Oxidative stress and Parkinsons disease -
Data from Gokce Cokal et al. showed that blood TBARS level was inversely correlated with the duration of PD Gökçe Çokal et al. demonstrated that blood TBARS level was negatively correlated with disease severity and age in PD patients Chen et al. However, since older ages were likely to be associated with longer disease duration or medication use in PD patients, these suggest another possibility that the moderating effect of age on MDA level was secondary to disease severity, disease duration or duration of medication use.
In addition, one study demonstrated strong and significant inverse correlations of uric acid with PD disease duration and daily levodopa dosage Andreadou et al.
Nevertheless, these results highlight the need for continued work on oxidative stress marker levels in PD patients, with control for disease severity, disease duration and medication status, and may provide markers to monitor disease progression in PD patients.
The third limitation of this meta-analysis is that we only included English-language articles, and this may generate publication bias. However, given the very limited number of non-English articles in this field, it is unlikely that this would significantly affect the outcome of our meta-analysis.
Our meta-analysis findings demonstrated elevated peripheral blood concentrations of 8-OhdG, MDA, nitrite and ferritin, and reduced blood levels of catalase, uric acid, glutathione, total-cholesterol in patients with PD.
This finding strengthens the clinical evidence that PD is accompanied by increased oxidative stress response, and manipulation of oxidative stress marker concentrations should be investigated for potential therapeutic strategies of the disease.
YC and QL conceived and designed the study, ZW, XiaL and XixL collected the data. All the authors analyzed and interpreted the data.
YC wrote the manuscript with editing from QL. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study was supported by the National Natural Science Foundation of China , Beijing Natural Science Foundation , the Minzu University Research Fund CXTD03 and the MUC project.
Alimonti, A. Serum chemical elements and oxidative status in Alzheimer's disease, Parkinson disease and multiple sclerosis.
Neurotoxicology 28, — doi: PubMed Abstract CrossRef Full Text Google Scholar. Andreadou, E. Serum uric acid levels in patients with Parkinson's disease: their relationship to treatment and disease duration.
Bhimani, R. Understanding the burden on caregivers of people with Parkinson's: a scoping review of the literature. Braak, H. Staging of brain pathology related to sporadic Parkinson's disease.
Aging 24, — Chen, C. Increased oxidative damage in peripheral blood correlates with severity of Parkinson's disease. Dias, V. The role of oxidative stress in Parkinson's disease. Flatow, J.
Meta-analysis of oxidative stress in schizophrenia. Psychiatry 74, — Gaki, G. Oxidative stress-induced signaling pathways implicated in the pathogenesis of Parkinson's disease. Gökçe Çokal, B.
Serum glutathione peroxidase, xanthine oxidase, and superoxide dismutase activities and malondialdehyde levels in patients with Parkinson's disease. Hauser, D.
Mitochondrial dysfunction and oxidative stress in Parkinson's disease and monogenic parkinsonism. Jankovic, J. Parkinson's disease: clinical features and diagnosis. Jesús, S. Low serum uric acid concentration in Parkinson's disease in southern Spain. Jiang, P. Parkinson's disease: experimental models and reality.
Acta Neuropathol. Kalra, J. Serum antioxidant enzyme activity in Parkinson's disease. Liu, T. A meta-analysis of oxidative stress markers in depression. PLoS ONE e Maass, A. Sleep and non-motor symptoms in Parkinson's disease.
J Neural Transm. Medeiros, M. Iron and oxidative stress in Parkinson's DISEASE: an observational study of injury biomarkers. Moher, D. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. CrossRef Full Text.
Niranjan, R. The role of inflammatory and oxidative stress mechanisms in the pathogenesis of Parkinson's disease: focus on astrocytes. Ouchi, Y. Microglial activation and dopamine terminal loss in early Parkinson's disease. Qin, X. Psychiatry 22, — Association of peripheral blood levels of brain-derived neurotrophic factor with autism spectrum disorder in children: a systematic review and meta-analysis.
JAMA Pediatr. A meta-analysis of peripheral blood nerve growth factor levels in patients with schizophrenia. Aberrations in peripheral inflammatory cytokine levels in Parkinson disease: a systematic review and meta-analysis.
JAMA Neurol. Schrag, M. Oxidative stress in blood in Alzheimer's disease and mild cognitive impairment: a meta-analysis.
Stojkovska, I. Parkinson's disease and enhanced inflammatory response. Surendran, S. Parkinson's disease: oxidative stress and therapeutic approaches. Vinish, M. Altered oxidative stress levels in Indian Parkinson's disease patients with PARK2 mutations.
