Biomechanistic insights into the roles of oxidative stress in generating complex neurological disorders
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Mohammad Yusuf
,
Maria Khan
Abstract
Neurological diseases like Alzheimer’s disease, epilepsy, parkinsonism, depression, Huntington’s disease and amyotrophic lateral sclerosis prevailing globally are considered to be deeply influenced by oxidative stress-based changes in the biochemical settings of the organs. The excess oxygen concentration triggers the production of reactive oxygen species, and even the intrinsic antioxidant enzyme system, i.e. SOD, CAT and GSHPx, fails to manage their levels and keep them under desirable limits. This consequently leads to oxidation of protein, lipids and nucleic acids in the brain resulting in apoptosis, proteopathy, proteasomes and mitochondrion dysfunction, glial cell activation as well as neuroinflammation. The present exploration deals with the evidence-based mechanism of oxidative stress towards development of key neurological diseases along with the involved biomechanistics and biomaterials.
Introduction
The brain comprises approximately 2% of human body weight, yet it consumes about 20% of the total inhaled oxygen (Clarke and Sokoloff, 1999). The neurons and glial cells are the main types of brain cells extremely accountable for high oxygen consumption (Malonek and Grinvald, 1996; Thompson et al., 2003). However, the oxygen is indispensable for the biological functioning of all the living cells, but its surplus leads to yield reactive oxygen species (ROS) (Yu, 1994), which recompense oxidative stress (OS) trailing to neurodegeneration (Uttara et al., 2009). The free radicals and ROS are normally produced inside the brain and are dedicated for the oxidations of protein, nucleic acids and lipids’ peroxidation (Lobo et al., 2010). The concentration of ROS in the brain is regulated by endogenous antioxidant defense (EAS) system, which is composed of several enzymes, mainly copper-zinc superoxide dismutase (CuZn SOD), manganese superoxide dismutase (MnSOD), catalase and glutathione peroxidases (GSHPx) (Sies, 1997; Halliwell and Gutteridge, 1999). The reduced EAS and increased ROS are entitled for the induction of OS in the system. The neurodegeneration causes aggravation of several neurological diseases, among them Alzheimer’s disease (Rosini et al., 2014), epilepsy (Shin et al., 2011), parkinsonism (Hwang, 2013), depression (Michel et al., 2012), Huntington’s disease (Gil-Mohapel et al., 2014) and amyotrophic lateral sclerosis (Barber et al., 2006) are the prominent ones encountered globally. The biomechanics involving free radicals generation, the damage due to DNA oxidation, the mitochondrial DNA aberrations as well as apoptosis dysregulation are some of the common connection points in these diseases (Jabir et al., 2015).
Concept of free radicals and their generation
In an atomic orbital, the electron pairs always occur to neutralize their spins, i.e. clockwise (ms=+1/2) and anticlockwise (ms=−1/2) (Merzbacher, 1998), but in the case of free radicals, the spin of the unpaired electron is not neutralized, which transforms them to more reactive and damaging entities (Lobo et al., 2010). Several external factors have also been reported for spin impairment of electrons, and among them, age, malnutrition, stress, chemicals, radiation, pollution and drugs are important (Aseervatham et al., 2013). The main free radicals found inside the OS cascade are oxygen free radical (O˙), superoxide free radical (O2˙−), hydroxyl (OH˙) and nitric oxide (NO˙) (Gibson and Lilley, 1997). The external factors trigger both the enzymes, i.e. xanthine oxidase (XO) and NADPH oxidase-2 (NOX-2). The xanthine oxidase or xanthine dehydrogenases are interconvertible oxidoreductase molybdoflavoenzyme responsible for purine catabolism to form a superoxide, hydrogen peroxide and uric acid by catalyzing the dismutation of the SOD enzyme. Typically, this enzyme exists in xanthine dehydrogenase, but Ca+2-induced proteases convert it into XO. The low oxygen levels lead to ATP metabolism and hypoxanthine accumulation, but reperfusion of oxygen triggers XO causing the reduction of hypoxanthine to xanthine molecule and producing the superoxide and H2O2, (Auscher et al., 1979; Kennedy et al., 1989). Moreover, the NADPH oxidase (NOX−2) enzyme, which is a complex of cytochrome b558 (p22PHOX, gp91PHOX), cytosolic proteins (p40PHOX, p47PHOX and p67PHOX) and Rac G-protein (Granger and Kvietys, 2015), produce superoxide free radical as the result of cytosolic protein’s phosphorylation and Rac activation processes. The SOD enzyme exist in three isoforms: Cu/ZnSOD (copper-zinc superoxide dismutase), MnSOD (manganese superoxide dismutase) and ECSOD (extracellular superoxide dismutase) encoded by genes sod1, sod2 and sod3 (Weydert and Cullen, 2010). Additionally, the neuronal nitric oxide synthases (NOS) are found in both central and peripheral nervous systems and are responsible for the metabolism of arginine to NO but in conjunction with superoxide result in the formation of ONOO−. H2O2, ONOO− or both are transformed to OH˙ free radical, and with NO˙, they together act as prominent agents for the neurodegeneration.
