310 CNS & Neurological Disorders - Drug Targets, 2016, 15, 310-320
Recent Updates on the Dynamic Association Between Oxidative Stress and Neurodegenerative Disorders
Taqi A. Khan
1,§, Iftekhar Hassan
2,§, Ausaf Ahmad
3, Asma Perveen
4, Shazia Aman
5, Saima Quddusi
3, Ibrahim M. Alhazza
2, Ghulam M. Ashraf
*,6and Gjumrakch Aliev
7,8,91Applied Biotechnology Department, Sur College of Applied Sciences, Sur, Oman; 2Department of Zoology, College of Sciences, King Saud University, Riyadh, Saudi Arabia; 3Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow, Uttar Pradesh, India; 4Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India; 5Department of Biochemistry, J L N Medical College and Hospital, Aligarh Muslim University, Aligarh, India; 6King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; 7GALLY International Biomedical Research Consulting LLC., San Antonio, TX, 78229, USA; 8School of Health Science and Healthcare Administration, University of Atlanta, Johns Creek, GA 30097, USA; 9Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia
Abstract: Free radicals are generated as byproduct of our body metabolism, and their adverse effect on normal functioning of our body is prevented by body’s own antioxidant machinery. Any perturbation in the defense mechanism of antioxidants inside body, its abnormal production or its induction from environment to our body lead to serious threats and is responsible for the development of various neurodegenerative disorders (NDDs). Perturbed antioxidants result in sensory and functional impairments in neuronal cells, which in turn cause NDDs. Free radical attack on neuronal cells plays a catastrophic role in NDDs. Impaired metabolism and generation of excessive reactive oxygen species also lead to a range of NDDs. Free radical induced toxicity is responsible for DNA injury, protein degradation, damage to tissue inflammation and cell death. Besides various genetic and environmental factors, free radical induced oxidative stress is also a major cause of NDDs. Application of upstream and downstream antioxidant therapy to counter oxidative stress can be an effective option in alteration of any neuronal impairment besides free radical scavenging. In the present manuscript, we have presented a comprehensive update on the symptoms, causes and cures of NDDs in relation with their dynamic association with oxidative stress.
Keywords: Aging, antioxidant proteins, free radicals, mitochondrial dysfunction, neurodegenerative disorders, oxidative stress.
INTRODUCTION
Neurodegenerative disorders (NDDs) are a group of disorders associated with progressive loss of neuronal function and death, with Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and Amyotrophic lateral sclerosis (ALS) being the most common NDDs [1-3]. NDDs are growing at an alarming rate, especially reported from advanced countries, and have been a major concern amongst neuroscientists. The researchers have been continually trying to make breakthroughs in developing novel treatment options for NDDs. Recent researches have depicted a plethora of mechanistic and therapeutic updates on NDDs.
Stress is an important factor reported to be intrinsically associated with various NDDs [4-6]. Hydrogen peroxide (H2O2) produced during oxidative deamination of
*Address correspondence to this author at the King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; Tel: +966593594931;
E-mails: [email protected], [email protected]
§Equally contributing authors.
catecholamines has been reported to be involved in AD and PD, presumably via oxidative damage to the mitochondrial membrane [7]. Free radicals are produced as byproduct of metabolism and our body has its own antioxidant machinery which plays a decisive role in the prevention of any loss due to free radicals [8]. Perturbations in the defense mechanism of antioxidants inside our body, their abnormal production or induction in our environment result in serious threats responsible for various NDDs [8-10]. Apart from many other genetic and environmental factors, oxidative stress is a major cause of NDDs [11-14]. Free radical attack on neuronal cells play a catastrophic role in NDDs [15]. Impaired metabolism and excessive generation of reactive oxygen species (ROS) leads to AD, PD and other neural disorders [16]. Application of upstream and downstream antioxidant therapies to counter oxidative stress has been proclaimed as an effective option in alteration of any neuronal impairment other than free radical scavenging [17]. A recent study demonstrated the involvement of oxidative stress in high glucose induced cardiomyocyte apoptosis via caspase-3 activation [18].
Moreover, AD and PD have been reported to be linked with other chronic diseases [19], further enhancing the need to explore their linkage with major causative factors.
1996-3181/16 $58.00+.00 © 2016 Bentham Science Publishers
In the present manuscript, we have presented a comprehensive review on the dynamic association between oxidative stress and NDDs with the aim of providing a definitive pattern towards the better and improved understanding of causes and cures of NDDs.
SYMPTOMS OF NDDs
Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide [20]. Patients affected by the normal pressure form of glaucoma are more likely to harbour the risk alleles for glaucoma-related optic nerve disease [20]. Genomic pathway analysis of transforming growth factor beta (TGF-β) signaling showed an important association between the TGF-β pathway and normal pressure glaucoma [20]. These results suggest that neuroprotective therapies targeting TGF-β signaling could be quite effective in controlling multiple forms of glaucoma [20]. Efferent nerves under outer hair cells (OHCs) play an important role in the protection of these cells from loud stimuli [21]. Due to differential expression of α -synuclein, efferent nerve degeneration has been suggested to be a potential cause of early-onset presbycusis [21]. High levels of deleted mtDNA were detected when substantia niagra neurons were compared between aged controls and PD patients, thus suggesting high impact of somatic mtDNA deletions in elective neuronal loss observed in brain aging and PD [22]. Moreover, age-related defects in erythrocyte 2,3-diphosphoglycerate metabolism has also been reported in various dementia forms [23].
The molecular mechanism of axonal degenerationin the optic nerveremains unclear [24].A tumor necrosis factor- induced optic nerve degenerationmodel demonstrated primary axonal degeneration and subsequent retrograde loss of retinal ganglion cell bodies [24].Brain derived neurotrophic factor and amyloidogenic pathway have been suggested to play an important role in glial events [24].
Other than aging and environmental factors, redox sensitive genes have also been reported to increase the sensitivity of cells to oxidative stress. Mutations in PARK7 gene encoding DJ-1 results in oxidative damage and significant enhancement in brains of sporadic PD patients [25].
Neurodegeneration is a hallmark of the human disease ataxia-telangiectasia (A-T) that is caused by the mutation of A-T mutated (ATM) gene [26]. Signal responsible for neurodegeneration in ATM mutants activates a specific NF- κB protein via an unknown activator, thus suggesting that neurodegeneration in human A-T is caused by activation of a specific NF-κB protein in glial cells [26]. Proteinacious fibril accumulation is a common neuropathological feature of NDDs [27]. Aggregation of α -synuclein into protofibrils induced by Cu-Zn-SOD/H2O2 system via OH· generation results in the loss of its normal function and impairs dopaminergic neurotransmission [28]. Activated microglia release free radicals like NO and O2·-
, thus forming the most abundant source of free radicals in brain [29].
Axonal degeneration is related to neuronal cell death andis a common hallmark of many NDDs [24]. Over- expression of nicotinamide mononucleotide adenylyl- transferase 3 (NMNAT3) exerts axonal protection against tumor necrosis factor and intraocular pressure (IOP)
elevation induced optic nerve degeneration [24].Axonal protective effect of NMNAT3 may be involved in autophagy machinery, and NMNAT3 modulation and autophagy may lead to potential strategies against degenerative optic nervedisease [24]. Retinal ganglion cells (RGC) project their long axons composing the optic nerve to the brain, and transmits the visual information gathered by retina resulting in the formation of vision in visual cortex [30]. The RGC cellular system represents the anterior part of the visual pathway and is vulnerable to mitochondrial dysfunction and optic atrophy, which are common features of NDDs and mitochondrial diseases [30].