Acta Biochim. PubMed Abstract Google Scholar. Yuan, Y. Plasma antioxidant status and motor features in de novo Chinese Parkinson's disease patients. Keywords: oxidative stress, Parkinson's disease, peripheral blood, cerebrospinal fluid, meta-analysis. Citation: Wei Z, Li X, Li X, Liu Q and Cheng Y Oxidative Stress in Parkinson's Disease: A Systematic Review and Meta-Analysis.
Received: 12 April ; Accepted: 18 June ; Published: 05 July Copyright © Wei, Li, Li, Liu and Cheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY.
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Introduction Parkinson's disease PD is the second most common neurodegenerative disease after Alzheimer's disease Bhimani, Methods The meta-analyses implemented in this study conform to the instructions that are recommended by the PRISMA statement Preferred Reporting Items for Systematic Reviews and Meta-analysis; Moher et al.
Search Strategy and Study Selection A systematic review of peer-reviewed English articles from the databases of PubMed and Web of Science were performed by three investigators from September to March Data Extraction One investigator extracted the data from the included articles in the meta-analysis, and the data was verified by another investigator.
Statistical Analysis All statistical analyses were performed by the Comprehensive Meta-analysis Version 2 software. Results The initial search generated 6, records from PubMed database and 5, records from Web of Science, and then the titles and abstracts were screened.
Figure 1. PRISMA flowchart of the literature search. Table 2. Summary of Comparative Outcomes for Measurements of CSF Marker Levels.
x PubMed Abstract CrossRef Full Text Google Scholar. Keywords: oxidative stress, Parkinson's disease, peripheral blood, cerebrospinal fluid, meta-analysis Citation: Wei Z, Li X, Li X, Liu Q and Cheng Y Oxidative Stress in Parkinson's Disease: A Systematic Review and Meta-Analysis.
Parkin is also covalently modified by DA and becomes insoluble, which leads to inactivation of its E2 ubiquitin ligase activity [ 10 ]. Catechol-modified parkin has been detected in the substantia nigra but not other regions of the human brain, and parkin insolubility is observed in PD brain [ 10 ].
In addition, DA quinone modification of UCH-L1 and DJ-1 has also been observed both in brain mitochondrial preparations and DAergic cells [ 11 ]. Since both UCH-L1 and DJ-1 contain a cysteine residue that is important for their activity [ 12 , 13 ] and their oxidative modification at cysteine has been observed in PD [ 14 , 15 ], the DA quinone modification is likely the cause of inactivation of these enzymes.
DA quinone has also been shown to cause inactivation of the DA transporter and tyrosine hydroxyalse [ 16 ]. In addition, it leads to mitochondrial dysfunction [ 17 ] and swelling of brain mitochondria [ 18 ]. Accordingly, the subunits of Complex I and Complex III of the electron transport chain, whose dysfunction will deter mitochondrial respiration and cause ROS production, were also shown to be targets of DA quinone modification [ 11 ].
DA metabolites have also been shown to induce proteasomal inhibition, which can lead the cells to undergo apoptosis [ 19 ]. Furthermore, DA quinone can cyclize to become the highly reactive aminochrome, whose redox-cycling leads to generation of superoxide and depletion of cellular NADPH, and which ultimately polymerizes to form neuromelanin.
Neuromelanin in turn can exacerbate the neurodegenerative process by triggering neuroinflammation [ 20 ]. Moreover, hydrogen peroxide is generated during DA metabolism by monoamine oxidase and is subsequently converted to the highly reactive hydroxyl radical in the presence of transition metal ions [ 6 ], contributing to oxidative stress.
Evidence of the existence of in vivo DA oxidation and its toxicity is also available. Neuromelanin, the final product of DA oxidation, is accumulated in the nigral region of the human brain [ 21 ]. Higher levels of cysteinyl-catechol derivatives are found in postmortem nigral tissues of PD patients compared to age-matched controls, suggesting cytotoxic nature of DA oxidation [ 22 ].
In animals, DA directly injected into the striatum caused selective toxicity to DAergic terminals that was proportional to the levels of DA oxidation and quinone-modified proteins [ 23 ]. Mice expressing a low level of ventricular monoamine transporter-2, presumably with increased cytosolic DA level, showed evidence of DA oxidation and age-dependent loss of nigral DA neurons [ 24 ].