The production of OH˙ free radical readily oxidizes (a) structural proteins, (b) nucleic acid and (c) lipids of the neuronal cells. They also disrupt their biological functioning (Pacher et al., 2007; Kong and Lin, 2010). The enzyme, glutathione peroxidase (GPX), uses reduced glutathione (GSH) to remove hydrogen peroxide as H2O (H2O2+2GSH→GS-SG+2H2O) (Ng et al., 2007). Simultaneously, the catalase enzyme, which is localized in peroxisomes, works by sensing the higher concentrations of the hydrogen peroxide by converting it into water and oxygen. Additionally, the monoamine oxidase-B, a type of brain redox enzyme, accountable for metabolism of monoamines into aldehyde, H2O2 and ammonia (RCH2NH2+FAD+O2+H2O→RCHO+FADH2+HOOH+NH3), is also responsible for producing an additional load of H2O2 (Girgin et al., 2004; Yusuf et al., 2008; Weinreb et al., 2016).
Influence of OS on cellular mechanisms
The OS critically affects apoptosis, proteopathy, proteasome dysfunction, mitochondrion dysfunction, glial cell activation, neuroinflammation and vice versa. (Guo et al., 2013). The apoptosis is a physiological process of programmed cell death for destroying unwanted cells overloading, thus maintaining the tissue homeostasis (Hengartner, 2000). The apoptosis can proceed extrinsically and inducted by death receptors or intrinsically by the cytochrome c, caspase-8, 9 releases and formation of apoptosome complex in the mitochondrion (Kajta, 2004; Lavrik et al., 2005). Both the pathways synchronize to release caspase-3, which further activates the caspase-activated DNase, nuclease (CAD) or DNA fragmentation factor 40, a heterodimer of 40 kDa, resulting into the specific DNA fragmentations and apoptotic cell death (Engel and Henshall, 2009; Panickar and Anderson, 2011). This has been evidenced experimentally in animals for seizure-induced neuronal death (Chuang et al., 2007). The apoptotic cells can be distinguished by certain biochemical and morphological changes, such as chromatin condensation, cell shrinkage and internucleosomal DNA fragmentation (Hengartner, 2000) (Figure 1).
The oxidative stress cascade illustrating production of reactive oxygen species (ROS), and their involvement in neurodegeneration.
The OS-induced ROS and mitochondrial Ca2+ efficiently initiates the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) linked channel opening, thereby resulting in free diffusion of the cytochrome c release through the inner and outer membranes of the mitochondria to the cytoplasm where it activates caspase-9 and further the caspase-3 (Emerit et al., 2004; Lavrik et al., 2005). The MPTP opening is also favored by certain mitochondrial-linked proapoptotic (Bax, Bad and Bim) and antiapoptotic (Bcl-xl, Bcl-2 and Bcl-w) proteins (Kajta, 2004; Engel and Henshall, 2009; Henshall and Engel, 2013). The pro-apoptotic signal enhances the release of other mitochondrial-linked protein from the intermembrane space of the mitochondrion called apoptosis-inducing factor (AIF). The AIF triggers DNA fragmentation and also participates in the activation of caspase-9 in the cytoplasm (Kajta, 2004).
The abnormal structure and function of proteins are the main characteristics of proteopathy (Walker and LeVine, 2000). The misfolding and peculiar polymerization of β-amyloid, including the misfolding of the tau protein in the nervous system, has been primarily attributed to the pathogenesis of Alzheimer’s disease (Jucker and Walker, 2011). The repeated triplet codes occurrence in Huntington’s disease (Walker, 2007), protein structure changes in SOD 1 in the case of amyotrophic lateral sclerosis (Rosen et al., 1993) and conformational conversion of α-helix-rich prion protein (PrPC) into PrPSc (β-structure-rich insoluble) (Eghiaian et al., 2004) as well as mutations of α-synuclein have been thought to be responsible in Parkinsonism (Stefanis, 2012). The OS induces protein misfolding via DNA and mtDNA (mitochondrial DNA) mutations (Ling and Söll, 2010).
