Superoxide Dismutase in Psychiatric Diseases

*Vladimir Djordjević*

### **Abstract**

As with many other human diseases, oxidative stress is implicated in many neuropsychiatric disorders, including schizophrenia, bipolar disorder, depression and Alzheimer's disease. Due to high oxygen consumption and a lipid-rich environment, the brain is highly susceptible to oxidative stress or redox imbalance. Both increased production of reactive oxygen species and antioxidant defense disorders have been demonstrated in psychiatric patients. Superoxide dismutase (SOD) is the primary, critical enzyme in the detoxification of superoxide radicals, because they are the main ROS, primarily generated in the most biological reactions of free radical formation. There are inconsistent data on this enzyme activity in patients with different psychoses. Since psychotic disorders are complex and heterogeneous disorders, it is not surprising that different authors have found that SOD activity is increased, decreased, or unchanged in the same type of psychosis. This review examines and discusses some recent findings linking SOD activity to schizophrenia, bipolar disorder, depression and Alzheimer's disease.

**Keywords:** superoxide dismutase, schizophrenia, bipolar disorder, depression, Alzheimer's disease

### **1. Introduction**

More than 90% of molecular oxygen (which is essential for aerobic lifestyle) intaken in the human body is reduced into water by receiving four electrons from the electron-transport system in the respiratory chain of mitochondria. A small amount of oxygen is incorporated in biological substrates, and rest of oxygen is transformed into reactive oxygen species (ROS) that include potentially toxic oxygen free radicals [1] and very reactive non-radical species. The reduction of oxygen by one electron at a time produces superoxide anion radical (O2 .−), the precursor of most ROS and a mediator in oxidative chain reactions. Superoxide is then dismutated either spontaneously or by superoxide dismutase into hydrogen peroxide (H2O2). H2O2 can be fully reduced to water or partially reduced (in a reaction catalyzed by reduced transition metals) to hydroxyl radical (OH. ) which is one of the strongest oxidants in nature. Except the respiratory chain of mitochondria, enzymatic sources of superoxide production include phagocyte NADPH (nicotinamide adenine dinucleotide phosphate) oxidase, cytochrome P450−dependent oxygenases and xanthine oxidase (XO). Non-enzymatic production occurs when a single electron is directly transferred to oxygen by reduced

coenzymes or prosthetic groups (flavins or iron sulfur clusters), by xenobiotics previously reduced by certain enzymes (adriamycin or paraquat), or by mitochondrial redox centres that may leak electrons to oxygen [2].

Basal cellular metabolism continuously produces ROS that occurs in endogenous sources such as mitochondria, peroxisomes, cytochrome P450, inflammatory cell activation and other cellular elements [3], but *in vivo* the mainly ROS production occurs within the mitochondria [4]. In physiological conditions, when the redox status is balanced, ROS are produced in appropriate levels because they are necessary and beneficial for normal physiological functions: they can protect the cell from infections [5, 6]; they play a role in the regulation of cardiac and vascular cell functioning [6]; they regulate intracellular processes such as calcium concentration, protein phosphorylation/dephosphorylation and transcription factor activation. ROS directly interact with critical signaling molecules to initiate signaling in a broad variety of cellular processes, such as proliferation and survival (MAP kinases and PI3 kinase), apoptosis, ROS homeostasis, and antioxidant gene regulation (Ref-1 and Nrf-2) [7].

Maintenance of ROS at the physiological level is enabled by the antioxidant system which consists of antioxidative enzymes (superoxide dismutase, peroxidase, catalase, glutathione reductase and thioredoxin) and non-enzymatic antioxidants including reduced glutathione (GSH), vitamins (A, C, E), thiols, zinc, selenium, uric acid, albumin, bilirubin, N-acetylcysteine, and melatonin). Any disturbance of the balance between radical production and antioxidant defense (the overproduction of ROS and/or insufficiency of the antioxidant defense mechanisms) [8, 9], leads to oxidative stress and the manifestation of toxic effects of reactive species. The brain is especially sensitive to oxidative damage because it has high capacity to consume large amounts of oxygen (more than 20% of totally inhaled oxygen) that directly enhances the production of free radicals [5]; it has scarce antioxidant system; low expression of SOD, GPx and catalase; a significantly lower concentration of reduced GSH in comparison with other tisses; in some regions, the brain contains high concentrations of vitamin C and metals (e.g. iron, zinc, copper and manganese) which makes favorable conditions for the production of free radicals through the Fenton reaction; it is rich in polyunsaturated fatty acids that make it susceptible to oxidative attack. This situation is exacerbated by many factors including oxidative potential of monoamines, secondary oxidative cell damage induced by neurotoxic effects of excitotoxic amino acids (glutamate), and secondary inflammatory response. Due to the inability of neurons to produce glutathione which plays the main role in the protection of neuronal tissue from ROS [10], and in the modulation of redox-sensitive sites including NMDA receptors [11], the brain has the limited capacity to scavenge ROS. Besides, neurons are the first cells that can be affected if the concentration of ROS enhances or the concentration of antioxidants declines. Increasing body of evidence shows that partially reduced oxygen species are involved in the pathogenesis of more than hundred human diseases including psychiatric diseases such as schizophrenia, bipolar disorder, depression and Alzheimer's disease.