Mitochondrial dysfunction is another source of oxidative stress associated with the pathogenesis of PD. Neurons depend heavily on aerobic respiration for ATP, and hydrogen peroxide and superoxide radicals are normally produced during oxidative phosphorylation as byproducts in the mitochondria.
Any pathological situation leading to mitochondrial dysfunction can cause a dramatic increase in ROS and overwhelm the cellular antioxidant mechanisms. Oxidative stress causes peroxidation of the mitochondria-specific lipid cardiolipin, which results in release of cytochrome c to the cytosol, triggering apoptosis.
Because DAergic neurons are intrinsically more ROS-generating and vulnerable as described above, any event that triggers further oxidative stress can be harmful to the cell. Damage to mitochondrial Complex I in the electron transport chain causes leakage of electrons, which in turn causes ROS generation.
As such, the Complex I inhibitors rotenone and 1-methylphenyl-1,2,3,6-tetrahydropyridine MPTP , when injected intraperitoneally, exert preferential cytotoxicity to the DAergic neurons [ 25 ].
Indeed, reduced Complex I activity has been found in tissues from subjects with PD [ 26 ]. Higher numbers of respiratory chain deficient DA neurons have been found in PD patients than in age-matched controls [ 27 ].
A line of evidence for mitochondrial dysfunction related to oxidative stress and DAergic cell damage comes from the findings that mutations in genes of mitochondrial proteins parkin, DJ-1, and PINK are linked to familial forms of PD.
Cells derived from patients with parkin gene mutation show decreased Complex I activity [ 28 ]. Mice deficient in parkin gene have shown reduced striatal respiratory chain activity along with oxidative damage [ 29 ]. Mutations in PINK1 induce mitochondrial dysfunction including excess free radical formation [ 30 ].
DJ-1 is a mitochondrially enriched, redox-sensitive protein and an atypical peroxiredoxin-like peroxidase that scavenges H 2 O 2 , and DJ-1 KO mice accumulate more ROS and exhibit fragmented mitochondrial phenotype [ 31 ]. In addition, α-synuclein, although mostly cytosolic, seems to interact with mitochondrial membranes and to inhibit Complex I [ 32 ].
Mice overexpressing mutant α-synuclein exhibit abnormalities in the mitochondrial structure and function [ 33 ]. Neuronal loss in PD is associated with chronic neuroinflammation, which is controlled primarily by microglia, the resident innate immune cells and the main immune responsive cells in the central nervous system.
Microglia are activated in response to injury or toxic insult as a self-defensive mechanism to remove cell debris and pathogens. When activated, they release free radicals such as nitric oxide and superoxide, which can in turn contribute to oxidative stress in the microenvironment.
This is thought to be exacerbated by inflammatory signals generated by molecules released from damaged neurons, leading to induction of reactive microgliosis. The oxidized or ROS-induced molecules that are released from damaged nigral DAergic neurons and trigger microglial activation include neuromelanin, α-synuclein, and active form of MMP-3, as described below.
Neuromelanin is the dark insoluble polymer produced from DA oxidation and confers the dark pigmentation to the substantia nigra. Insoluble extraneuronal neuromelanin granules have been observed in patients of juvenile PD [ 38 ] and idiopathic PD, as well as those with MPTP-induced parkinsonism [ 39 ].
Addition of neuromelanin extracted from PD brain to microglia culture caused increases in and nitric oxide [ 40 ]. Intracerebral injection of neuromelanin caused strong microglia activation and a loss of DAergic neurons in the substantia nigra [ 20 ].
Neuromelanin appears to remain for a very long time in the extracellular space [ 39 ] and thus thought to be one of the molecules responsible for inducing chronic neuroinflammation in PD.
Although mostly intracellular, a fraction of α-synuclein fibril is released from neurons [ 41 ], and α-synuclein is found in the cerebrospinal fluid from PD patients and normal subjects [ 42 ], and in human plasma [ 43 ].
The addition of aggregated human α-synuclein to a primary mesencephalic neuron-glia culture causes activation of microglia and DAergic neurodegeneration, and this cytotoxicity does not occur in the absence of microglia [ 44 ].
In addition, neuron-derived α-synuclein stimulates astrocytes to produce inflammatory modulators that augment microglial chemotaxis, activation and proliferation [ 45 ]. Nitration of α-synuclein, presumably due to increased nitric oxide, facilitates the neuroinflammatory responses [ 46 ].