Among other mechanistic details, the ubiquitin-proteasome system (UPS), which is a foremost pathway for protein and is needed for cellular protein homeostasis by eliminating misfolded or damaged proteins, their oxidative modifications reduces their functions and stability (Droge, 2002; Martindale and Holbrook, 2002). The proteasomal activity declines with aging, resulting in the decreased expression and oxidative modifications (Keller et al., 2000; Carrard et al., 2002). The proteasomal dysfunction causes accumulation of proteins aggregates and is considered to be a hallmark of aging and neurodegeneration. The proteasome inhibition may cause cell death via several factors; among them is the lack of free amino acids produced in the proteasomal degradation (Suraweera et al., 2012). The interaction between protein aggregate-induced ROS generation and redox-active metal ions is the defining key causes (Tabner et al., 2005; Allsop et al., 2008; Jomova et al., 2010).
Besides the oxidative phosphorylation, the mitochondria also assists in apoptosis, ROS signaling and Ca2+ homeostasis in neurons and influence neurodegeneration (Danial and Korsmeyer, 2004; Lin and Beal, 2006). The mitochondrial intracellular ROS production via electron leakage as a by-product of oxidative phosphorylation is an important step. The mitochondrial antioxidative enzymes, such as MnSOD, and glutathione peroxidase maintain the level of ROS, but their excess production can lead to mitochondrial damage and dysfunction. The mitochondrial components, i.e. the electron transport chain (ETC), and mtDNA are very susceptible to ROS linked oxidative damage (Sohal et al., 1995; Lin and Beal, 2006). The mtDNA is 10 times more prone to mutations as compared to nuclear DNA (Mecocci et al., 1993). The mitochondrial dysfunction progresses with age (Turner and Schapira, 2001; Trifunovic and Larsson, 2008) and results in affecting the ATP-dependent processes, such as receptors function, ion channels, vesicle release, pumps and neurotransmitter recycling. During neuron degeneration, the glial cells assist in regulating the metabolism of stressed neurons (Zabel and Kirsch, 2013), and this can be achieved by the up-regulation of glial cell activities, which in itself is a promising indicator of stress and confirms the onset of degeneration and chemical imbalances (Kamal et al., 2014). The frenzied glial stimulation and neuroinflammation critically add to the brain damage, and it was reported in cyanide-induced toxicity (Skaper et al., 2013). The ROS-generated and ROS-activated glial cells lead to cognition linked brain damage. Further, it was also evidenced that the antioxidant compounds reduce the detrimental effects of ROS, OS and the extent of glial activation (Hui et al., 2013).
Mechanisms of protein, lipid and DNA damage
The brain cells are composed of numerous lipidic entities, i.e. fatty acyls, prenol lipids, glycerophospholipids, sterol lipids, glycerolipids, saccharolipids, polyketides and sphingolipids. Their basic functions are (a) lipid bilayers formation providing structural integrity, (b) providing energy reservoir and (c) generating precursors of secondary messengers, such as 1,2-diacylglycerol (DAG), arachidonic acid (ArAc), ceramide, phosphatidic acid, docosahexaenoic acid (DHA) and lysophosphatidic acid (Adibhatla et al., 2006; Adibhatla and Hatcher, 2007). Mostly, the fatty acids are monocarboxylic and straight-chain with one or, two unsaturated bonds in cis (Z) configuration, and usually, they are of even carbons ranging from C12 to C26. The lipids from neuronal membranes contribute in lipid peroxidation, and it is a free radical chain reaction in which lipids hydrocarbon reacts with the free OH˙ radical formed via Fenton’s reaction to eliminate H from a fatty acid side-chain thereby forming a carbon radical. Furthermore, the oxidation of carbon radical further forms peroxyl radicals that damage the membrane proteins, and the fatty acid side-chains. Again, the peroxyl radical reacts with hydrocarbon to form the lipid hyperperoxide, and also a carbon radical; hence, it retains a free radical and forms continuous chain reaction (Figure 2). As reported, the unsaturation of fatty acid’s side chain is essential for fluidity, but also it is very susceptible to free radicals (Halliwell, 2015). Patients suffering from OS condition were found to be more prone to excrete aldehydes, like 4-hydroxynonenal, and malondialdehyde along with thiobarbituric acid-reactive substances in their urine which are the by-products of the lipid peroxidation.
Mechanism of lipid peroxidation via OH free radicals formed during oxidative stress.