### **2. Superoxide dismutase**

Superoxide dismutase (SOD; EC 1.15.1.1) is an enzyme that catalyzes the dismutation of the toxic superoxide radical, into either molecular oxygen or hydrogen peroxide, thus preventing peroxynitrite production and further damage [12].

#### *Superoxide Dismutase in Psychiatric Diseases DOI: http://dx.doi.org/10.5772/intechopen.99847*

Superoxide anion radical (O2 .−) can be formed by one-electron reduction of molecular oxygen or by one-electron oxidation of hydrogen peroxide. It is highly effective in the inactivation of some enzymes, but it cannot directly oxidize unsaturated faty acids. In biological systems, it is generated accedentally via the electron transport systems in either the endoplasmic reticulum or mitochondria via electron leakage from intermediate electron carriers onto oxygen; via autooxidation of redox-active chemicals [13]; via glycation of proteins [14]; and via thiol oxidation. By various mechanisms superoxide is generated by oxidases, in particular, xanthine oxidase and NADPH oxidase of the phagocytic cells. During phagocytosis, neutrophils produce 16 times more superoxide (4.7 nmol/106 cells per minute) than that produced in resting cells [15]. The superoxide produced in this manner allows phagocytes to kill the microorganisms in the invading host. Vascular endothelial cells, fibroblasts, lymphocytes and many other human cells release superoxide involved in intracellular signaling in physiological conditions. Xanthine oxidoreductase (XOR), which has a key role in purine catabolism, may exists in two forms, xanthine oxidase (XO) and xanthine dehydrogenase (XDH). The enzyme originally exists in its XDH form, but is readily converted to XO either irreversibly by proteolysis or reversibly by oxidation of Cys residues to form disulfide bridges [16, 17]. The reoxidation of fully reduced XO yields two H2O2 and two superoxide radicals [18], which may lead to the formation more toxic reactive species. However, low concentrations of superoxide and hydrogen peroxide are initially used by the cell for the mobilization of the antioxidative system.

Since superoxide is the primary ROS produced from a variety of sources, its dismutation by SOD is of primary importance for each cell. Three forms of superoxide dismutase are present in humans: a copper- and zinc-containing superoxide dismutase (CuZnSOD/SOD1) localized predominantly in cytoplasmic and nuclear compartments as well as peroxisomes of all mammalian cells [19], a manganese superoxide dismutase (MnSOD/SOD2) localized within the mitochondrial matrix, and a copper- and zinc containing SOD predominantly found in extracellular compartments (EC SOD/SOD3). CuZnSOD present in eukaryotic cell is found sensitive to cyanide and located in the form of dimer. It may be inactivated by hydrogen peroxide, leading to the generation of either Cu (II)-OH. or its ionized form Cu (II)-O.- [20]. This enzyme can further catalyze the peroxidation of a wide vaiety of compounds.

EC SOD is homotetrameric glycoprotein whose each subunit contains a copper and zinc atom, has a high affinity for heparin sulfate and presumably scavenges superoxide that is released from the cell surface. Besides EC SOD important role in the regulation of extracellular superoxide levels, it is also important as a modulator of NO activity. EC SOD is highly expressed in blood vessels constituting up to 70% of the SOD activity in both pulmonary and systemic arteries. Its expression is mainly regulated by cytokines which increase (IFNγ) or decrease (TNFα and TGFß) EC SOD expression [21].

In eukaryotic cells MnSOD is a homotetramer located in the matrix of mitochondria. It is produced constitutively but can also be induced by cytokines (IL-1, TNF) or endotoxin [22]. In addition to cytokines, a wide range of reactive oxygen metabolites, both inducible and basal levels, may induce Mn SOD expression in distinct cell types [23] that may play a decisive role in the pathogenesis of tissue injury following oxidative stress. There are indices that transcriptional upregulation of MnSOD is mediated through the activation of nuclear transcriptional factor κB (NF- κB) by oxidants.
