Coenzyme Q

Coenzyme Q (CoQ) is a remarkable liposoluble ubiquinone with a long isoprenoid side chain and a main component of the internal mitochondria membrane, Golgi complex membrane, and lysosomal membrane. CoQ is an endogenous free radical scavenger and enzyme cofactor produced by most human cells and is abundant in the brain and intestine in mitochondria, the site of oxidative phosphorylation [108]. It is biosynthesized by all membranes and a component of the mitochondrial respiratory chain, which participates in electron transport [109]. CoQ in either reduced form, hydroquinone or ubiquinol, is a potent lipophilic antioxidant and is also involved in the regeneration and recycling of other antioxidants such as tocopherol and ascorbate [110]. CoQ is an important antioxidant that protects cellular membranes and lipoproteins against the toxic effects of free radicals that are generated during general metabolism [111]. The redox functions of CoQ mainly occur in the mitochondria as electrons shuttle between complexes I and II of the respiratory chain. Dehydrogenases oxidize NADH, NADPH, and dihydroflavine-adenine dinucleotide (FADH2) and transfer protons and electrons to ubiquinone, which is converted to ubiquinol. Finally, the protons transfer to the mitochondrial matrix and the electrons move to the cytochromes. Thus, cytochromes reduce the

superoxide radical anion to water with electrons and protons from the matrix. These processes are required to produce ATP [108]. TrxRs within the cytosol induce the reduction of CoQ to ubiquinol and maintain the extra-mitochondrial antioxidant defense [112]. CoQ is synthesized by at least 12 proteins that form a multiprotein complex in the mitochondria, and the pathogenesis of CoQ10 deficiency involves deficient ATP production and excessive ROS formation in humans. However, CoQ10 deficiency is unique among mitochondrial disorders because an effective treatment is available by oral CoQ10 supplementation, to which many patients respond well [113,114]. However, dietary supplementation is still challenging due to the low bioavailability of the compound. Because CoQ10 levels decline with age, it has been studied in a variety of neurodegenerative disorders and aging but with disparate results [115].

In KA-induced oxidative injury in vitro [116], an increased number of surviving CA3 neurons was observed at 0.1 and 1 μM concentrations in CoQ10-treated groups using cresyl violet staining. CoQ10 (0.01, 0.1, and 1 μM) treatment significantly decreased 2,7-dichlorofluorescein fluorescence, and the expression of NQO1 in the CoQ10-treated groups was significantly lower than that in controls, indicating the protective role of CoQ10 in hippocampal neurons against oxidative stress. Rats exposed to intrastriatal CoQ10 showed a larger number of dopaminergic neurons, higher expression of neurogenetic and angiogenetic factors, and less inflammation, and these effects were more prominent than the orally administered CoQ10. Thus, continuous intrastriatal administration of low doses of CoQ10 showed a more effective strategy to prevent dopaminergic neuronal degeneration in a PD rat model induced by 6-hydroxydopamine [117]. In patients with acute ischemic stroke, a significant increase in CoQ10 level was observed with the administration of CoQ10 (300 mg/day group) compared with the placebo group. CoQ10 supplementation attenuated oxidative stress and neuroinflammatory marker levels and improved the neurological outcome scale and antioxidant enzyme activity [118]. In PD patients, the total Unified Parkinson's Disease Rating Scale (UPDRS) scores decreased in the CoQ10-treated group, indicating amelioration of the symptoms and significant improvement in wearing-off in PD [119]. CoQ10 increased a reduced glutathione and SOD levels in patients with pregabalin-treated fibromyalgia. The supplementation of CoQ10 effectively reduced pain sensation, anxiety and brain activity, mitochondrial oxidative stress, and inflammation [120].