CAUSES OF NDDs
NDDs are one of the least understood category of diseases even after great advancements made by science in last few decades. The exact cause of most of the NDDs is generally unknown, and even if they have been identified, the exact mechanism at the best is speculative. However, some hypotheses that have been proposed to identify their causes are discussed below (Fig. 1).
Fig. (1). Causes of neurodegenerative disorders (NDDs).
Genetic Link
Genetic link is considered as one of the most speculated reasons behind clinical manifestation of NDDs as some of them have shown a clear familial occurrence, strongly suggesting their genetic basis [31]. NDDs have been found to run as an autosomal dominant trait among the affected families [32]. Moreover, NDDs can arise as an autosomal recessive trait (e.g., familial spastic paraparesis), a maternally inherited trait (e.g., mitochondrial Leber optic neuropathy) or an X-linked trait (e.g., spinal and bulbar muscular atrophy) [32].
Besides purely genetic NDDs, other cases might be idiopathic and a small contingent of such patients have been reported to inherit the disease [33]. This notion is further supported by the fact that 10% of PD, AD and even ALS patients have a clear family history [34]. In spite of sporadic nature of these diseases, a great deal of evidences entail that a large proportion of these cases are also significantly influenced by genetic factors. These genetic factors are numerous; displaying intricate patterns of interaction with each other as well as with non-genetic variable, and unlike classical Mendelian disorders exhibit no simple or single mode of inheritance [35]. The origin, prevalence and sequential expression of the symptoms at varying rate in different NDDs indicate mutation in certain genes although
they have been inconsistent in nature. Mutations involved in NDDs are characterized by polymorphism and population dependent variance that have been found to be associated with clinical manifestations of these diseases. For example, according to a meta-analysis the APOE polymorphism might contribute not only in AD, but also in PD and FTD (albeit with different alleles) [35]. Successful execution of these studies might pave the way for common genetic and mechanistic denominators for NDDs. Hence, the genetic link of NDDs is certain but complicated.
Environmental Link
Various epidemiological and case studies have speculated environmental link as the second most speculated reason after genetic link that has been strongly associated with the occurrence of NDDs [36]. Mutations causing NDDs have been reported to be accompanied by certain environmental factors in most of the cases as the interaction between genotype and phenotype finally cause and/or affect a trait in any living organism [37]. Recent reports entail that chemical fertilizers, malnutrition, heavy metals, prolonged exposure of pesticides, abnormal medications, mental trauma, exposure of electromagnetic field and food adulterants are few of the factors that facilitate the mutations leading to neurodegeneration [38]. Alcohol, smoking, caffeine, gender, socioeconomic status, education and ethnicity have been also found to be attributive in many studies [39]. Pro-oxidant DNA breakage induced by the interaction of L-DOPA with Cu(II) has also been suggested to be a putative mechanism of neurotoxicity [23]. Such neurotoxicant sources accumulate over long period of exposure and cause mutation in related gene(s) or proteins, consequently leading to NDDs [40].
Oxidative Stress and Protein Aggregation
Most of the neurotoxins are either exogenous or endogenous and exerts toxicity via elevating oxidative stress, which in turn has been reported to play a remarkable role in the onset and progression of various NDDs [8, 14, 41-47].
Brain itself has many endogenous oxidant sources like enzymes such as monoamine oxidase, xanthine oxidase, NADPH oxidase, and mitochondrial activity [48]. Although brain is well equipped to face free radical mediated injury, yet high demand of oxygen with an abundance of oxidizable substrates make it quite vulnerable in old individuals or the individuals with compromised redox status [49]. In such condition, the free radicals invade on cell organelles and macromolecules resulting in membrane disruption, enzyme denaturation, and formation of advanced glycated products by protein oxidation and lipid peroxidation [50-58].
Moreover, they cause inflammation, necrosis or delayed apoptosis that further exacerbate the overall functionality and control of brain [59]. They also cause aggregation of abnormal proteins that are unable to be cleared off by proteasomal action that can further form Aβ protein which is now an established marker in many NDDs [60]. Moreover, even few of the neurotransmitters like dopamine can also generate free radicals that can elevate oxidative stress in brain [39]. ROS can react with nitrogenous compounds in vivo and generate highly reactive peroxynitrite radicals [61].
ROS may also invade nuclear DNA and induce hallmark
mutations or affect the expression of genes coding antioxidant proteins like SOD and GSH [62]. The same is also evident from oxidative DNA damage and chromosomal aberrations in most NDDs [8, 63].
Altered Immune Response and Inflammation
It is now well established that abnormal immune response followed by chronic and systemic inflammation is one of the common features in most NDDs [63]. It has now been considered as reason as well as effect of neurodegeneration in the etiology of NDDs, although these findings still remain inconclusive. These degenerative changes are more obvious in the individuals having certain underlying genetic predisposition or experiencing degenerative pathology and/or primed microglia [64].
Surprisingly, a recent report on aging study implies that simple exposure of an aged bloodstream is sufficient to induce neurogenesis with significant learning and memory deficits in which chemokines seem to play a key role [65].
Despite tightly regulated immune system in central nervous system (CNS), it can exert aggressive immune response triggered by any viral infection, neurotoxin, heavy metals, drugs, trauma, stroke, ischemia, and other stimulating factors like heat shock proteins or aggregation and misfolding of abnormal protein(s) [66]. Normally, immune activation is essential to counter any such infection or damaging factor. Microglia plays dual role as guardians to maintain brain homeostasis and also as originator of damage.
Though still unclear, T cells have also been reported to assist in neuroprotection [67]. Hence, there is an intricate interaction at cellular and molecular levels demonstrating that these immune cells secrete neurotoxic as well as neuroprotective molecules [63, 68]. If such situation persists for long time, then the non-dividing and delicate nerve cells are bound to be affected leading to systemic neurodegeneration. Recently, a protein named C1q has been discovered in aged individuals and is considered as a key instigator for immunological response at the synaptic points in nerve cells. C1q has been found to be elevated in the people having vulnerability of NDDs in which it can scale up immune response to catastrophic level by neuroimmune cells upon being triggered by brain injury, strokes or infection [69]. Hence, inflammation is a highly speculated reason behind many of the NDDs yet there are many gaps that need to be filled for better comprehension and utilisation in designing novel treatment strategies.
Aging and Accumulation of Consecutive Mutations One of the most common aspects of all NDDs is their occurrence in elderly people with gradual worsening of systemic symptoms with aging, thus making aging as one of the major contributors in the etiology of NDDs and make elders more vulnerable to NDDs and also deprives their self repair ability [70]. According to the theory of aging, the delicate balance between free radical generation and potential antioxidant system in elderly population is disturbed due to many factors including decreasing mitochondrial efficiency, accumulation of mutation, decreased ability of tissue repair, impaired DNA repair system, and lowered activity of telomerase [71]. These
factors together can weaken the metabolism, co-ordination of bodily actions, brain functioning in aged individuals, and life processes. Hence, any immunological (inflammation or infections), environmental (low food quality, stroke, or shock) or genetic (mutation) factor, or sustained deficit in cellular functions can trigger the onset of NDDs. It can lead to formation of abnormal protein aggregation, compromised proteolysis and aggressive immune response that consequently facilitate the prevalence of such diseases. Thus, the relationship between aging and NDDs is certain but not vivid.
Apart from above-mentioned causes, silent strokes, accidental injury, sustained stress, emotional shock, social pressure, malnutrition and pollution can be additional factors in the etiology of NDDs.
CURES OF NDDs
Despite extensive research on NDDs for over four decades, modern science is yet to identify their exact causes and drug targets. Hence, cures for these slow death diseases arepalliative and symptomatic. However, rodents based animal model systems and modern technological advancements have stimulated the identification of potential drug targets, and moderate breakthroughs have been achieved as well [72-74]. Few of them are discussed below (Fig. 2).