The proteins also play an important role in strengthening and sensory communication among the neurons. The molecules embedded in the membrane, e.g. ion channels, and receptors are responsible for communication between inside and outside located neurons. The actin, spectrins, neurofilaments and microtubules forming the cytoskeleton assist the neurotransmitter release and another regulatory mechanism as part of their functions. The damage caused by the OS to proteins results in their irregular functions. The OH free radical directly attacks the α-carbon of the amino acid chains via extracting hydrogens to form water and leaving the carbon radical. These carbon radicals are responsible for cross-linking. The carbon radicals are easily oxidized into peroxides, and Fenton’s reaction, which changes Fe+2 to Fe+3 with the production of a proton from the conversion of hydrogen dioxide radical to oxygen, is an important initiation. Thus, the produced proton reacts with the peroxides forming the hydrogen peroxides. Further, the dehydroxylation from hydrogen peroxides of amino acid takes place via the oxidation of Fe+2 to Fe+3 resulting in the formation of amino acid oxides. These oxides are responsible for peptide bond cleavage. The hyperperoxides and carbonyls proteins are the major products of protein peroxidation and oxidation, which are accumulated in the brain regions of the oxidatively stress patients, and are excreted in their urine (Figure 3).
Mechanism of protein damage via OH free radicals formed during oxidative stress.
The DNA copying errors and the faulty RNA transcripts lead to protein damage. The proteins’ sequences and shapes are dependent upon the genes (sequence of DNA), which determines the sequence of amino acid in a given polypeptide chain. The ambiguous base pair mismatch results in change of amino acids leading to an ambiguous translation. The hydroxyl free radical assists the nitrogen bases to form hydroxyl compounds. The purines nitrogenous bases, i.e. guanine, and adenine mostly form the 8-hydroxy products, whereas the pyrimidine nitrogenous bases, i.e. the cytosine, and thymine form 5-hydroxy or 4,5-dihydroxy product, e.g. thymine glycol. Also, a very common somatic mutation is found among guanosine and thymidine, achieved by the hydroxylation of guanosine at the eighth position, which further goes to keto-enol tautomerism, mimicking the thymidine. During DNA replication, the 8-hydroxyguanosine complements the adenosine-containing template. The rate of this mutation depends upon the proportion of oxidized DNA damage resulting in the base pair mismatch. The mismatched pairing leads to translation of abnormal proteins (Figure 4). This whole mechanism also slows down the transcription and the translation (Cutler and Rodrigues, 2002; Maehara et al., 2008; Moreira et al., 2008). In the past researches, the elevated concentration of 8-hydroxy deoxyguanosine (8-OHdG) was established as a biomarker for DNA damage in animals kept under OS conditions. The same pattern of 8-hydroxy deoxyguanosine (8-OHdG) and damaged nitrogenous base products have been found in the urine of smokers and rheumatoid arthritis patients (Nunomura et al., 2007), and have also been debated as cancer risk (Halliwell 1998).
Mechanism of DNA damage via OH free radicals formed by the oxidative stress.
Generally, the nerve cells are incapable of division on maturity, which restricts them to a constant number of populations inside the fixed volume of the cranial capacity. The learned skills depend upon the interconnection of neurons and the loss of neurons or interruption in its function leads to several neurological disorders, prominent among them are amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, depression and epilepsy. The OS, directly or, indirectly, influences the pathogenesis of these diseases.
Amyotrophic lateral sclerosis
The amyotrophic lateral sclerosis (ALS) is characterized by dysfunction of motor neurons. It is designated as a chronic neurodegenerative disorder due to damage of the motor neurons in motor cortex, brain stem, corticospinal tract and spinal cord leading to muscle dimness (Neymotin et al., 2009). The factors responsible for the ALS pathogenesis are OS, cytoskeletal abnormalities, mitochondrial dysfunction and protein aggregation (Shaw, 2005). Around 20% of amyotrophic lateral sclerosis cases are found to be caused by the mutation of genes in the enzyme Cu-Zn superoxide dismutase (SOD1). Until date, a number of mutations have been reported, among them, H46R (characterize by the replacement of histidine to arginine at codon 46), A4V (replacement of alanine to valine at codon 4) and G93A (characterized by the replacement of glycine to alanine at codon 93) are well-known mutations (Vargas et al., 2011; Bhattacharya et al., 2012; Pan et al., 2012). The SOD1 imparts an active role in the endogenous antioxidant system by protecting the body from the damage caused by the highly reactive superoxide free radical produced by the mitochondrion during OS. Similar results of impairment of calcium transport, electron transport system and ROS production have been confirmed in a study on SOD1 mutated mice (Mattiazzi et al., 2002; Lin and Beal, 2006). The increased mutants SOD1 are responsible for the impairment of cellular activities by damaging the proteasomes, mitochondria and chaperones biomolecules (Boillée et al., 2006).
