 2000. Chronic antidepressant treatment increases

neurogenesis in adult rat hippocampus. J Neurosci. 20, 9104-9110.

Mantamadiotis, T., Lemberger, T., Bleckmann, S. C., Kern, H., Kretz, O., Martin Villalba, A., Tronche, F.,

Kellendonk, C., Gau, D., Kapfhammer, J., Otto, C., Schmid, W., and Schutz, G., 2002. Disruption of CREB

function in brain leads to neurodegeneration. Nat Genet. 31, 47-54.

Manto, M., Laute, M. A., and Pandolfo, M., 2005. Depression of extra-cellular GABA and increase of NMDA-

induced nitric oxide following acute intra-nuclear administration of alcohol in the cerebellar nuclei of the

rat. Cerebellum. 4, 230-238.

Marin-Garcia, J., Ananthakrishnan, R., and Goldenthal, M. J., 1995. Heart mitochondria response to alcohol

is different than brain and liver. Alcohol Clin Exp Res. 19, 1463-1466.


36/50

anuscript

Mattson, M. P. and Camandola, S., 2001. NF-kappaB in neuronal plasticity and neurodegenerative

disorders. J Clin Invest. 107, 247-254.

McClain, C. J. and Cohen, D. A., 1989. Increased tumor necrosis factor production by monocytes in alcoholic

hepatitis. Hepatology. 9, 349-351.

McClain, C. J., Barve, S., Deaciuc, I., Kugelmas, M., and Hill, D., 1999. Cytokines in alcoholic liver disease.

Semin Liver Dis. 19, 205-219.

Montoliu, C., Valles, S., Renau-Piqueras, J., and Guerri, C., 1994. Ethanol-induced oxygen radical formation

and lipid peroxidation in rat brain: effect of chronic alcohol consumption. J Neurochem. 63, 1855-1862.

Nakamura, Y., Feng, Q., Kumagai, T., Torikai, K., Ohigashi, H., Osawa, T., Noguchi, N., Niki, E., and Uchida, K.,


37/50

anuscript

O'Donovan, A., Hughes, B. M., Slavich, G. M., Lynch, L., Cronin, M. T., O'Farrelly, C., and Malone, K. M.,

2010. Clinical anxiety, cortisol and interleukin-6: Evidence for specificity in emotion-biology relationships.

Brain Behav Immun. Epub ahead of print.

O'Neill, L. A. and Kaltschmidt, C., 1997. NF-kappa B: a crucial transcription factor for glial and neuronal cell

function. Trends Neurosci. 20, 252-258.

Parks, C. G., Miller, D. B., McCanlies, E. C., Cawthon, R. M., Andrew, M. E., DeRoo, L. A., and Sandler, D. P.,

2009. Telomere length, current perceived stress, and urinary stress hormones in women. Cancer Epidemiol

Biomarkers Prev. 18, 551-560.

Pawlosky, R. J. and Salem, N., Jr., 1995. Ethanol exposure causes a decrease in docosahexaenoic acid and an

increase in docosapentaenoic acid in feline brains and retinas. Am J Clin Nutr. 61, 1284-1289.


38/50

anuscript

Qin, L., He, J., Hanes, R. N., Pluzarev, O., Hong, J. S., and Crews, F. T., 2008. Increased systemic and brain

cytokine production and neuroinflammation by endotoxin following ethanol treatment. J

Neuroinflammation. 5, 10.

Rammal, H., Bouayed, J., Younos, C., and Soulimani, R., 2008a. Evidence that oxidative stress is linked to

anxiety-related behaviour in mice. Brain Behav Immun. 22, 1156-1159.

Rammal, H., Bouayed, J., Younos, C., and Soulimani, R., 2008b. The impact of high anxiety level on the

oxidative status of mouse peripheral blood lymphocytes, granulocytes and monocytes. Eur J Pharmacol.

589, 173-175.