Fig. (2). Cures of neurodegenerative disorders (NDDs).
Neurosurgery Approaches: Lesions, Stimulation, and Transplants
One of the most common and logical treatments for NDDs is the removal of affected portion of lesion, brain and protein aggregates, and then stimulating the remaining brain cells for normal growth and functioning. Destructive lesions formed of alcohol, freezing, battery-run stimulation or radio frequency pulses have also been found to be effective in alleviation of the symptoms of PD as well as L-DOPA- induced dyskinesias [75]. These lesion/stimulation based treatments merely offer symptomatic reliefs, yet recent attempts to replace lost neurons by fetal transplants, embryonic stem cells, cellular transplants expressing growth factors, and enzymes have shown great promise [76].
Although their effect might be transient and may generate other complications [77], these trials based on modern technology can be a success and open new vistas for treatment of NDDs.
Target Specific Drug: Designing, Testing and Confirming For the last four decades, numerous drugs and naturaceuticals have been tried as trials for treatment of NDDs. Most of them are designed on the basis of neurotransmitter replacement by giving suitable precursors, uptake inhibitors, releasing agents, enzyme inhibitors, second messenger modulators, and direct receptor agonists [78]. However, for the last two decades, aggregates of abnormal proteins has been targeted for their delay in the formation/inhibition/destruction without harming the neighbouring healthy neurons [79]. Various approaches like targeting specific mRNA for particular abnormal proteins, regulation of transcription and usage of RNA interference to silent the target genes provide an extremely promising avenue for therapeutics of NDDs [80]. Target specific drugs can also be designed by utilizing some modern approaches like machine learning approaches [81], region-specific treatment strategy [82], and support vector machine, artificial neural network and bayesian classifier [83]. Moreover, recently reported proteomics and nanotechnological advancements can also be employed for developing target specific drugs [2, 84-88]. Excitingly, investigators believe that these therapies will be a reality soon in terms of prevention of disease progression and delayed onset. Clinical trials are underway with the intention to turn off protein aggregates without triggering any aggression and, more impressively, reversed if caught in the early stages [89].
Supplementation of Anti-Aging Agents: Antioxidants and Neuroprotectants
As pathogenesis and progression of NDDs are directly or indirectly linked to oxidative stress that exacerbates with age and intake of low quality foods, the advice to take good quality antioxidants (vitamins, selenium, glutathione, co- enzyme Q10 etc.) and neuroprotectants (nicotine, gingko, nuts, and herbal medicines) is quite logical [46, 47, 70, 90].
These are prescribed to the patients in most of the treatment centres. It is believed that nutritional requirements of body change with age and clinical conditions. Although their exact mechanism and effects are still under investigation, the patients have been reported to get relief from the symptomatic discomforts and improved quality of life.
Restoration of Neurons: Stem Cells and Umbilical Cord Blood
Recent researches are highly focussed on the exploration of stem cells, human mesenchymal cells and umbilical cord blood in the treatment of NDDs, as these are source of pluripotent cells that can differentiate into any cell type under proper microenvironment and medium [91]. These can be administered by intracerebral and intrathecal injections into affected areas of brain, and can act as paracrine as well as autocrine hormones by promotion of induction of apoptosis in ailing neurons, endogenous neuronal regeneration, reduction of oxidative stress, encouraging synaptic connection from damaged neurons, and regulate inflammation [92, 93].
Gene Therapy: Planning and Application
Gene therapy is also under extensive research interest for treatment of NDDs, although no major breakthrough has been achieved so far. Researchers are now screening the gene map of patients and trying to identify the responsible genes for finding any clue to stop or silent their harmful expression in the brain. As brain is a very complicated organ and many of its aspects are still unresolved, the reality of gene therapy will take some time. Recently, sirtuin enzymes, a family of highly conserved protein deacetylases in mammals have been reported to be associated with genomic stability, caloric restriction, stress resistance, and aging by modulating energy metabolism [94]. They have thus been identified as potential therapeutic targets in NDDs by the virtue of their modulating role in pathogenesis and progression of NDDs by transcription factor activity and directly deacetylating proteotoxic species, thus projecting them as attractive drug targets [95].
Apart from above discussed methods of cure for NDDs, there are many other lines of research with same target.
Altered galectin glycosylation is being targeted for potential diagnostics and therapeutics of various NDDs [58].
Nutritional and non-nutritional factors have also been implicated in preservation of cognitive performance in patients with dementia/depression and AD [96]. However, there are still lot of challenges that need to be overcome for the management of NDDs [87].
SUPEROXIDE RADICALS AND H2O2 IN NDDs
ROS in the CNS play an important role in the regulation of blood pressure and genesis of hypertension [17].
Oxidative damage includes α -synuclein aggregation, mitochondrial dysfunction, excess free iron, glial cell activation, dopamine auto-oxidation and alterations in calcium signaling [97]. Oxidative stress is a metabolic condition arising from imbalance between the production of potentially damaging ROS and scavenging activities [98].
Mitochondria are the main producers as well as the main scavengers of cell oxidative stress [98].
The role of iron in PD cannot be ignored because of the cytotoxic nature of iron and its ability to promote oxygen free radical generation [17]. Oxygen free radical induced oxidative stress is a possible link between the PD pathology and brain iron metabolism [99]. This is not improbable as divalent metals like Al, Zn, Se, Li, Cu and Mn are closely linked with a number of neuropsychiatric diseases. As compared to liver, iron has extremely slow turnover in brain;
hence, most of iron that gets deposited in brain before the maturation of blood brain barrier remains for lifetime [100].
However, it is now quite evident that neuronal transport aids in translocation of iron from one brain site to another [101].
Highly conserved nature of iron is important for the maintenance of brain iron homeostasis and for normal functioning of this complex organ, as any excess or deficiency in brain iron content would affect brain function [102]. Optic neuritis is a common manifestation of multiple sclerosis, which is an inflammatory demyelinating disease of the CNS [103]. Increased calpain-specific spectrin cleavage has revealed that calcium elevation is correlated with enhanced calpain activation during the induction phase of
optic neuritis [104]. Elevation of retinal calcium levels and calpain activation are early events in autoimmune optic neuritis, providing a potential therapeutic target for neuroprotection [104].
In human brain, highest iron content is present in putamen, dentate gyrus, globus pallidus, caudate, and red nucleus [105]. Iron is also present in fiber tract running from pallidum to striatum, microglia, astrocytes, macrophages, and neuronal fibres [106]. Accumulation of α-synuclein and iron in substantia nigra has been reported to establish the favorable local conditions required for α-synuclein mediated H2O2 formation and its conversion to OH· via the Fenton reaction, thus resulting in death of vulnerable nigral neurons [107]. The rostral ventrolateral medulla (RVLM) in the brainstem is responsible for the regulation of sympathetic nervous system [108].In RVLM, nitric oxide (NO)-mediated γ-amino butyric acid (GABA) is a major sympatho- inhibitory amino acid neurotransmitter and superoxideis a major sympatho-excitatory factor [109]. Reduction of NO- mediated GABA release in the RVLM has been reported to be partly involved in superoxide-induced sympatho- excitation of stroke-prone spontaneously hypertensive rats [110].