Alzheimer’s disease
Alzheimer’s disease (AD) is characterized by cognitive dysfunctions, memory loss with irreversible pathological condition. Unfortunately, it is followed by vascular dementia (Ashraf et al., 2016). In this disease, the neuronal cells gradually and over time degenerate and allow the disorder to take control due to extracellular amyloid beta (Aβ) depositions, intracellular neurofibrillary tangles (NFTs) retention and neuronal decline, which leads to neurotransmitter system derangement for the patient. The receptors acetylcholine (Bourin et al., 2003; Kihara and Shimohama, 2004; Zuchner et al., 2005; Oddo and LaFerla, 2006; Barrantes et al., 2010), N-methyl d-aspartate (NMDA), adenosine, histamine, insulin (Islam et al., 2017a,b), glutamate (Anggono et al., 2016), serotonin (Butzlaff and Ponimaskin, 2016) and others (Chu et al., 1987; Ramirez, 2013; Jin et al., 2015; Su et al., 2016; Zhao et al., 2017) are responsible. The affected subjects have also shown neuronal damage at the parietal lobe, temporal lobe, cingulate gyrus, frontal cortex and subcortical regions of the brain (Orth and Schapira, 2001; Wenk, 2006). The histopathological observations revealed the presence of masses of hyperphosphorylated tau protein (neurofibrillary tangles) and β-amyloid plaques (derived from the amyloid precursor protein) in the neuronal cytoplasm (LaFerla and Oddo, 2005; Anandatheerthavarada and Devi, 2007; Duyckaerts et al., 2009). The oxygen radical expedites the formation of glycated end products, lipid peroxidation, nitration, adduction products, carbonyl-modified neurofilament protein and free carbonyls (Smith et al., 1994; Montine et al., 1996; Smith et al., 1997). The glycated products are mainly linked to accumulation of β-amyloid and NFT deposits (Smith et al., 1994). The mitochondria are said to be the major source of oxidative radicals, and the major precursors are superoxide free radicals, i.e. O2˙− and H2O2. In an in situ hybridization study, the chimeric cDNA involvement and common deletion of 5 kb 3× folds increased the mitochondrion mutation as compared to control. The imbalances of trace elements and redox-active metals were seen in AD encountering among them the Cu (II), Zn (II) and Fe (II), which play an important role in the OS (Smith et al., 1994, 1995). A microplate X-ray emission study revealed higher concentrations of these metals in neuropil as well in the NFT and senile plaques of AD subjects (Lovell et al., 1998), thus confirming the earlier connotation concerning the role of iron, ferritin, transferrin and redox active iron in the mechanism of NFT and the senile plaques formation in AD patients (Perez et al., 1998). Certain proteins and sirtuins, secretase, lipoxygenases, glycogen synthase kinase 3 (GSK-3), acetylcholinesterase and caspases also play part towards pathogenesis of the disease (Islam and Tabrez, 2017; Islam et al., 2017a,b). The inflammation and insulin-based studies have lately provided the disease’s connection with the type 2 diabetes (Kamal et al., 2014), whereas the nitric oxide-dependent mitochondrial DNA overproliferation has been linked to the cancer (Aliev et al., 2013). Importantly, the inhibitors acting against the involved these enzymes and the targeting of the OS, auto-phagocytosis biomechanistics, as well as RNA interference can have primal role in developing suitable treatment and containment strategy for the disease (Jabir et al., 2014; Islam et al., 2017a,b). Recently, piperine based solid lipid nanoparticles were evaluated with successful results against experimentally OS induced Alzheimer’s disease by ibotenic acid (Yusuf et al., 2013).