Reynolds, A., Laurie, C., Mosley, R. L., and Gendelman, H. E., 2007. Oxidative stress and the pathogenesis of


39/50

anuscript

Salim, S., Sarraj, N., Taneja, M., Saha, K., Tejada-Simon, M. V., and Chugh, G., 2010. Moderate treadmill

exercise prevents oxidative stress-induced anxiety-like behavior in rats. Behav Brain Res. 208, 545-552.

Schneider, A., Martin-Villalba, A., Weih, F., Vogel, J., Wirth, T., and Schwaninger, M., 1999. NF-kappaB is

activated and promotes cell death in focal cerebral ischemia. Nat Med. 5, 554-559.

Selek, S., Herken, H., Bulut, M., Ceylan, M. F., Celik, H., Savas, H. A., and Erel, O., 2008. Oxidative imbalance

in obsessive compulsive disorder patients: a total evaluation of oxidant-antioxidant status. Prog

Neuropsychopharmacol Biol Psychiatry. 32, 487-491.

Simon, N. M., Smoller, J. W., McNamara, K. L., Maser, R. S., Zalta, A. K., Pollack, M. H., Nierenberg, A. A.,

Fava, M., and Wong, K. K., 2006. Telomere shortening and mood disorders: preliminary support for a

chronic stress model of accelerated aging. Biol Psychiatry. 60, 432-435.


40/50

anuscript

brain of patients with posttraumatic stress disorder (PTSD) revealed by human mitochondria-focused cDNA

microarrays. Int J Biol Sci. 4, 223-235.

Suganuma, H., Arai, Y., Kitamura, Y., Hayashi, M., Okumura, A., and Shimizu, T., 2010. Maternal

docosahexaenoic acid-enriched diet prevents neonatal brain injury. Neuropathology . Epub ahead of print.

Sun, G. Y., Xu, J., Jensen, M. D., and Simonyi, A., 2004. Phospholipase A2 in the central nervous system:

implications for neurodegenerative diseases. J Lipid Res. 45, 205-213.

Suomalainen, A., Majander, A., Haltia, M., Somer, H., Lonnqvist, J., Savontaus, M. L., and Peltonen, L., 1992.

Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and

familial progressive external ophthalmoplegia. J Clin Invest. 90, 61-66.


41/50

anuscript

Tyrka, A. R., Price, L. H., Kao, H. T., Porton, B., Marsella, S. A., and Carpenter, L. L., 2010. Childhood

maltreatment and telomere shortening: preliminary support for an effect of early stress on cellular aging.

Biol Psychiatry. 67, 531-534.

Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T., Mazur, M., and Telser, J., 2007. Free radicals and

antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 39, 44-84.

van Praag, H., Christie, B. R., Sejnowski, T. J., and Gage, F. H., 1999. Running enhances neurogenesis,

learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A. 96, 13427-13431.

van Praag, H., Shubert, T., Zhao, C., and Gage, F. H., 2005. Exercise enhances learning and hippocampal

neurogenesis in aged mice. J Neurosci. 25, 8680-8685.


42/50

anuscript

von Zglinicki, T., Pilger, R., and Sitte, N., 2000. Accumulation of single-strand breaks is the major cause of

telomere shortening in human fibroblasts. Free Radic Biol Med. 28, 64-74.

von Zglinicki, T., 2002. Oxidative stress shortens telomeres. Trends Biochem Sci. 27, 339-344.

Xu, D., Neville, R., and Finkel, T., 2000. Homocysteine accelerates endothelial cell senescence. FEBS Lett.

470, 20-24.

Yu, W. Y., Chang, H. W., Lin, C. H., and Cho, C. L., 2008. Short telomeres in patients with chronic

schizophrenia who show a poor response to treatment. J Psychiatry Neurosci. 33, 244-247.

Zafir, A. and Banu, N., 2009. Modulation of in vivo oxidative status by exogenous corticosterone and


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Zou, J. and Crews, F., 2010. Induction of innate immune gene expression cascades in brain slice cultures by

ethanol: key role of NF-kappaB and proinflammatory cytokines. Alcohol Clin Exp Res. 34, 777-789.