ANTIOXIDANT PROTEINS IN NDDs
Life quality and aging are important topics of research nowadays in areas such as life sciences, pharmacology, chemistry etc, and antioxidant proteins may influence the aging process [111]. Proteins have been reported to possess excellent potential as antioxidant additives in foods, as they can inhibit lipid oxidation through multiple pathways like reduction of hydroperoxides, chelation of prooxidative transition metals, including scavenging of free radicals and ROS inactivation [112]. The overall antioxidant activity of a protein can be enhanced by disruption of its tertiary structure to increase the solvent accessibility of amino acid residues that can scavenge free radicals and chelate pro-oxidative metals [112].
Metal binding proteins like metallothionein, ceruloplasmin, transferrin and ferritin are of prime importance in the control of potential radical-generating reactions [113]. Selenium is an essential micronutrient required for cellular antioxidantsystems, yet at higher doses it induces oxidative stress.For radical compounds, the final deactivation consists of the formation of non-radical and non-reactive end-products [17]. Coconut kernel protein has potential beneficial effect in lowering oxidative stress associated with diabetes, which has been attributed to the presence of high biologically potent ariginine [114]. SOD and glutathione peroxidase are the major protective enzymes dealing with superoxide and H2O2 in brain [111].
Antioxidant activity of milk proteins by the combination of the Maillard reaction and enzymatic hydrolysis showed significantly higher antioxidant activity when compared with other protease products, and the antioxidant activity was higher for whey protein concentrate groups as compared to sodium caseinate groups [115].Milk proteins and fats together, but not alone, are responsible for the inhibitory effect of milk on the absorption of phenolic acids and changes in plasma antioxidant capacity [116]. The metal
chelating capacities (MCC) and oxygen radical absorbance capacities (ORAC) of protein concentrates prepared from cheese and buttermilk have been reported to show that peptides derived from milk fat globule membrane proteins, primarily butyrophilin, could be responsible for the superior antioxidant activity of buttermilk [117].
MITOCHONDRIAL DYSFUNCTION IN NDDs
Mitochondria provides energy to cells and are involved in various cellular activities such as induction of apoptosis, beta-oxidation of fatty acids, regulation of redox potential of cells, scavenging of free radicals and cellular calcium, and iron homeostasis [118, 119]. These activities are tightly regulated by nuclear and mtDNA, and associated proteins.
Being metabolically active and burdened with variety of cellular functions, mitochondria is one of the most vulnerable organelles in the cell. Oxidative stress and mitochondrial failure has been reported to be the indicators of brain hypoperfusion [44], with coenzyme Q and creatine reported to exert potential protective effects on brain energy metabolism in cerebral hypoperfusion [120]. The continuous energy production by oxidative phosphorylation generates many ROS that can damage the structure and function of cells and organelles [49]. Numerous factors such as strenuous exercises, stress, environmental toxicants, aging, injury and cancer have been reported to cause the dysfunction or malfunction of mitochondria [63, 121]. The most common form of cell death involved in neurode- generation is by the intrinsic mitochondrial apoptotic pathway [122].
Mitochondria also have mtDNA as their own genome that must be replicated and maintained by nuclear encoded proteins, and hence its functionality is co-operatively integrated with cell biology [123]. ROS can either introduce mutations in mtDNA directly or may affect the same via exerting effects on nuclear DNA if they leaks out of the organelle [124]. Although both mitochondria and cell are well equipped with antioxidant enzymes yet their efficacy and effectiveness are dependent on many factors like age, extent of stress, nutritional status and immunity of the individual [125]. Hence, mitochondrial dysfunctions have been reported to be responsible for many NDDs like AD, PD and HD [1]. Mitochondrial dysfunction has been reported to be the cause of sporadic AD [126], while amyloid accumulation has been reported to be the cause of inherited AD [127]. PD also occurs because of introduction of genetic alterations in nuclear gene coding or controlling mitochondrial proteins or dysfunction in ETC complex I of mitochondria triggered by environmental factors [128]. The increase in number of CAG repeats in HD has also been indirectly related to dysfunction of complex II that arises because of ROS induced damage to mtDNA [129].
Research works based on NDD patients, post-mortem brains and animal models have now established mitochondrial dysfunction in various NDDs like AD, PD, HD and ALS [118, 130, 131]. Mitochondrial abnormalities like enhanced accumulation of mtDNA defects, mounting of mutant proteins in mitochondria, perturbation in oxidative phosphorylation, mitochondrial membrane potential dissipation, and impaired calcium influx are important features observed in early as well as late onset NDDs [131].
Histopathological studies have also demonstrated critical structural alterations in mitochondria such as decreased mitochondrial fusion, increased mitochondrial fragmentation and distorted structure, thus confirming the involvement of mitochondrial dysfunction and cell death in aging and NDDs [132]. However, the dynamic functions performed by mitochondria have got a recent twist in its mechanistic capabilities, further opening up new permutations and combinations [133, 134].
PROTEIN CARBONYLATION IN NDDs
Besides oxidative damage to carbohydrates, lipids and nucleic acids, protein carbonylation is a major ill-effect of elevated oxidative stress [135]. Oxidative damage of proteins hampers all the major functions performed by proteins.
Recently, oxidative insult of proteins have drawn significant attention for their remarkable role in the pathogenesis of various human disorders including NDDs [136]. Although the backbone of proteins and side chain of most of their constituting amino acid residues are vulnerable to oxidation, yet non-enzymatic introduction of aldehyde or ketone functional groups to specific amino acid residues (i.e., carbonylation) amounts to the most common type of oxidative alteration [137, 138]. They have been extensively detected in conditions of considerable oxidative stress and strongly implicated in etiology and progression of various chronic inflammatory diseases and NDDs [8].
It is now well established that reduced glutathione (GSH) level is directly linked to the amount of carbonyl contents in many studies [139]. GSH is one of the chief protective proteins against oxidative stress and free radical mediated damage to the cells. It is assumed that when GSH level decreases in the brain following any oxidant exposure, aging or infection, the free radicals invade biomolecules including proteins leading to their structural and functional distortions that consequently give rise to accumulation of abnormal proteins, their aggregation and formation of amyloid like structure. These abnormal proteins are unable to be cleared by proteasomal proteolysis as it is a GSH-dependent process [140]. Thus, the defects in clearance of proteins, either because of their resistance to proteolysis (e.g., amyloid peptides and abnormal prion proteins) or because of defective proteolytic systems, their inhibition or overloading is considered as primary hallmark of NDDs.
LIPID PEROXIDATION IN NDDs
Lipid peroxidation is one of the most obvious consequences of elevated oxidative stress in brain, because lipids present in brain have highest rate of oxygen consumption and is highly vulnerable to oxidative stress [63]. Oxidation of neuronal lipids results in direct damage to cellular organelles and neuronal membrane, which in turn allows free radicals to invade polyunsaturated fatty acids leading to the formation of major lipid peroxidation products like 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA) as the most abundant products, and acrolein as the most reactive one [141, 142]. Lipid peroxidation causes impairment of membrane receptors, loss of membrane fluidity, alteration of intracellular and intercellular communication and transport, and decrease in activity of
membrane-bound enzymes [143]. Moreover, activated lipid free radicals invade on membrane proteins that form protein- protein and lipid-protein cross-links and protein aggregates resulting in loss of neuronal homeostasis, neuronal chaos and brain dysfunction [144]. Prevalent presence of elevated level of lipid peroxidation markers in most of NDD brain samples have been further consolidated by these findings [145].
LINKAGE BETWEEN OXIDATIVE STRESS AND NDDs
The generation of ROS and oxidative damage is believed to be involved in the pathogenesis of NDDs [146]. Oxidative stress results from a misbalance between ROS generation and antioxidant defences [147]. There is evidence that homocysteine-related vitamins, oxidative stress and malnutrition play an important role in AD pathogenesis [148]. Multivitamin-mineral and vitamin supplementation have been reported to modulate chronic unpredictable stress- induced oxidative damage in mice brain [90]. Garlic extract has been reported to induce reno-protective effect against immobilization stress induced changes in rats [45]. Oxidative stress has long been linked to neuronal cell death that is associated with certainneurodegenerative conditions [149].