More recently, it has been shown that transgenic mice expressing mutant α-synuclein developed persistent neuroinflammation and chronic progressive degeneration of the nigrostriatal DA pathway when inflammation was triggered by a low level of lipopolysaccharide [ 47 ]. The active form of MMP-3 is increased in response to oxidative stress in DAergic cells, and MMP-3 causes activation of microglia, which in turn would generate reactive nitrogen species and ROS [ 48 - 51 ].
In MMP-3 knockout mice, the microglial activation following exposure to MPTP is abrogated, and this is accompanied by a lower level of superoxide production compared to their wild type [ 52 ]. MMP-3 causes cleavage of protease activated receptor-1 PAR-1 [ 53 ], whose removal of N-terminal extracellular domain renders the remaining domain acting as a tethered ligand, subsequently triggering generation of intracellular signals [ 54 ] and activation of microglia [ 55 ].
Furthermore, MMP-3 participates in formation of the biologically active IL-1β from the proform [ 56 ]. In addition, MMP-3 participates in expression of inflammatory cytokines in activated microglia [ 57 ], and conversely, MMP-3 is induced by free radicals and the cytokines in these cells [ 58 ].
Therefore, a vicious cycle may exist, where MMP-3, whose expression is induced by oxidative stress, is released from DAergic neurons and leads to production of free radicals and cytokines in the microglia.
MMP-3 can also cause degradation of blood brain barrier and infiltration of neutrophils, which can further contribute to neuroinflammation [ 59 ]. Currently, there is no therapy clinically available that delays the neurodegenerative process itself, and therefore modification of the disease course via neuroprotective therapy is an important unmet clinical need.
As described above, oxidative stress originating from DA metabolism, neuroinflammation and mitochondrial dysfunction is thought to be the hallmark of PD pathogenesis, and antioxidant mechanism should prove to be an effective neuroprotective therapy for PD. However, no direct antioxidant, such as vitamin C, vitamin E, and coenzyme Q10, has provided disease modification in PD patients.
Attempts have also been made to design therapies against neuroinflammation. Doxycycline, a tetracycline derivative that penetrates the blood brain barrier, suppresses the increase in MMP-3 gene expression as well as nitric oxide and inflammatory cytokines and provides protection of the nigral DAergic neurons in the MPTP-induced mouse model of PD [ 60 ].
A novel synthetic compound 7-hydroxymethoxypropionyl-1,2,3,4-tetrahydroisoquinoline, which downregulated expression of MMP-3 along with IL-1β, TNF-α and cyclooxygenase-2, provided neuroprotection in both cell culture and animal models of PD [ 61 ]. The enzyme NAD P H:quinone reductase DT-diaphorase; NAD P H- quinone acceptor oxidoreductase; EC 1.
Since DA and its metabolites have been implicated in the pathogenesis of PD, NQO1 may exert a protective effect against such conditions. Indeed, NQO1 protected against damaging effects of cyclized quinones and oxidative stress induced during their redox cycling [ 19 ].
Induction of NQO1 by sulforaphane protected against neurocytotoxicity associated with DA quinone in vitro [ 62 ] and against MPTP-elicited toxicity in vivo [ 63 ]. In addition, NQO1 is known to maintain both α-tocopherol and coenzyme Q10 in their reduced, antioxidant state [ 64 ].
While NQO1 is abundant in the liver where it participates in the phase II detoxification, the enzyme is also expressed in the brain [ 65 ]. In addition to its predominant expression in astrocytes [ 66 ], NQO1 is also expressed, albeit to a lesser degree, in DArgic neurons in the substantia nigra [ 67 ].
Moreover, a marked increase in the neuronal expression of NQO1 was consistently observed in the Parkinsonian substantia nigra [ 67 ]. A polymorphism CT of NQO1 that results in a decrease or total loss of its expression is reported to be associated with PD [ 68 ], although another group reported no such association [ 69 ].
Cellular induction of NQO1 is achieved by the transcription factor Nrf-2 binding to a cis-acting enhancer sequence termed antioxidant response element ARE. Nrf-2 is normally present in the cytosol bound by the cytosolic protein keap1, but is released and translocated into the nucleus in response to a variety of cellular or exogenous signals.
Ways to induce NQO1 expression and Nrf2 activation should therefore serve as viable approaches to develop neuroprotective therapy for PD. PD pathogenesis seems to be closely related to oxidative stress due to ROS generated by DA metabolism, mitochondrial dysfunction and neuroiniflammation.
Because there is no current therapy available that delays the neurodegenerative process, development of drugs that will modify the course of PD is crucial. Intensive studies are being carried out worldwide toward understanding the molecular mechanism of cell demise in PD, and the results are actively being utilized in attempts to design disease-modifying drugs for this devastating disease.