Huntington’s disease
Huntington’s disease (HD) is a genetic neurodegenerative disorder inherited in an autosomal dominant pattern and usually has an adult onset of the disease in thirties or late thirties of the person. It is characterized by emotional problems, depression and loss of cognition, trouble in speaking, swallowing, uncontrolled and jerking movements termed as chorea with changes in personality. A juvenile form may start in early childhood and adolescence, and is exhibited by movement disorders, frequent falling, drooling, emotional changes and slurred talk (Walker, 2007). It severely affects a person’s cognitive, functional and psychiatric abilities (DiFiglia, 1990). The disease involves neuron degradation in striatum via autosomal dominant mutation of the Huntingtin (Htt) gene. This gene has more than 36 (up to 120, 40 being the threshold) repetitions of CAG (cytosine, adenine and guanine) trinucleotide repeat for glutamine amino acid (CAGCAG.....CAG), which codes for a mutant huntingtin protein. The methylation of DNA is also altered (Glajch and Sadri-Vakili, 2015). The huntingtin protein is involved in multiple proteins interactions and a larger set of biological functions. It is toxic to brain cells and with disease progression affects large part of the brain (Goehler et al., 2004). On a biomechanistics scale, a higher oxidative damage in HD leads to the DNA strands breaking down (Hersch et al., 2006), an increase in unsaturated fatty acid per-oxidations (Browne et al., 1999) with increased oxidation of proteins as well as lipids (Browne and Beal, 2006) and an impaired SOD activity (Santamaría et al., 2001; Sorolla et al., 2008). The mutant huntingtin (Htt) can effectively cause mitochondrial dysfunction via decreased mitochondrial enzyme activity. Other studies have proposed that mtDNA is the key target of mutant Htt-linked OS, probably leading to mitochondrial alteration, and the impairment of the apurinic/apyrimidinic (AP) endonuclease enzyme 1 (APE1) that is involved in the base excision repair (BER) pathway, which is one of the important targets in mitochondrial activity in HD patients (Oliveira and Lightowlers, 2010; Ayala-Pena, 2013). In other studies, the mutant Htt-expressing cells have showed reduced APE1 with reduced respiratory functions in comparison with control (Siddiqui et al., 2012). It has also increased the Ca2+-mediated ROS generation (Wang et al., 2013) with greater mtDNA damages. The implications of these biochemical processes provide an insight into the disease where no permanent cure is available but only symptomatic improving of conditions is possible.
Parkinson’s disease
Parkinson’s disease (PD) is a progressive degeneration of dopaminergic neurons in the substantia nigra and pars compacta (Braak et al., 2003; Hirsch et al., 2013). It is characterized by Lewy bodies’ inclusions and α-synuclein accumulation in the neurons. Several gene mutations are reported in leucine-rich repeat kinase 2 (LRRK2), α-synuclein, DJ-1, ATP13A2 and PINK1 (PTEN-induced putative kinase 1) (Biskup et al., 2008) that are involved. The oxidative damage induced mitochondrial alteration, mtDNA mutations and mitochondrial dysfunctions can aggravate the degeneration of dopaminergic neurons (Jin et al., 2014). The OS-mediated modification of α-synuclein by oxidation and nitration leads to oligomerization (Xiang et al., 2013; Shimoji et al., 2013). The antioxidant therapy could protect Parkinson’s disease by reducing OS as demonstrated in an in vitro study where ascorbic acid implementation decreased the death rate of dopaminergic neurons (Ballaz et al., 2013). The low ascorbic acid levels were found in the lymphocytes of PD (Ide et al., 2015). In other studies, it was concluded that dopamine self-metabolizes to produce ROS, which could aggravate the PD condition (Bindoff et al., 1989; Mizuno et al., 1989; Schapira et al., 1989; Henchcliffe and Beal, 2008). Many studies have proposed that the mitochondrial dysfunction is linked to PINK1. The disproportionate mitochondrial fission also obstructs the maintenance of oxidative phosphorylation (OP) mechanism with PINK1 losses, which results in defective OP complex assembly leading to reduced mitochondrial OP (Liu et al., 2011; Tufi et al., 2014). In another study, an increased mtDNA deletion was found associated with ETC (electron transport chain) paucity in substantia nigra neurons (Kraytsberg et al., 2006). Similar findings have been observed in PD-mito-Pst1 mouse, which expressed a restriction enzyme for damaging mtDNA (Pickrell et al., 2011). OS and tyrosine hydroxylase have been suggested as the mechanistic and molecular targets for developing the cure for the disease (Khan et al., 2012).