Mitochondria are deeply involved in the production of ROS through the electron carriers of respiratory chain and have an important role in NDDs [150, 151]. Semi-quantitative histological evaluation of brain iron and ferritin in AD and PD performed in paraffin sections of brain regions that included frontal cortex brainstem, basal ganglia and hippocampus have indicated a selective increase of Fe3+ and ferritin in substantia nigra zona compacta but not in zona reticulate [152].
The enzyme monoamine oxidase present in mitochondrial outer membrane have been reported to catalyze the oxidative deamination of biogenic amines and is a prime source of H2O2 that contributes to an increase in the steady state concentrations of reactive species within cytosol and mitochondrial matrix [153]. H2O2 generated during the outer membrane monoamine oxidase-catalyzed oxidation of amines seems to be a central metabolite contributing through different critical bimolecular reactions to mitochondrial matrix oxidative damage [153]. Oxidative stress has been consistently linked to age-related NDDs leading to the generation of carbonyl proteins and lipid peroxides, and oxidative DNA damage in affected brain tissues [154].
Mitochondrial dysfunction as an early event in neurodegeneration is now well established [154]. Most of the disease specific pathogenic mutant proteins have been shown to target mitochondria, thus promoting oxidative stress and the mitochondrial apoptotic pathway [155]. ROS-mediated defective mitochondria have been reported to accumulate and contribute to disease progression [155].
Damages due to excessive ROS and oxidative stress are the two most common causes of injuries to cells and organisms [156]. The prevalence of NDDs increases with aging and most of research involving oxidative stress and ROS has emerged from works in this field [156]. Oxidative stress has an intimate connection with NDDs, albeit low levels of ROS seem to protect the brain [156].Enhanced lipid peroxidation and decreased antioxidant protection
generate epoxides that may spontaneously react with nucleophilic centres in the cell and thereby covalently bind to RNA, DNA and protein [157], and such reaction may result in carcinogenicity, cytotoxicity, mutagenicity and/or allergy [158].
Although ROS such as hydroxyl radical, H2O2 and superoxide are generated as the natural byproduct of normal oxygen metabolism, they can create oxidative damage via interaction with various biomolecules [8]. As of now, the role of ROS in cellular damage and death is well established with significant implications in a broad range of degenerative alterations like oxidative stress, carcinogenesis, diseases and aging [159]. Superoxide also wreaks havoc by reacting with nitric oxide to form peroxynitrite, which is a highly reactive molecule that subsequently induces cellular and tissue injury [160]. Peroxynitrite is implicated in several diseases, including atherosclerosis, stroke and AD [161].
PD, the most frequent neurodegenerative condition after AD, is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and loss of striatal dopamine content [162]. In the pathology of NDDs, the generation of free radicals, particularly reactive nitrogen species and ROS, are quite harmful as they affect nucleic acids, lipids and proteins [163]. The role of free radicals is now well established in aging [164], and aging is now considered as one of strongest risk factors for PD [165].
Electron microscopy revealed a significant decrease in mitochondrial number during the mitochondrial swelling, chromatin condensation and loss of cristae in aluminium treated rats as compared to control [50]. So, peroxisome proliferator activated receptor gamma co-activator-1α (PGC- 1α) has been reported to be a potent target for aluminium neurotoxicity, thus making it an ideal target to control the damage associated with defective mitochondrial function observed in NDDs [50]. Prion diseases characterize a category of fatal NDDs [166], and reports have increasingly shown that oxidative stress plays an important role in the progression of prion diseases [167]
.
Mitochondrial damage and dysfunction in prion disease progression suggests that mitochondrial damage and neuron cell damage may well be induced by oxidative stress, which can act as the initial cause of a given prion disease [167].Monoamine oxidase B activity increases with age which results in decreased availability of catecholamines in the synaptic cleft [168, 169]. Oxidative deamination of primary monoamine oxidase produces H2O2 and NH3 with established toxicity [170]. Microglia are the primary resident immune cells of the CNS and play a critical role in NDDs [171].
Moreover, over-activated microglia contributes to neurodegenerative processes by producing various neurotoxic factors including free radicals and proinflam- matory cytokines [172]. Fig. (3) summarizes the linkage between oxidative stress and NDDs.
CONCLUSION
The various methods of treatment of NDDs and suggested cures are under clinical trials at different phases with moderate success and efficacy. So far, NDDs can be managed with healthy diet, planned exercise, better patient
Fig. (3). Linkage between oxidative stress and neurodegenerative disorders (NDDs).
care, and symptomatic treatments. However, with the fast pace of advent of modern technology and advanced future research, the treatment of various life threatening NDDs will hopefully become a reality in near future.
LIST OF ABBREVIATIONS
A-T = Ataxia-Telangiectasia AD = Alzheimer’s Disease ALS = Amyotrophic Lateral Sclerosis CNS = Central Nervous System HD = Huntington’s Disease NDDs = Neurodegenerative Disorders NMNAT3 = Nicotinamide Mononucleotide Adenylyltransferase 3
PD = Parkinson’s Disease ROS = Reactive Oxygen Species RVLM = Rostral Ventrolateral Medulla TGF-β = Transforming Growth Factor Beta
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of interest.
ACKNOWLEDGEMENTS
The authors are grateful to the King Fahd Medical Research Center, King Abdulaziz University (Jeddah, Saudi Arabia) for the facilities provided. Financial support from the Russian Science Foundation is greatly acknowledged (RSCF: № 14-23-00160).
REFRENCES
[1] Hroudová J, Singh N, Fišar Z. Mitochondrial Dysfunctions in Neurodegenerative Diseases: Relevance to Alzheimer's Disease.
Biomed Res Int 2014; 2014: 175062.
[2] Mirza Z, Ali A, Ashraf GM, et al. Proteomics approaches to understand linkage between Alzheimer's disease and type 2 diabetes mellitus. CNS Neurol Disord Drug Targets 2014; 13: 213- 25.
[3] Ashraf GM, Greig NH, Khan TA, et al. Protein misfolding and aggregation in Alzheimer's disease and type 2 diabetes mellitus.
CNS Neurol Disord Drug Targets 2014; 13: 1280-93.
[4] Fischer R, Maier O. Interrelation of Oxidative Stress and Inflammation in Neurodegenerative Disease: Role of TNF. Oxid Med Cell Longev 2015; 2015: 610813.
[5] Li J, O W, Li W, et al. Oxidative Stress and Neurodegenerative Disorders. Int J Mol Sci 2013; 14: 24438-75.
[6] Radi E, Formichi P, Battisti C, et al. Apoptosis and oxidative stress in neurodegenerative diseases. J Alzheimer Dis 2014; 42(Suppl 3):
S125-52.
[7] Zhang R, Zhang Q, Niu J, et al. Screening of microRNAs associated with Alzheimer's disease using oxidative stress cell model and different strains of senescence accelerated mice. J Neurol Sci 2014; 338: 57-64.
[8] Uttara B, Singh AV, Zamboni P, et al. Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options. Curr Neuropharmacol 2009; 7: 65-74.
[9] Fulda S, Gorman AM, Hori O, et al. Cellular Stress Responses:
Cell Survival and Cell Death. Int J Cell Biol 2010; 2010: 214074.
[10] Rahal A, Kumar A, Singh V, et al. Oxidative Stress, Prooxidants, and Antioxidants: The Interplay. Biomed Res Int 2014; 2014:
761264.
