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| REVIEW ARTICLE |
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| Year : 2016 | Volume
: 6
| Issue : 4 | Page : 139-145 |
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An empirical review on oxidative stress markers and their relevance in obsessive-compulsive disorder
Sujita Kumar Kar1, Ipsita Choudhury2
1 Department of Psychiatry, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Biochemistry, Rama Medical College and Research Institute, Kanpur, Uttar Pradesh, India
| Date of Submission | 23-May-2016 |
| Date of Acceptance | 01-Jul-2016 |
| Date of Web Publication | 7-Oct-2016 |
Correspondence Address:
Sujita Kumar Kar
Department of Psychiatry, King George's Medical University, Lucknow, Uttar Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2231-0738.191641
 Abstract | | |
Oxidative stress results from imbalance in the generation of oxidative free radicals in the body and neutralizing antioxidant mechanisms. It hampers various cellular biochemical processes causing dysfunction of the neurons. Reactive oxygen species and reactive nitrogen species are the two important systems regulating the body's oxidative stress. Oxidative stress has a role in several psychiatric disorders including obsessive-compulsive disorder (OCD) and other anxiety disorders. Various studies have found elevated levels of malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase in patients with OCD, which are considered the markers of oxidative stress. This review discusses the relevance of oxidative stress in OCD.
Keywords: Markers of oxidative stress, obsessive-compulsive disorder, oxidative stress
How to cite this article:
Kar SK, Choudhury I. An empirical review on oxidative stress markers and their relevance in obsessive-compulsive disorder. Int J Nutr Pharmacol Neurol Dis 2016;6:139-45 |
How to cite this URL:
Kar SK, Choudhury I. An empirical review on oxidative stress markers and their relevance in obsessive-compulsive disorder. Int J Nutr Pharmacol Neurol Dis [serial online] 2016 [cited 2022 Jan 17];6:139-45. Available from: https://www.ijnpnd.com/text.asp?2016/6/4/139/191641 |
| Introduction | |  |
Oxidative stress usually results from the excessive production of reactive oxygen species (ROS) or due to failure of the enzymatic and nonenzymatic systems regulating the ROS. [1] Oxidative stress is responsible for the causation of various physical as well as mental illnesses. To counter the oxidative stress, the body has its own antioxidant system, which tries to control the oxidative injury.
ROS and reactive nitrogen species are the two important systems that regulate the body's oxidative activity. [2],[3] Excessive production of ROS in the body leads to more oxidative stress, which results in intracellular signaling impairment and cellular aging that direct to apoptosis. [2] Free radicals are highly reactive species, generated from the metabolism of oxygen and nitrogen. They have a very short half-life and usually inactivated by the antioxidant system of the body. [3] The generation of free radicals may be due to accidental leakage of electrons from electron transport chain [Figure 1] or from the respiratory burst of neutrophils and macrophages as shown in [Figure 2]. [4] Respiratory burst (sometimes called oxidative burst) is the rapid release of ROS (superoxide radical and hydrogen peroxide) from the cells. | Figure 1: The formation of superoxide ion leaking from electron transport chain of mitochondria
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ROS generation commonly occurs at the mitochondria, which becomes dysfunctional under oxidative stress resulting in the release of calcium into the intracellular compartment and lysosomal activation, triggering the apoptotic process [Figure 1] and [Figure 2]. [5]
Antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and nonenzymatic antioxidants such as - Vitamin A, C, E, β-carotene, zinc, copper, selenium, and flavonoids act as scavengers of free radicals; hence reduce oxidative stress and resultant cell injury. [3],[5],[6] Protein molecules such as albumin, ceruloplasmin, haptoglobin, and transferrin also act as the scavengers of toxic free radicals. [5]