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Figure captions:

Figure 1. Major biochemical pathways of free radical production, and enzymatic and non-enzymatic

antioxidative defenses. Abbreviations: CAT = catalase; GPX = glutathione peroxidase; GSSG/GSH =

oxidized/reduced glutathione; GSR = glutathione reductase; NADP+/NADPH = oxidized/reduced

nicotinamide adenine dinucleotide phosphate; NOS = nitric oxide synthase; RNS = reactive nitrogen species;

SOD = superoxide dismutase.

Figure 2. Hypothetical mechanisms of oxidative stress-induced neuronal damage. Abbreviations: COX-2 =

cyclooxygenase 2 ; CREB = cAMP response element-binding; GABA = aminobutyric acid; NADPH =

nicotinamide adenine dinucleotide phosphate; NFB = Nuclear factor B; NO = nitric oxide; NOS = nitric

oxide synthase; RNS = reactive nitrogen species; ROS = reactive oxygen species.

FindingN b f

Table 1. Oxidative stress markers and antioxidant levels measured in anxiety, depressive, and alcohol use disorders.

Table 1


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Marker Assessed in

d g

compared to

controls

PhenotypeNumber of

cases/controlsReference

Oxidative stress markers

Lipid peroxidation / MDA and TBARS Plasma OCD with or

without MD

27 OCD-MDD, 15

OCD+MDD / 32Kuloglu et al., 2002a

Erythrocytes OCD 30 / 30 Ersan et al., 2006Plasma OCD 28 / 28 Ozdemir et al., 2009

Serum OCD 39 / 33 Chakraborty et al., 2009

Plasma SP 39 / 39 Atmaca et al., 2004

Plasma SP 18 / 18 Atmaca et al., 2008

Plasma PD 20 / 20 Kuloglu et al., 2002b

Urine HADS 31 / 31 Ratnakar et al., 2008

Erythrocytes MD 50 / 30 Galecki et al., 2009

Erythrocytes and

plasma MD 30 / 32 Bilici et al., 2001

Plasma MD 96 / 54 Sarandol et al., 2007

Serum Alc. dep. 28 / 19 Peng et al., 2005Plasma - PTSD 14 / 14 Tezcan et al., 2003

Lipid peroxidation / HNE Plasma MD 25 / 25 Selley et al., 2004

Lipid peroxidation / 8-iso -PGF2a Plasma Geriatric

Depression Scale66 Dimopoulos et al., 2008

Lipid peroxidation / Conjugated dienes Serum MD 35 / 35 Kodydkova et al., 2009

DNA oxidation / 8-OHdG Serum MD 84 / 85 Forlenza et al., 2006

Leukocytes in F, - in M POMS 362 Irie et al., 2001

Pcx and cb - Alc. dep. 6-22 / 3-21 Gtz et al., 2001

NO generation / Total nitrite or nitrate Plasma OCD 23 / 23 Atmaca et al., 2005

Seminal plasma STAI 29 Eskiocak et al., 2006

Plasma in MD, - in

anx. dis.MD or anx. dis.

17 MD, 6 anx. dis.

/ 12Suzuki et al., 2001

Serum - PD 32 / 20 Herken et al., 2006

Serum - MD 36 / 20 Herken et al., 2007

CSF - Alc. dep. 12 / 16 Neiman et al., 1997

PML MD 30 / 114 Srivastava et al., 2002

Plasma MD 25 / 25 Selley et al., 2004

Erythrocytes OCD 28 / 28 Ozdemir et al., 2009

OCD with or 27 OCD MDD 15


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GPX activity Erythrocytes OCD with or