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Schapira AH, Jenner P. Etiology and pathogenesis of Parkinson's disease. Mov Disord ; Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M, Schapira AH, Halliday G. Missing pieces in the Parkinson's disease puzzle.
Nat Med ; Bosco DA, Fowler DM, Zhang Q, Nieva J, Powers ET, Wentworth P, Lerner RA, Kelly JW. Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization. Nat Chem Biol ; Nakabeppu Y, Tsuchimoto D, Yamaguchi H, Sakumi K.
Oxidative damage in nucleic acids and Parkinson's disease. J Neurosci Res ; Zeevalk GD, Razmpour R, Bernard LP. Glutathione and Parkinson's disease: is this the elephant in the room?.
Biomed Pharmacother ; Halliwell B. Reactive oxygen species and the central nervous system. J Neurochem ; Conway KA, Rochet JC, Bieganski RM, Lansbury PT. Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science ; Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D, Cuervo AM.
Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest ; Lotharius J, Brundin P. Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease. Hum Mol Genet ; LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ.
Dopamine covalently modifies and functionally inactivates parkin. Van Laar VS, Mishizen AJ, Cascio M, Hastings TG. Proteomic identification of dopamine-conjugated proteins from isolated rat brain mitochondria and SH-SY5Y cells.
Neurobiol Dis ; Nishikawa K, Li H, Kawamura R, Osaka H, Wang YL, Hara Y, Hirokawa T, Manago Y, Amano T, Noda M, Aoki S, Wada K. Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants.
Biochem Biophys Res Commun ; Qu W, Fan L, Kim YC, Ishikawa S, Iguchi-Ariga SM, Pu XP, Ariga H. Kaempferol derivatives prevent oxidative stress-induced cell death in a DJdependent manner.
J Pharmacol Sci ; Choi J, Levey AI, Weintraub ST, Rees HD, Gearing M, Chin LS, Li L. Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases. J Biol Chem ; Choi J, Sullards MC, Olzmann JA, Rees HD, Weintraub ST, Bostwick DE, Gearing M, Levey AI, Chin LS, Li L.
Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. Kuhn DM, Arthur RE, Thomas DM, Elferink LA. Tyrosine hydroxylase is inactivated by catechol-quinones and converted to a redox-cycling quinoprotein: possible relevance to Parkinson's disease.
Lee CS, Han JH, Jang YY, Song JH, Han ES. Neurochem Int ; Berman SB, Hastings TG. Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson's disease. Zafar KS, Inayat-Hussain SH, Ross D.
A comparative study of proteasomal inhibition and apoptosis induced in N27 mesencephalic cells by dopamine and MG Zecca L, Wilms H, Geick S, Claasen JH, Brandenburg LO, Holzknecht C, Panizza ML, Zucca FA, Deuschl G, Sievers J, Lucius R. Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease.
Acta Neuropathol ; Zecca L, Zucca FA, Wilms H, Sulzer D. Neuromelanin of the substantia nigra: a neuronal black hole with protective and toxic characteristics. Trends Neurosci ; Spencer JP, Jenner P, Daniel SE, Lees AJ, Marsden DC, Halliwell B.
Conjugates of catecholamines with cysteine and GSH in Parkinson's disease: possible mechanisms of formation involving reactive oxygen species. Rabinovic AD, Lewis DA, Hastings TG.
Role of oxidative changes in the degeneration of dopamine terminals after injection of neurotoxic levels of dopamine. Neuroscience ; Caudle WM, Colebrooke RE, Emson PC, Miller GW. Altered vesicular dopamine storage in Parkinson's disease: a premature demise. Betarbet R, Sherer TB, Greenamyre JT.
Animal models of Parkinson's disease. Bioessays ; Parker WD, Boyson SJ, Parks JK.
Thank you for visiting nature. You oxidatove using oxiddative browser Bone health and weight-bearing exercises with limited support for CSS. To Antioxidant-rich snacks the best experience, we Bone health and weight-bearing exercises you use a Parkinsnos up to date browser Parkinsojs turn off compatibility mode strses Oxidative stress and Parkinsons disease Energy and metabolism supplements. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The specific interactions between mitophagy and reactive oxygen species ROS have attracted considerable attention even though their exact interplay in PD has not been fully elucidated. We highlight the interactions between ROS and mitophagy, with a focus on the signalling pathways downstream to ROS that triggers mitophagy and draw attention to potential therapeutic compounds that target these pathways in both experimental and clinical models.
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