The neuronal tissue of the brain is rich in lipid and consumes large quantities of oxygen. When the brain's oxidative by-products over take the antioxidant mechanism, damage to the brain components occurs. [7] Oxidative stress-related damage to the brain can be in the form of disruption in the membrane integrity, oxidative damage of lipid, protein, & nucleic acid, and neuronal dysfunction leading to apoptosis. [3] The process of neuroplasticity (axonal sprouting, neurite formation, synaptogenesis, synaptic remodeling, and neuronogenesis) is impaired due to oxidative stress. [5] [Figure 3] shows the mechanism of the generation of oxidative free radicals and their impact on the cellular biochemical process. Failure in the regulation of the endogenous oxidative processes leads to brain insult, which may be implicated in various psychiatric disorders including anxiety disorder and depression [Figure 3]. [8] | Figure 3: Generation of oxidative free radicals and their impact on the cellular biochemical process
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| Role of Oxidative Stress in Psychiatric Disorders with Focus on Anxiety Disorders | | |
Oxidative stress has a close association with anxiety and depression. [3] Anxiety is a common manifestation of anxiety disorders, obsessive-compulsive disorder (OCD), depression, substance use disorder, stress-related disorder, bipolar disorder and schizophrenia. [1],[9] Even oxidative stress can mediate the psychotropic drug-induced side effects such as tardive dyskinesia. [9] Oxidative stress also has an influence on the genes responsible for various psychiatric disorders. Genetic polymorphism of disrupted-in-schizophrenia-1, neuregulin 1, and many other genes occurs due to oxidative stress, which is responsible for the causation of schizophrenia. [10] Some similar genetic mechanisms induced by oxidative stress also might be responsible for the generation of anxiety and depression. Oxidative stress plays a pivotal role in the interface of gene and environment interaction. [10] Both ROS and nitrogen species damage the DNA, proteins, and lipids by several mechanisms. [11] Activation of stress-sensitive genes further facilitates the oxidative injury of body tissues including the neuronal tissue, which may result in neurodegeneration. [11]
The biological markers of anxiety, such as the oxidative stress markers are expected to be clinically evident in these groups of psychiatric disorders and many other conditions where anxiety is prominent. [3] The cause and consequence relationship between anxiety and oxidative stress markers seems to be bidirectional. Low level of total antioxidant state is associated with depression and anxiety. [5] Oxidative stress can be the result as well as the cause of stress and anxiety. When an individual is under stress or experiences anxiety, the metabolic process of the body is adversely affected, which may facilitate the generation of oxidative free radicals causing dysfunction in cellular processing, which through a cascade of biochemical events lead to the generation of anxiety. Repetition of this vicious cycle leads to the persistence of oxidative stress as well as anxiety. Recent evidences suggest about the potential etiologic role of oxidative stress in anxiety disorders and depression. [1] Excessive glutaminergic transmission occurs during stressful situations, which causes mitochondrial dysfunction mediated by excessive calcium influx. Excessive calcium influx in the neurons triggers the apoptotic process resulting in neurodegeneration. [12] [Figure 4] shows the pathophysiology of anxiety, depression, and obsession induced by oxidative stress [Figure 4]. | Figure 4: Pathophysiology of anxiety, depression, and obsession induced by oxidative stress
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| Oxidative Stress in Anxiety and Obsessive-Compulsive Disorder: Evidences from Animal Studies | | |
Several studies have been conducted in experimental animals to find the association of oxidative stress markers with anxiety. Bouayed et al. in their study on mice found a positive correlation with peripheral oxidative markers and anxiety. [13] Hovatta et al. in their study on mice found that overexpression of two genes, glyoxalase 1 and glutathione reductase 1, has a major role in the production of anxiety, and these two genes have been associated with oxidative metabolism. [14] Glyoxalase 1 may be considered a biological marker of anxiety phenotype due to its consistent and close association with anxiety production in mice. [15],[16]
Studies on experimental animals (mice) suggest that an increased level of nitric oxide (NO) in the brain which is mostly generated from oxidative dysregulation may be responsible for the obsessive-compulsive behavior (marble-burying behavior in mice), [17],[18] and selective serotonin reuptake inhibitors (SSRIs) are effective in controlling the obsessive-compulsive behavior by decreasing the NO level in brain. [17] In another study on mice, it was found that high level of anxiety has a significant association with the generation of free radicals in leukocytes. [19]