[11] Shukla V, Mishra SK, Pant HC. Oxidative Stress in Neurodegeneration. Adv Pharmacol Sci 2011; 2011: 572634.
[12] Varçin M, Bentea E, Michotte Y, et al. Oxidative Stress in Genetic Mouse Models of Parkinson’s Disease. Oxid Med Cell Longev 2012; 2012: 624925.
[13] Aliev G, Priyadarshini M, Reddy VP, et al. Oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of Alzheimer disease. Curr Med Chem 2014; 21:
2208-17.
[14] Aliev G, Burzynski G, Ashraf GM, et al. Implication of Oxidative Stress-Induced Oncogenic Signaling Pathways as a Treatment Strategy for Neurodegeneration and Cancer. In: Laher I, Ed.
Systems Biology of Free Radicals and Antioxidants. Springer Berlin Heidelberg, 2011; pp. 2325-47.
[15] Parmar P. Hazards of Free Radicals in Various Aspects of Health – A Review. J Forens Toxicol Pharmacol 2014; 2014: 03.
[16] Berndt N, Holzhütter H-G, Bulik S. Implications of enzyme deficiencies on mitochondrial energy metabolism and reactive oxygen species formation of neurons involved in rotenone-induced Parkinson's disease: a model-based analysis. FEBS J 2013; 280:
5080-93.
[17] Lobo V, Patil A, Phatak A, et al. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacog Rev 2010; 4:
118-26.
[18] Zhou X, Lu X. The role of oxidative stress in high glucose-induced apoptosis in neonatal rat cardiomyocytes. Exp Biol Med 2013; 238:
898-902.
[19] Jabir NR, Firoz CK, Baeesa SS, et al. Synopsis on the linkage of Alzheimer's and Parkinson's disease with chronic diseases. CNS Neurosci Ther 2015; 21: 1-7.
[20] Wiggs JL, Yaspan BL, Hauser MA, et al. Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma. PLoS Genet 2012; 8(4):
e1002654.
[21] Park SN, Back SA, Choung YH, et al. α-Synuclein deficiency and efferent nerve degeneration in the mouse cochlea: a possible cause of early-onset presbycusis. Neurosci Res 2011; 71: 303-10.
[22] Bender A, Krishnan KJ, Morris CM, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 2006; 38: 515-7.
[23] Kaminsky YG, Reddy VP, Ashraf GM, et al. Age-related defects in erythrocyte 2,3-diphosphoglycerate metabolism in dementia. Aging Dis 2013; 4: 244-55.
[24] Kitaoka Y. Tumor necrosis factor-induced optic nerve degeneration and axonal protection. Nippon Ganka Gakkai Zasshi 2013; 117:
878-85.
[25] Lesage S, Brice A. Role of mendelian genes in "sporadic"
Parkinson's disease. Parkinson Relat Disord 2012; 18(1): S66-70.
[26] Petersen AJ, Katzenberger RJ, Wassarman DA. The innate immune response transcription factor relish is necessary for neurodegeneration in a Drosophila model of ataxia-telangiectasia.
Genetics 2013; 194: 133-42.
[27] Trojanowski JQ, Lee VM. "Fatal attractions" of proteins. A comprehensive hypothetical mechanism underlying Alzheimer's disease and other neurodegenerative disorders. Ann NY Acad Sci 2000; 924: 62-7.
[28] Kim KS, Choi SY, Kwon HY, et al. Aggregation of alpha- synuclein induced by the Cu,Zn-superoxide dismutase and hydrogen peroxide system. Free Radic Biol Med 2002; 32: 544-50.
[29] Price NE, Wadzinski B, Mumby MC. An anchoring factor targets protein phosphatase 2A to brain microtubules. Mol Brain Res 1999;
73: 68-77.
[30] Maresca A, la Morgia C, Caporali L, et al. The optic nerve: a
"mito-window" on mitochondrial neurodegeneration. Mol Cell Neurosci 2013; 55: 62-76.
[31] Simón-Sánchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 2009; 41: 1308-12.
[32] Przedborski S, Vila M, Jackson-Lewis V. Series Introduction:
Neurodegeneration: What is it and where are we? J Clin Invest 2003; 111: 3-10.
[33] Lill CM, Bertram L. Towards unveiling the genetics of neurodegenerative diseases. Semin Neurol 2011; 31: 531-41.
[34] Bosco DA, LaVoie MJ, Petsko GA, et al. Proteostasis and Movement Disorders: Parkinson’s Disease and Amyotrophic Lateral Sclerosis. Cold Spring Harb Perspect Biol 2011; 3(10):
a007500.
[35] Bertram L, Tanzi RE. The genetic epidemiology of neurodegenerative disease. J Clin Invest 2005; 115: 1449-57.
[36] Brown RC, Lockwood AH, Sonawane BR. Neurodegenerative Diseases: An Overview of Environmental Risk Factors. Environ Health Perspect 2005; 113: 1250-6.
[37] De Felice A, Ricceri L, Venerosi A, et al. Multifactorial Origin of Neurodevelopmental Disorders: Approaches to Understanding Complex Etiologies. Toxics 2015; 3: 89-129.
[38] Campdelacreu J. Parkinson disease and Alzheimer disease:
environmental risk factors. Neurologia 2014; 29: 541-9.
[39] Migliore L, Coppedè F. Genetic and environmental factors in cancer and neurodegenerative diseases. Mutat Res 2002; 512: 135- 53.
[40] Kanthasamy A, Jin H, Anantharam V, et al. Emerging neurotoxic mechanisms in environmental factors-induced neurodegeneration.
Neurotoxicology 2012; 33: 833-7.
[41] Ahmad A, Rasheed N, Ashraf GM, et al. Brain region specific monoamine and oxidative changes during restraint stress. Can J Neurol Sci 2012; 39: 311-8.
[42] Ahmad A, Rasheed N, Gupta P, et al. Novel "Ocimum sanctum"
compounds modulate stress response: Role of CRF, POMC, GR and HSP-70 in the hypothalamus and pituitary of rats. Med Plants 2013; 5(4): 194-201.
[43] Ahmad A, Rasheed N, Gupta P, et al. Novel Ocimumoside A and B as anti-stress agents: modulation of brain monoamines and antioxidant systems in chronic unpredictable stress model in rats.
Phytomedicine 2012; 19: 639-47.
[44] Aliev G, Horecký J, Vančová O, et al. The Three-Vessel Occlusion as a Model of Vascular Dementia – Oxidative Stress and Mitochondrial Failure as an Indicator of Brain Hypoperfusion. In:
Laher I, Ed. Systems Biology of Free Radicals and Antioxidants.
Springer Berlin Heidelberg, 2009; pp. 2023-32.
[45] Zaidi SK, Ansari SA, Ashraf GM, et al. Reno-protective effect of garlic extract against immobilization stress induced changes in rats.
Asia Pacif J Trop Biomed 2015; 5: 364-9.
[46] Suhail N, Bilal N, Hasan S, et al. Chronic unpredictable stress (CUS) enhances the carcinogenic potential of 7,12- dimethylbenz(a)anthracene (DMBA) and accelerates the onset of tumor development in Swiss albino mice. Cell Stress Chaper 2015;
20: 1023-36.
[47] Hasan S, Suhail N, Bilal N, et al. Chronic unpredictable stress deteriorates the chemopreventive efficacy of pomegranate through oxidative stress pathway. Tumor Biol 2015; Epub ahead of print.
[48] Santos CXC, Anilkumar N, Zhang M, et al. Redox signaling in cardiac myocytes. Free Radic Biol Med 2011; 50: 777-93.