Epilepsy
Epilepsy is a chronic neurological disorder, characterized by recurrent and unprovoked seizures, which are proposed to be caused by an imbalance of oxidants, and antioxidants because of the excitotoxic OS (Shivakumar et al., 1991). A mathematical model have also been proposed (Rai and Khan, 2009; Khan and Rai, 2016). The human brain, rich in mitochondrion, generates highly reactive superoxide radicals during the respiratory cascade, which efficiently starts the pathological oxidative metabolism of bio-macromolecules leading to seizures (Turrens et al., 1982; Liang and Patel, 2006). Numerous findings concluded that an increase in mitochondrial O and NS (oxidative and nitrosative stress) followed by cell impairment causes persistent seizures (Cock, 2002; Liang and Patel, 2006; Waldbaum et al., 2010). It has also been reported that extended seizures can result in the production of superoxides by a series of mechanism initiated by extreme neuronal firing, ATP consumption, NMDA receptor activation, glutamate release, mitochondrial and cytosolic calcium influx (Patel, 2004). The mitochondrial dysfunction influences epilepsy in humans (Kunz and Oliw, 2001; Lee et al., 2008) and animal models (Cock et al., 2002; Kudin et al., 2002; Chuang et al., 2004; Liang and Patel, 2004) as a consequence of faulty oxidative phosphorylation complexes, which results into excessive superoxide production. In a previous study, reductive iron salts (Willmore et al., 1978) and toxins (Zuchora et al., 2001) enhanced the free radical load and seizure activity. On the other hand, an increased superoxide production was found in Mn-SOD mice via synaptic NMDA receptor activation, which also resulted in seizure activity (Melov et al., 1998). In status epilepticus (SE), a variation in redox potential with a drop of ATP was encountered, which resulted in a downfall of production and supply of energy to the brain (Wasterlain et al., 1993). The myoclonic epilepsy with ragged red fibers (MERRF) is a rare mutation syndrome caused by the transition mutation of A to G (A8344G mutation) in human mitochondrial DNA (Wallace et al., 1988), and it is said to be responsible for impaired biosynthesis of mitochondrial proteins that are linked with the oxidative phosphorylation (Shoffner et al., 1990). The excessive ROS generation, impaired expression of antioxidant enzymes and insufficient ATP generation are some of the consequences reported in MERRF (Wu et al., 2010). Other mitochondrial mutations involved are DNA polymerase γ (POLG1) (Zsurka et al., 2008) and tRNAPhe (phenylalanine-tRNA ligase) MT-TF (Mitochondrially Encoded TRNA Phenylalanine, RNA gene) (Zsurka et al., 2010) which are reported to be associated with generalized seizures, and affects the mitochondrial respiratory cascade along with ATP production (Zsurka and Kunz, 2010).
In animal models, kainic acid (KA), an epileptogenic, caused an increase in the ROS and NO syntheses, mitochondrial dysfunction and apoptosis of neurons when it was directly administered into CA3 area of the hippocampus (Liang et al., 2000; Chuang et al., 2007; Shin et al., 2011), whereas other KA-induced seizures reduced the activity of the nicotinamide adenine dinucleotide cytochrome c reductase (NCCR) in the hippocampus (Waldbaum and Patel, 2010). The mitochondrial OS can cause oxidative damage to DNA at different stages of seizures as elicited by pilocarpine or KA (Waldbaum et al., 2010). The pilocarpine-induced seizures have also been reported for enhancing the lipid peroxidation, ROS and nitrite production in the hippocampal, striatum and frontal cortex (Folbergrová and Kunz, 2012). The OS connection of epilepsy was substantiated by eliciting seizures via removal of the MnSOD enzyme in comparison with the MnSOD (SOD2) super-expressed animals, and it showed improved survival in comparison to KA-induced SE (Milder and Patel, 2012). The antioxidants, e.g. melatonin, and vitamin C-SOD mimic had shown prevention in experimentally induced seizures. A daily supplementation of coenzyme Q10 reduces the SE-induced RNA oxidation and protects individual from neuronal loss (Kong and Lin, 2010). Another antioxidant, β-carotene, had shown decent prevention of seizure as observed in the brain-targeted polysorbate-80-coated PLGA nanoparticles delivery in MES (maximal electroshock seizure), and PTZ (pentylenetetrazol) induced albino mice epileptics (Yusuf et al., 2012). In another study, higher concentrations of ceruloplasmin and lower concentrations of vitamins C, E and A were found epileptics in comparison to the controls (Sudha et al., 2001).
Major depressive disorder
Major depressive disorder (MDD) or clinical depression is the common mental disorder extending over 2 weeks in nearly all situations, resulting in behavioral changes, ideas of self-harm and suicide, low self-esteem and low energy, and often pain without any clear cause (Kessler et al., 2003; Mehlum et al., 2016). The role of oxidative disturbances is evidenced in the MDD, which was observed through oxidative marker studies and antioxidant effects of antidepressants. The oxidative stress biomarkers, such as increased serum levels of XO (xanthine oxidase) in thalamus (Herken et al., 2006; Leonard and Maes, 2012), the elevated levels of MAO (monoamine oxidase) (Sacher et al., 2015), SOD and catalase (Scapagnini et al., 2012; de Sousa et al., 2014) and the lowered activity of GPX (glutathione peroxidase) (Maes et al., 2010) were found in this disorder (Khanzode et al., 2003). The elevated ROS/RNS (reactive oxygen and nitrogen species) and suppressed antioxidant defenses also resulted in oxidative and nitrosative modifications of cellular biomolecules, i.e. fatty acids, proteins and DNA.