without MD

27 OCD-MDD, 15

OCD+MDD / 32Kuloglu et al., 2002a

Erythrocytes SP 39 / 39 Atmaca et al., 2004

Erythrocytes SP 18 / 18 Atmaca et al., 2008

Erythrocytes PD 20 / 20 Kuloglu et al., 2002b

Erythrocytes and

plasma

in

erythrocytes,

- in plasma

MD 30 / 32 Bilici et al., 2001

Erythrocytes - PTSD 14 / 14 Tezcan et al., 2003

Erythrocytes - MD 50 / 30 Galecki et al., 2009

Whole blood - MD 96 / 54 Sarandol et al., 2007

PML - MD 12 / 18 Srivastava et al., 2002

Erythrocytes OCD 28 / 28 Ozdemir et al., 2009

Erythrocytes MD 35 / 35 Kodydkova et al., 2009

Serum Alc. dep. 28 / 19 Peng et al., 2005

Total peroxidase activity Serum MD 29 / 30 Szuster-Ciesielska et al., 2008

GSR activity Erythrocytes MD 35 / 35 Kodydkova et al., 2009

Erythrocytes and

plasma

in plasma,

- in erythrocytesMD 30 / 32 Bilici et al., 2001

Serum - Alc. dep. 28 / 19 Peng et al., 2005

XDH activity Serum PD 32 / 20 Herken et al., 2006

Serum MD 36 / 20 Herken et al., 2007

PON1 activity Serum - MD 35 / 35 Kodydkova et al., 2009

Total oxidant status Serum MD 57 / 40 Cumurcu et al., 2009

Plasma - PD 19 / 40 Ersoy et al., 2008

Plasma OCD 37 / 40 Selek et al., 2008

Oxidative stress index Plasma PD 19 / 40 Ersoy et al., 2008

Serum MD 57 / 40 Cumurcu et al., 2009Plasma OCD 37 / 40 Selek et al., 2008

Ant ioxidants

Vitamin E Plasma MD 96 / 54 Sarandol et al., 2007

Plasma OCD 30 / 30 Ersan et al., 2006

Serum MD 42 / 26 Maes et al., 2000

Plasma MD 49 Owen et al., 2005

Vitamin C Plasma - OCD 30 / 30 Ersan et al., 2006

Plasma - MD 96 / 54 Sarandol et al., 2007

Table 2


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Table 2. Oxidative stress markers and antioxidant levels in animal models of anxiety, depressive, and alcohol use disorders

Markers Assessed in (findings compared to controls) Paradigm Reference

Oxidative stress markers

Lipid peroxidation / MDA and

TBARSPfcx (-), cx (), hp (-) CMS in rats Lucca et al., 2009a

Pfcx (-), cx (-), hp (-), st (), cb () CMS in rats Lucca et al., 2009bFcx (), hp (), st () Restraint stress in rats Atif et al., 2008

Ccx (), cb (), pmo (-), st (-), mb (), hp (), ht (-

), plasma (), liver (), kidney (-)Immobilization stress in rats Liu et al., 1996

Brain () Chronic immobilization stress in rats Sahin et al., 2004

Brain () Cold stress in rats Sahin et al., 2004

Brain ()Chronic immobilization stress combined

with cold stress in ratsSahin et al., 2004

Brain (), liver (), heart (), serum () Chronic restraint stress in rats Zafir et al., 2009

Brain (), liver (-), serum (-) Psychological distress in mice Matsumoto et al., 1999

Cx (), plasma () CMS in rats Eren et al., 2007

Brain (), isolated synaptosomes () Chronic EtOH diet in rats Montoliu et al., 1994

Cx (-), st (-), hp (-), cb (), plasma (), liver (-) Chronic EtOH treatment in rats Calabrese et al., 1998

Serum () CMS in rats Kamper et al., 2009

Brain () Olfactory bulbectomy in rats Tunez et al., 2010

Cb (-) Chronic EtOH diet in rats Rouach et al., 1997

Lipid peroxidation / LSFP cx (), st (-), hp (-), cb (), plasma (), liver () Chronic EtOH treatment in rats Calabrese et al., 1998

Lipid peroxidation / Conjugated

dienesBrain () Chronic immobilization stress in rats Sahin et al., 2004




Protein carbonylation Pfcx (), cx (), hp (), st (), cb (-) CMS in rats Lucca et al., 2009bCcx (), cb (-), pmo (), st (-), mb (-), hp (-), ht

(), plasma (), liver (), kidney (-)Immobilization stress in rats Liu et al., 1996