[49] Camara AKS, Lesnefsky EJ, Stowe DF. Potential Therapeutic Benefits of Strategies Directed to Mitochondria. Antioxid Redox Signal 2010; 13: 279-347.
[50] Sharma DR, Sunkaria A, Wani WY, et al. Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression. Toxicol Appl Pharmacol 2013;
273: 365-80.
[51] Ashraf GM, Perveen A, Zaidi SK, et al. Studies on the role of goat heart galectin-1 as an erythrocyte membrane perturbing agent.
Saudi J Biol Sci 2015; 22: 112-6.
[52] Ashraf GM, Perveen A, Tabrez S, et al. Studies on the role of goat heart galectin-1 as a tool for detecting post-malignant changes in glycosylation pattern. Saudi J Biol Sci 2015; 22: 85-9.
[53] Ashraf GM, Rizvi S, Naqvi S, et al. Purification, characterization, structural analysis and protein chemistry of a buffalo heart galectin- 1. Amino Acids 2010; 39: 1321-32.
[54] Ashraf GM, Banu N, Ahmad A, et al. Purification, characterization, sequencing and biological chemistry of galectin-1 purified from Capra hircus (goat) heart. Protein J 2011; 30: 39-51.
[55] Ashraf GM, Perveen A, Zaidi SK, et al. Integrating Qualitative and Quantitative Tools for the Detection and Identification of Lectins in Major Human Diseases. Protein Pept Lett 2015; 22: 954-62.
[56] Ashraf GM, Bilal N, Suhail N, et al. Glycosylation of purified buffalo heart galectin-1 plays crucial role in maintaining its structural and functional integrity. Biochem Mosc 2010; 75: 1450- 7.
[57] Hasan SS, Ashraf GM, Banu N. Galectins – Potential targets for cancer therapy. Cancer Lett 2007; 253: 25-33.
[58] Ashraf GM, Perveen A, Tabrez S, et al. Altered galectin glycosylation: potential factor for the diagnostics and therapeutics of various cardiovascular and neurological disorders. Adv Exp Med Biol 2015; 822: 67-84.
[59] Diers AR, Broniowska KA, Hogg N. Nitrosative stress and redox- cycling agents synergize to cause mitochondrial dysfunction and cell death in endothelial cells. Redox Biol 2013; 1: 1-7.
[60] Nisbet RM, Polanco J-C, Ittner LM, et al. Tau aggregation and its interplay with amyloid-β. Acta Neuropathol 2015; 129: 207-20.
[61] Pacher P, Beckman JS, Liaudet L. Nitric Oxide and Peroxynitrite in Health and Disease. Physiol Rev 2007; 87: 315-424.
[62] Trachootham D, Lu W, Ogasawara MA, et al. Redox Regulation of Cell Survival. Antioxid. Redox Signal 2008; 10: 1343-74.
[63] Hassan I, Chibber S, Khan AA, et al. Cisplatin-induced neurotoxicity in vivo can be alleviated by riboflavin under photoillumination. Cancer Biotherm Radiopharm 2013; 28: 160-8.
[64] Cunningham C. Microglia and neurodegeneration: the role of systemic inflammation. Glia 2013; 61: 71-90.
[65] Villeda SA, Luo J, Mosher KI, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 2011; 477: 90-4.
[66] Frank-Cannon TC, Alto LT, McAlpine FE, et al. Does neuroinflammation fan the flame in neurodegenerative diseases?
Mol Neurodegener 2009; 4: 47.
[67] Liu J, Johnson TV, Lin J, et al. T cell independent mechanism for copolymer-1-induced neuroprotection. Eur J Immunol 2007; 37:
3143-54.
[68] Amor S, Peferoen LAN, Vogel DYS, et al. Inflammation in neurodegenerative diseases--an update. Immunology 2014; 142:
151-66.
[69] Stephan AH, Madison DV, Mateos JM, et al. A dramatic increase of C1q protein in the CNS during normal aging. J Neurosci 2013;
33: 13460-74.
[70] Hung C-W, Chen Y-C, Hsieh W-L, et al. Ageing and neurodegenerative diseases. Ageing Res Rev 2010; 9(1): S36-46.
[71] Sahin E, Depinho RA. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 2010; 464: 520- 8.
[72] Ali A, Sheikh IA, Mirza Z, et al. Application of Proteomic Tools in Modern Nanotechnological Approaches Towards Effective Management of Neurodegenerative Disorders. Curr Drug Metab 2015; 16(5): 376-88.
[73] Fazili NA, Naeem A, Md Ashraf G, et al. Therapeutic Interventions for the Suppression of Alzheimer's disease: Quest for a Remedy.
Curr Drug Metab 2015; 16(5): 346-53.
[74] Syed Mohd Danish Rizvi SS. Role of anti-diabetic drugs as therapeutic agents in alzheimer's disease. 2015; 14: 684-96.
[75] Laitinen LV, Bergenheim AT, Hariz MI. Leksell's posteroventral pallidotomy in the treatment of Parkinson's disease. J Neurosur 1992; 76: 53-61.
[76] Abeliovich A, Doege CA. Reprogramming therapeutics: iPS cell prospects for neurodegenerative disease. Neuron 2009; 61: 337-9.
[77] Kordower JH, Chu Y, Hauser RA, et al. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease.
Nat Med 2008; 14: 504-6.
[78] Young AB. Four decades of neurodegenerative disease research:
how far we have come! J Neurosci 2009; 29: 12722-8.
[79] Jones DR, Moussaud S, McLean P. Targeting heat shock proteins to modulate α-synuclein toxicity. Ther Adv Neurol Disord 2014; 7:
33-51.
[80] Fiszer A, Krzyzosiak WJ. Oligonucleotide-based strategies to combat polyglutamine diseases. Nucl Acids Res 2014; 42(11):
6787-810.
[81] Rajnish Kumar AS. Classification of oral bioavailability of drugs by machine learning approaches: a comparative study. J Comp Interdisc Sci 2011; 2: 1-18.
[82] Shakil S, Ahmad A, Tabrez S, et al. A Region-specific Treatment Strategy To Address The Problem Of Drug Resistance By NDM-1- producing Pathogens. Enzyme Engineer 2013; 2: 1-3.
[83] Sharma A, Kumar R, Varadwaj PK, et al. A comparative study of support vector machine, artificial neural network and bayesian classifier for mutagenicity prediction. Interdiscip Sci 2011; 3: 232- 9.
[84] Jabir NR, Tabrez S, Ashraf GM, et al. Nanotechnology-based approaches in anticancer research. Int J Nanomed 2012; 7: 4391- 408.
[85] Soursou G, Alexiou A, Ashraf GM, et al. Applications of Nanotechnology in Diagnostics and Therapeutics of Alzheimer's and Parkinson's Disease. Curr Drug Metab 2015; 16: 705-12.
[86] Sheikh IA, Mirza Z, Ali A, et al. A proteomics based approach for the identification of gastric cancer related markers. Curr Pharm Des 2015; In press.
[87] Khan NM, Ahmad A, Tiwari RK, et al. Current challenges to overcome in the management of type 2 diabetes mellitus and associated neurological disorders. CNS Neurol Disord Drug Targets 2014; 13: 1440-57.
[88] Tabrez S, Priyadarshini M, Urooj M, et al. Cancer chemoprevention by polyphenols and their potential application as nanomedicine. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2013; 31: 67-98.
[89] Morgan D. Immunotherapy for Alzheimer’s Disease. J Intern Med 2011; 269: 54-63.