The telomerase with critical role-play instability of genomic sequence is susceptible to oxidative damage. The telomere shortening owing to oxidative damages to a critical length, as found in depression and oxidative stress, is presumed to be a prime cause. OS can induce DNA damages in telomeres in comparison to non-telomeric DNAs (Simon et al., 2006; Wolkowitz et al., 2011). The oxidative deamination of monoamine neurotransmitters by MAO produces hydrogen peroxide as the by-product which overloads the ROS, trails to mitochondrial dysfunction and neuron apoptosis (Scapagnini et al., 2012). The GPX protects DNA, and neuronal damages in MMD subjects where decreased activity of GPX with excessive ROS accumulation have been found (Kodydková et al., 2009; Gawryluk et al., 2011). A lower activity of paraoxonase 1 (PON1) was found in MDD patients; this enzyme protects lipid peroxidation of lipids (Aviram et al., 1998). The improved results were observed in MDD experimental models while using polyenes and polyphenol antioxidants in pure or, different delivery doses form like curcumin (Yusuf et al., 2016), resveratrol, chlorogenic acid and Ginkgo biloba EGb761 (Gomez-Pinilla and Nguyen, 2012; Ogle et al., 2013). The lower concentrations of omega-3 polyunsaturated fatty acids (n-3 PUFA) (Gharekhani et al., 2014), coenzyme Q10 (CoQ10) (Schmelzer et al., 2008) and N-acetyl cysteine (NAC) (Berk et al., 2014) were found in MDD patients as low levels of CoQ10 is linked with higher concentrations of ROS, RNS and tumor necrosis factor alpha with mitochondrion dysfunctions.
Conclusions
The oxygen consumption by cells for their energy and other physiological needs generates free radicals in the biochemical processes which in uncontrolled abundance damages the cells through various reactions and involvements in the physiology and biochemical functioning of the cells. The higher oxygen demands and the presence of susceptible substrates make the human brain more vulnerable than other organs and tissues in the body. The resulting redox imbalances through excess ROS and/or dysfunctional natural antioxidant systems of the body, slowly and over time, lead to pathogenesis of neurodegenerative disorders due to OS’s continual pressing. The roles of hereditary and non-hereditary factors are other concerns in this context. The biotherapies and better drug designing based on curtailing the roles and controls of the OS generators, biochemical steps propagating biomolecular entities, the free-radical conveyors in biochemical steps along with the vulnerable biological steps as well as the involved biomechanistics will shed more light on precise and focused causes, biochemical, enzymatic processing and the target entities to provide realistic goals for better drug design and development of drugs with elaborate and understood use of natural products, natural products modified by design, and synthetic agents in curtailing, controlling and curing the diseases.
Conflict of interest statement: The authors have no conflict of interests.
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©2018 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Reviews
- Biomechanistic insights into the roles of oxidative stress in generating complex neurological disorders
- Metformin-induced anticancer activities: recent insights
- Research Articles/Short Communications
- Protein Structure and Function
- Interaction of the middle domains stabilizes Hsp90α dimer in a closed conformation with high affinity for p23
- How human serum albumin recognizes DNA and RNA
- In vitro reconstitution and biochemical characterization of human phospholipid scramblase 3: phospholipid specificity and metal ion binding studies
- Cell Biology and Signaling
- LncRNA KCNQ1OT1 ameliorates particle-induced osteolysis through inducing macrophage polarization by inhibiting miR-21a-5p
- LncRNA PART1 modulates toll-like receptor pathways to influence cell proliferation and apoptosis in prostate cancer cells
- High-content hydrogen water-induced downregulation of miR-136 alleviates non-alcoholic fatty liver disease by regulating Nrf2 via targeting MEG3
Artikel in diesem Heft
- Frontmatter
- Reviews
- Biomechanistic insights into the roles of oxidative stress in generating complex neurological disorders
- Metformin-induced anticancer activities: recent insights
- Research Articles/Short Communications
- Protein Structure and Function
- Interaction of the middle domains stabilizes Hsp90α dimer in a closed conformation with high affinity for p23
- How human serum albumin recognizes DNA and RNA
- In vitro reconstitution and biochemical characterization of human phospholipid scramblase 3: phospholipid specificity and metal ion binding studies
- Cell Biology and Signaling
- LncRNA KCNQ1OT1 ameliorates particle-induced osteolysis through inducing macrophage polarization by inhibiting miR-21a-5p
- LncRNA PART1 modulates toll-like receptor pathways to influence cell proliferation and apoptosis in prostate cancer cells
- High-content hydrogen water-induced downregulation of miR-136 alleviates non-alcoholic fatty liver disease by regulating Nrf2 via targeting MEG3