Stereotypic behavior in experimental animals is considered the human counterpart of repetitive compulsive acts of OCD. [20] A study focused on the stereotypic behavior of deer mouse in relation with the oxidative biomarkers revealed that deficient glutathione system in the frontal cortex is responsible for this behavior, [20] which suggests the possible scope of antioxidants related to the glutathione in patients with OCD. Chronic fluoxetine treatment in deer mice reduces the stereotypic behavior by attenuating prefrontal cortical cyclic adenosine monophosphate level as well as phosphodiesterase Type 4 activity. [21]
A recent study on experimental animals (rats) has demonstrated that SSRI (escitalopram) is effective in normalizing the oxidative stress in the body. [22] Endothelial functions and vascular contractility are also found to be modulated by SSRIs such as fluoxetine and Escitalopram through the oxidative pathway. [22],[23] Some contradicting evidences also exist such as chronic treatment with fluoxetine may induce oxidative stress resulting in endothelial dysfunction. [23]
| Oxidative Stress in Obsessive-Compulsive Disorder: Experiences from Human Studies | | |
Extensive search in MEDLINE database using the keywords - oxidative stress, free radicals, Superoxide Dismutase, Glutathione Peroxidase, nitric oxide, Catalase, malondialdehyde, ascorbate, total oxidant status, serum thiobarbituric acid reacting substances (TBARS) individually with "obsessive compulsive disorder" found eleven original research articles. These studies have been published between the years 2002 and 2016, with each study having a control group along with the patient group.
Studies done to measure oxidative stress in patients with OCD were mostly cross-sectional and had sample sizes ranging from 20 to 42, [24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34] except one study which studied the genetic variants of oxidative markers in patients with OCD, where the sample size was more than 100. [33] These studies measured different antioxidants and products of oxidative process. The antioxidants that are measured in most of the studies are Vitamin E, [24] Vitamin C, [24],[25] SOD, [26],[27],[30],[33] GSH-Px, [26],[30],[33] CAT, [26],[30] and serum selenium. [26] Lipid peroxidation metabolites such as malondialdehyde (MDA) [24],[26],[27],[30],[33] and Thiobarbituric acid reacting substances (TBARS) [25],[31] were also measured in various studies. Atmaca et al., in their study on patients with OCD, studied the plasma NO level. [32]
Other than the above parameters, total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) were also studied in patients with OCD. [28],[29],[34] Among the above-mentioned studies, most were done in adult patients with OCD and only one study evaluated the oxidative stress parameter in pediatric population. [28] Most studies had included patients of OCD without any psychiatric comorbidities; however, Kuloglu et al. had included OCD along with major depressive disorder (MDD) in their study and compared them with the patients of OCD without MDD and healthy controls. [30] All the above studies are cross-sectional, measuring oxidative markers at baseline, except one study, where patients were followed up for 12 weeks with fluoxetine treatment and the oxidative markers were measured during the follow-up. [25]
Chakraborty et al. in their study found that newly diagnosed, drug-naive patients with OCD had a higher level of TBARS and lower ascorbate level. [25] Ozdemir et al. in their study compared the oxidative stress parameters of patients with OCD, who were drug-free for at least 1 month with healthy controls. It was found that the level of MDA and SOD was significantly higher in patients than healthy controls. [26] Other markers of oxidative stress (serum selenium, GSH-Px, and CAT) in patient group were significantly lower than the healthy controls. [26] A significantly increased level of MDA was reported in patients with OCD in comparison to healthy controls, which was also found in other studies. [26],[27],[30] Kandemir et al. in their study on children and adolescents with OCD found that the patient group had more oxidative stress than their healthy counterparts. The patient group had a significantly higher TOS and OSI as well as significantly lower TAS than that of controls. [28] However, Alici et al. refuted this finding in a recent study, as they did not find any significant difference in TOS, OSI, and TAS between the patient and control groups. [34] This study had revealed about the increased oxidative damage of DNA in patients with OCD in comparison to the healthy controls. [Table 1] shows the studies evaluating various oxidative parameters in patients with OCD [Table 1]. | Table 1: Oxidative parameters in patients with obsessive-compulsive disorder