[90] Hasan S, Bilal N, Naqvi S, et al. Multivitamin-mineral and vitamins (E + C) supplementation modulate chronic unpredictable stress-induced oxidative damage in brain and heart of mice. Biol Trace Element Res 2011; 142: 589-97.
[91] Malgieri A, Kantzari E, Patrizi MP, et al. Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art. Int J Clin Exp Med 2010; 3: 248-69.
[92] Tanna T, Sachan V. Mesenchymal stem cells: potential in treatment of neurodegenerative diseases. Curr Stem Cell Res Ther 2014; 9:
513-21.
[93] Joyce N, Annett G, Wirthlin L, et al. Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen Med 2010; 5:
933-46.
[94] Herskovits AZ, Guarente L. Sirtuin deacetylases in neurodegenerative diseases of aging. Cell Res 2013; 23: 746-58.
[95] Duan W. Targeting Sirtuin-1 in Huntington’s disease: Rationale and Current Status. CNS Drugs 2013; 27: 345-52.
[96] Aliev G, Ashraf GM, Kaminsky YG, et al. Implication of the nutritional and nonnutritional factors in the context of preservation of cognitive performance in patients with dementia/depression and Alzheimer disease. Am J Alzheimers Dis Other Demen 2013; 28:
660-70.
[97] Kumar H, Lim H-W, More SV, et al. The role of free radicals in the aging brain and Parkinson's disease: convergence and parallelism. Int J Mol Sci 2012; 13: 10478-504.
[98] Ienco EC, LoGerfo A, Carlesi C, et al. Oxidative stress treatment for clinical trials in neurodegenerative diseases. J Alzheimer Dis 2011; 24(2): 111-26.
[99] Dashtipour K, Liu M, Kani C, et al. Iron Accumulation Is Not Homogenous among Patients with Parkinson's Disease. Parkinson Dis 2015; 2015.
[100] Qureshi GA, Memon SA, Memon AB, et al. The emerging role of iron, zinc, copper, magnesium and selenium and oxidative stress in health and diseases. Biogen Amines 2005; 19: 147-69.
[101] Zheng W, Monnot AD. Regulation of Brain Iron and Copper Homeostasis by Brain Barrier Systems: Implication in Neurodegenerative Diseases. Pharmacol Ther 2012; 133: 177-88.
[102] Ganz T. Systemic Iron Homeostasis. Physiol Rev 2013; 93: 1721- 41.
[103] Love S. Demyelinating diseases. J Clin Pathol 2006; 59: 1151-9.
[104] Hoffmann DB, Williams SK, Bojcevski J, et al. Calcium influx and calpain activation mediate preclinical retinal neurodegeneration in autoimmune optic neuritis. J Neuropathol Exp Neurol 2013; 72:
745-57.
[105] Ohta E, Takiyama Y. MRI Findings in Neuroferritinopathy. Neurol Res Int 2012; 2012: 197438.
[106] Choonara YE, Pillay V, du Toit LC, et al. Trends in the Molecular Pathogenesis and Clinical Therapeutics of Common Neurodegenerative Disorders. Int J Mol Sci 2009; 10: 2510-57.
[107] Turnbull S, Tabner BJ, El-Agnaf OM, et al. alpha-Synuclein implicated in Parkinson's disease catalyses the formation of hydrogen peroxide in vitro. Free Radic Biol Med 2001; 30: 1163- 70.
[108] Sugiyama Y, Suzuki T, Yates BJ. Role of the Rostral Ventrolateral Medulla (RVLM) in the Patterning of Vestibular System Influences on Sympathetic Nervous System Outflow to the Upper and Lower Body. Exp Brain Res 2011; 210: 515-27.
[109] Shinohara K, Hirooka Y, Kishi T, et al. Reduction of nitric oxide- mediated γ -amino butyric acid release in rostral ventrolateral medulla is involved in superoxide-induced sympathoexcitation of hypertensive rats. Circul J 2012; 76: 2814-21.
[110] Kishi T, Hirooka Y. Oxidative stress in the brain causes hypertension via sympathoexcitation. Front Physiol 2012; 3: 335.
[111] Fernández-Blanco E, Aguiar-Pulido V, Munteanu CR, et al.
Random Forest classification based on star graph topological indices for antioxidant proteins. J Ther Biol 2013; 317: 331-7.
[112] Elias RJ, Kellerby SS, Decker EA. Antioxidant activity of proteins and peptides. Crit Rev Food Sci Nutr 2008; 48: 430-41.
[113] Lee WL, Huang JY, Shyur LF. Phytoagents for Cancer Management: Regulation of Nucleic Acid Oxidation, ROS, and Related Mechanisms. Oxid Med Cell Longev 2013; 2013: 925804.
[114] Salil G, Nevin KG, Rajamohan T. Coconut kernel-derived proteins enhance hypolipidemic and antioxidant activity in alloxan-induced diabetic rats. Int J Food Sci Nutr 2013; 64: 327-32.
[115] Oh NS, Lee HA, Lee JY, et al. The dual effects of Maillard reaction and enzymatic hydrolysis on the antioxidant activity of milk proteins. J Dairy Sci 2013; 96: 4899-911.
[116] Zhang H, Jiang L, Guo H, et al. The inhibitory effect of milk on the absorption of dietary phenolic acids and the change in human plasma antioxidant capacity through a mechanism involving both milk proteins and fats. Mol Nutr Food Res 2013; 57: 1228-36.
[117] Conway V, Gauthier SF, Pouliot Y. Antioxidant Activities of Buttermilk Proteins, Whey Proteins, and Their Enzymatic Hydrolysates. J Agric Food Chem 2013; 61: 364-72.
[118] Reddy PH, Mao P, Manczak M. Mitochondrial structural and functional dynamics in Huntington's disease. Brain Res Rev 2009;
61: 33-48.
[119] Feissner RF, Skalska J, Gaum WE, et al. Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci 2009; 14:
1197-218.
[120] Aliev G, Ashraf GM, Horecký J, et al. Potential Preventive Effects of Coenzyme Q and Creatine Supplementation on Brain Energy Metabolism in Rats Exposed to Chronic Cerebral Hypoperfusion.
In: Laher I, Ed. Systems Biology of Free Radicals and Antioxidants. Springer Berlin Heidelberg, 2011; pp. 2033-48.
[121] Cui H, Kong Y, Zhang H. Oxidative Stress, Mitochondrial Dysfunction, and Aging. J Signal Trans 2012; 2012: 646354.
[122] Elmore S. Apoptosis: A Review of Programmed Cell Death.
Toxicol Pathol 2007; 35: 495-516.
[123] de Moura MB, dos Santos LS, Van Houten B. Mitochondrial dysfunction in neurodegenerative diseases and cancer. Environ Mol Mutagen 2010; 51: 391-405.
[124] Chatterjee A, Dasgupta S, Sidransky D. Mitochondrial Subversion in Cancer. Cancer Prev Res 2011; 4: 638-54.
[125] Rahman K. Studies on free radicals, antioxidants, and co-factors.
Clin Interv Aging 2007; 2: 219-36.
[126] Garc, xed, a-Escudero V, et al. Deconstructing Mitochondrial Dysfunction in Alzheimer Disease. Oxid Med Cell Longev 2013;
2013: 162152.
[127] Tang Y-P, Gershon ES. Genetic studies in Alzheimer's disease.
Dial Clin Neurosci 2003; 5: 17-26.
[128] Winklhofer KF, Haass C. Mitochondrial dysfunction in Parkinson's disease. Biochem Biophys Acta 2010; 1802: 29-44.
[129] Damiano M, Galvan L, Déglon N, et al. Mitochondria in Huntington's disease. Biochem Biophys Acta 2010; 1802: 52-61.