#### Zinc and Essential Metals

Zinc, a redox inactive metal, does not directly interact with ROS but has a crucial role in maintaining redox balance for the antioxidant defense system in various ways in the cell. Zinc increases the activation of antioxidant enzymes such as SOD, GPx, and CAT. It also acts as a direct cofactor of SOD-1 and SOD-3 and as an indirect cofactor for GPx [121]. Zinc inhibits important pro-oxidant enzymes such as NADPH oxidase, inducible nitric oxide synthetase (iNOS), and the reduced form of nicotinamide adenine dinucleotide (NMDA) and regulates oxidant production and metal-induced oxidative damage. Zinc is dynamically associated with sulfur in protein cysteine clusters. It mediates the induction of the zinc-binding protein metallothionein which releases the metal under oxidative conditions and acts as an Se scavenging oxidant. Zinc is involved in the regulation of glutathione metabolism and the overall protein thiol redox status [122]. Zinc competes with redox-active transition metals, iron and copper, for certain binding sites. When zinc binds to these sites, copper and iron are forced to undergo hydrolytic polymerization into unreactive structures, thereby prohibiting the catalysis of free radical formation and the initiation of lipid peroxidation [121–123]. Zinc is mainly expressed in the hippocampus, amygdala, cerebral cortex, thalamus, and olfactory cortex in the brain [124] and is stored as free zinc ions (Zn2<sup>+</sup>) in the presynaptic glutamatergic neurons. Zinc in synaptic vesicles is released with glutamate and acts as a potent extracellular modulator by interacting with many synaptic receptors during synaptic activity [123].

Co-treatment with zinc and Se significantly decreased mitochondrial dysfunction, ROS levels, and lipid peroxidation levels, while significantly increasing cognitive performance, SOD, glutathione peroxidase, and catalase activity in the mitochondria of the brain in an AD rat model [125]. In a

double-blind, placebo-controlled trial of zinc supplementation for premenstrual syndrome, sixty women (18–30 years) were randomly assigned to receive either 30 mg of zinc gluconate and/or placebo for 12 weeks. The zinc-administered group showed beneficial effects on physical and psychological symptoms of premenstrual syndrome, total antioxidant capacity, and brain-derived neurotrophic factor [126].

Other essential metals, such as copper, iron, and magnesium, play an important role in the maintenance of cell homeostasis and preservation of life. They display important structural, regulatory, and catalytic functions in different types of proteins, such as enzymes, receptors, and transporters. Cu<sup>+</sup> and magnesium are the cofactors for enzymes such as COX and/or supper zinc, SOD, and neuronal Cu enrichment predispose to Cu2<sup>+</sup>-catalyzed Fenton chemistry and H2O2-assisted protein oxidation. In particularly, iron continuously shifts between ferrous ion (Fe2<sup>+</sup>) and ferric ion (Fe3<sup>+</sup>) states in a redox reaction in the presence of O2. The constitution of iron in the body is in the form of 65% (Fe2<sup>+</sup>) ions bound to hemoglobin; less than 10% of ions are expressed with myoglobin (Fe2<sup>+</sup>), cytochromes (Fe2<sup>+</sup> or Fe3<sup>+</sup>), and iron-containing enzymes, and 25% of the ions are bound to iron-storage proteins such as transferrin, ferritin, and hemosiderin [127]. Iron present in the cells in the reduced (Fe2+) and oxidized (Fe3+) states can serve both as an electron donor and electron acceptor. Particularly, the ferrous form of iron can act as a catalyst in the potentiation of oxygen toxicity by generating a wide range of free radical species, including hydroxyl radicals. In addition, an excessive amount of this essential metal induces toxicity, leading to pathological conditions generated by oxidative stress and neurodegeneration [128]. Although homeostasis of iron is essential for physiological functions in the brain, less than 2% of total body iron is present in the brain. Iron contributes to the activity of various enzymes involved in neurotransmitter synthesis and myelination of axons of motor neurons in the brain. Iron accumulation induces features of neurodegenerative disorders including AD, PD, HD, ALS, and neurodegeneration with brain iron accumulation (NBIA). The pathogenesis of neurodegenerative diseases shows a relationship with a dramatic increase in iron content in the brain, which is correlated with the production of ROS [127].