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| Hopes and Scopes | | |
Published research data on oxidative stress in OCD are scarce. [34]
The same group of neurotransmitters (serotonin, noradrenaline, glutamate, and dopamine) is involved in the depression and anxiety disorders including OCD. Regulation of these neurotransmitters in the body is modulated by the ROS and NOS. [35]
Both depression and anxiety disorders are characterized by the deficiency of antioxidants such as Vitamin C, E, glutathione, and zinc; [24],[25],[35] hence, antioxidants possibly hold some promise in the management of depression as well as in anxiety disorder. Preclinical, clinical as well as epidemiological studies revealed the role of antioxidants in various neuropsychiatric disorders, where oxidative stress has an important role. [9] Therapies targeting the oxidative stress management may be effective in controlling the anxiety symptoms. [12]
Certain genotypes are encoding the antioxidant enzymes; mutation of these genotypes or genetic polymorphism of mitochondrial DNA or nuclear genes leads to oxidative stress. [33] This seems to be a new avenue for research. OCD is a chronic heritable illness, but it may follow a sporadic pattern (development of OCD without any family history). The sporadic variants of OCD need to be evaluated for mutation of genes responsible for the regulation of oxidative stress.
Recently, regulation of indolamine 2,3-dioxygenase enzyme is gaining interest among researchers. Indolamine 2,3-dioxygenase is a rate-limiting enzyme in the kynurenine pathway. [36] This enzyme metabolizes amino acid tryptophan, leading to a decrease in tryptophan level and an increase in kynurenine level. [36],[37] Increased breakdown of tryptophan results in fall in the level of serotonin in the brain, which may cause depression and anxiety. [36] The metabolites of kynurenine pathway (e.g., quinolinic acid) are neurotoxic and produce inflammatory changes in the brain by crossing the blood-brain barrier. [38] Activation of the enzyme indolamine 2,3-dioxygenase also impairs the immunoregulation, tumor defense as well as the oxidative regulation in the body. [36],[37] Many mediators of inflammation such as interferon gamma (IFN-γ), interleukin-6 (IL-6), and transforming growth factor regulate the activity of indolamine 2,3-dioxygenase. [36] It signifies the immuno-biological role of indolamine 2,3-dioxygenase in depression, anxiety as well as obsession. Immune mediators such as IL-6 and IFN-γ activate indolamine 2,3-dioxygenase and administration of agents that suppresses the activity of these immune mediators, which, in turn, deactivates indolamine 2,3-dioxygenase activity. [36],[39] Experimental animals deficient in indolamine 2,3-dioxygenase are resistant to depressive behavior, which might be due to the nondepletion of serotonin reserve of the brain. [40]
Oxidative stress may be induced in experimental animals by intraperitoneal injection of buthionine-(S, R)-sulfoximine, which provokes anxiety-like behavior. Regular exercise lead to diminution of this anxiety behavior. [41] Evidences suggest the pivotal role of regular physical exercise in reducing inflammation and oxidative stress, which improves neuroplasticity and optimizes neuronal functioning. [42] This may be beneficial in reducing the symptoms of anxiety disorders.
Hence, it may be reasonably argued that physical exercise, relaxation exercise as well as yoga may be beneficial in patients with OCD by reducing oxidative stress.
| Conclusion | | |
Oxidative stress has a major role in various neuropsychiatric disorders including anxiety disorders and OCD. It indicates the role of antioxidant medications and nonpharmacological measures (aerobic exercise, yoga, and relaxation techniques) that reduce oxidative stress in the treatment of these disorders. Antidepressants (e.g., SSRIs), which improve the anxiety and depressive symptoms as well as OCD, are known to attenuate the oxidative stress, other than their action through concerned neurotransmitter receptors. [43] It can be strongly recommended to see antidepressants beyond receptor modulators. Their anti-inflammatory as well as antioxidant properties are need to be evaluated.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1]
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