Brain (), liver (), heart () Chronic restraint stress in rats Zafir et al., 2009

Brain () Chronic immobilization stress in rats Sahin et al., 2004





Proteolytic activity Cx (-), cb (-), st () Acute EtOH treatment in rats Bondy et al., 1995


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Brain () Chronic EtOH diet in rats Montoliu et al., 1994

Fcx (), hp (), st () Restraint stress in rats Atif et al., 2008


Hp (), ht () Chronic restraint stress in rats Grundmann et al., 2010

Cx (-), st (-), hp (-), cb (), liver (-) Chronic EtOH administration in rats Calabrese et al., 1998

GPX activity Brain () Chronic immobilization stress in rats Sahin et al., 2004




Brain (-) Chronic EtOH diet in rats Montoliu et al., 1994


Cx (-), st (-), hp (-), cb (-), liver (-), plasma (-) Chronic EtOH treatment in rats Calabrese et al., 1998

Hp (protein levels ) Immobilization stress in rats Djordjevic et al., 2009

Hp () Chronic psychosocial isolation in rats Djordjevic et al., 2009

Hp ()Immobilization stress combined with

chronic psychosocial isolation in ratsDjordjevic et al., 2009


Brain () Olfactory bulbectomy in rats Tunez et al., 2010

Hp (), ht (-) Chronic restraint stress in rats Grundmann et al., 2010Serum ( in M, in F) CMS in rats Kamper et al., 2009

Cx () CMS in rats Eren et al., 2007

GSR activity Serum ( in M - in F) CMS in rats Kamper et al., 2009

Hp (protein levels ) Immobilization stress in rats Djordjevic et al., 2009

Hp (protein levels ) Chronic psychosocial isolation in rats Djordjevic et al., 2009

Hp (-)Immobilization stress combined with

chronic psychosocial isolation in ratsDjordjevic et al., 2009



Brain (), liver (), heart () Chronic restraint stress in rats Zafir et al., 2009

Cx (-), st (-), hp (-), cb (-) , liver (-), plasma () Chronic EtOH treatment in rats Calabrese et al., 1998

GST activity Cb () Chronic EtOH diet in rats Rouach et al., 1997




GLUL activity Cb () Chronic EtOH diet in rats Rouach et al., 1997

Cx (-), cb (-), st (-) Acute EtOH treatment in rats Bondy et al., 1995

Cx (-), cb (-), st () Subchronic EtOH treatment in rats Bondy et al., 1995

Ant iox idan ts

GSH or GSH/GSSG ratio Fcx () , hp () , st () Restraint stress in rats Atif et al., 2008

B i () li () h t () Ch i t i t t i t Z fi t l 2009

crFigure 1
http://ees.elsevier.com/nsr/download.aspx?id=80563&guid=5c5b785e-a8b5-48fe-8bce-b73258ecba8a&scheme=1


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ptedManu

scr

scr

Genetic and environmental factors: Genetic susceptibility

Pathological states (e.g. anxiety disorders or depression)

Ph i l d h l i l

Substance abuse

Diet and exercise

Figure 2


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Accep

tedMa

nuscr

Mitochondrial dysfunction:

ROS mtDNA damage

Ca2+

Membrane potential

ATP production

Altered neuronal signaling: Glutamate

GABA

Receptor modulation

Ca2+

NOS and NO

Inflammation:

Pro-inflammatory cytokines Pro-inflammatory signaling

NFB activity

CREB activity

NOS, COX-2 and NADPH oxidase

Inhibition of neurogenesis: Antioxidant protection

Oxidative stress:

Increased generation of reactive species ROS, RNS and NO

Impaired oxidative defences

Antioxidant enzyme activities

Antioxidants

Damage to macromolecules: Protein carbonylation

Protein oxidation

DNA damage

Lipid peroxidation

??

Apoptosis

Changes in plasticity

Neurodegeneration

Brain damage

Physical and psychological stress Aging

Accelerated telomere shortening Antioxidant protection

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Anxiety and Oxidative Distress