Lipophilic antioxidants in neurodegenerative diseases

Clinica Chimica Acta 485 (2018) 79–87

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Review

Lipophilic antioxidants in neurodegenerative diseases a

b,c

d

a,⁎

T

Kuo-Hsuan Chang , Mei-Ling Cheng , Mu-Chun Chiang , Chiung-Mei Chen a

Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan, Taiwan Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan d Cheltenhem General Hospital, Gloucestershire, United Kingdom b c

A R T I C LE I N FO

A B S T R A C T

Keywords: Lipophilic antioxidant Vitamin A Vitamin E Coenzyme Q10 Docosahexaenoic acid Eicosapentaenoic acid Oxidative stress Neurodegeneration Alzheimer's disease Parkinson's disease Huntington's disease Amyotrophic lateral sclerosis

Oxidative stress is commonly involved in the pathogenesis of various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. Therefore, lipophilic antioxidants, such as vitamin A, carotinoids, vitamin E, coenzyme Q10, docosahexaenoic acid and eicosapentaenoic acid, have received increasing attention as therapeutic and preventive intervention for neurodegenerative diseases. Although difficulties exist with clinical studies due to the nature of the long-standing progression of neurodegenerative diseases, findings in cell and animal models, as well as biomarker studies have implied a relationship between lipophilic antioxidants and neurodegeneration. By reviewing current findings and their implication in neurodegenerative diseases, we conclude that although none of these lipophilic antioxidants have yet provided clear-cut clinical evidence toward beneficial effects in neurodegenerative diseases, they could demonstrate neuroprotection in cellular and/or animal studies. Results from future multidisciplinary studies with optimization of factors including drug dosage, delivery route and chemical structure may provide us with novel treatments for neurodegenerative diseases using lipophilic antioxidants.

1. Introduction There is evidence to suggest that oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases. Oxidative stress occurs when there is an excess of free radicals and/or a reduction in antioxidant levels. It has been well known that an increase in aerobic metabolism increases the production of intracellular reactive oxygen species (ROS), which in turn enhances the autocatalysis of lipid peroxidation thereby damaging cell membranes. Furthermore, ROS disrupt signal and structural proteins leading to misfolding and aggregation [1], and also interrupt transcription via DNA/RNA oxidization [2, 3]. Among various tissues in the body, the central nervous system (CNS) is particularly vulnerable to oxidative stress due to its high oxygen utilization and high content of polyunsaturated fatty acids [4]. Antioxidants have physiological defence mechanisms against oxidative stress by neutralizing free radicals and prohibiting the chain reactions that contribute to various diseases and premature aging. Thus, suppressing oxidative stress by antioxidants is considered as a therapeutic strategy in neurodegenerative diseases. Lipophilic antioxidants, such as vitamin A, carotinoids, vitamin E, coenzyme Q10 (CoQ10), docosahexaenoic (DHA) and eicosapentaenoic acids (EPA), are important nutrients that are drawing growing attention

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in treating neurodegenerative diseases. These compounds may prevent cell membranes from damage of free radicals by readily scavenging peroxyl radicals, and thus prevent lipid, protein, and DNA oxidation [5]. Several lines of experimental evidence, mainly in animal studies support the hypothesis that a diet supplemented with lipophilic antioxidants may aid in halting the progression of neurodegeneration. This review summarizes current findings and the significance of these lipophilic antioxidants as a potential treatment for neurodegenerative diseases. 2. Oxidative stress and neurodegenerative diseases 2.1. Aggregation of misfolded proteins in neurodegenerative diseases Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS) share a similarity in the aggregation of diseasespecific misfolded proteins in the CNS. AD is characterized by the presence of two pathological features in patients' brains: senile plaques and neurofibrillary tangles [6]. Senile plaques are composed of β amyloid peptides (Aβ), fragments of the amyloid peptide precursor protein (APP) [7, 8]. The transmembrane protein APP is critical to the

Corresponding author at: Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, 333, Kueishan, Taoyuan, Taiwan. E-mail address: [email protected] (C.-M. Chen).

https://doi.org/10.1016/j.cca.2018.06.031 Received 1 May 2018; Received in revised form 20 June 2018; Accepted 21 June 2018 Available online 22 June 2018 0009-8981/ © 2018 Elsevier B.V. All rights reserved.

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38, 48], neuroprastanes [39, 48], HNE [40–44] and malondialdehyde (MDA) [45–47], in post-mortem brain tissues of patients with neurodegenerative diseases. Significant increases of free HNE in cerebrospinal fluid was found and higher levels of HNE were correlated to the degree of cognitive impairment in AD [49–52]. Similarly, HNE in cerebrospinal fluid was also elevated in PD [53] and ALS patients [54, 55]. HNE levels were significantly elevated in the sera of sporadic ALS patients compared with the controls and positively correlated with extent of disease [54]. High plasma or serum levels of MDA has been identified in patients with AD [56–64], PD [65–68], HD [69, 70] and ALS [71, 72], although serum MDA levels were similar in both the PD and control groups in another two studies [73, 74]. The level of F2isoprostanes was also increased in the cerebrospinal fluids (CSFs) of AD [75, 76] and HD patients [77]. In the plasma of patients with PD, the level of F2-isoprostanes was also higher compared to controls [78], where as another study showed no difference in plasma F2-isoprostanes between PD or AD and the normal controls [79]. High urinary levels of F2-isoprostanes were found in ALS patients [80]. Moreover, significantly elevated levels of hydroxyoctadecanoic acid and oxidatively modified peroxiredoxin-2 and 6 were also found in the plasma of patients with AD [81], while hydroxyoctadecanoic acid levels are in keeping with the clinical dementia severity score. In PD patients, the levels of plasma hydroxyeicosatetraenoic acids, 7β- and 27-hydroxycholesterol, 7-ketocholesterol, and neuroprostanes were all elevated compared to controls with a negative correlation between hydroxyeicosatetraenoic acids and the cumulative intake of levodopa [78].

survival, growth and repair of neurons [9, 10]. In the metabolism of APP in AD, β- and γ-secretase cleave APP into small peptides called Aβ that are 39–43 amino acids in length.[11]. Aβ aggregates to form oligomers and other polymerized structures that may be toxic to neurons [12]. The main component of neurofibrillary tangles is the cytoskeleton protein known as the tau protein, in a hyperphosphorylated form [13]. The abnormal accumulation of hyperphosphorylated tau protein also appears to be involved in neurodegeneration [14]. In PD, the protein αsynuclein (αSYN) binds to ubiquitin and forms cytoplasmic inclusions, named Lewy bodies [15]. Aberrant accumulation and post-translational modification of αSYN result in death of dopaminergic neurons, particularly in the ventral midbrain [16, 17]. The genetic cause of HD is a long polyglutamine tract encoded by expanded CAG trinucleotide repeats in the exon 1 of HUNTINTIN (HTT) [18]. The polyQ expansion can cause a conformational change in the mutant protein leading to intranuclear and intracytoplasmic aggregates, which subsequently lead to neurodegeneration particularly in the striatum and cerebral cortex [19]. Abnormal protein inclusions are also found in the motor neurons of ALS patients [20]. These inclusions often contain ubiquitin, and generally incorporate one of the ALS-associated proteins: superoxide dismutase 1 (SOD1), TAR DNA binding protein (TDP-43) or FUS RNA binding protein (FUS) [20]. The aberrant accumulation of ubiquitin and misfolded proteins affects the normal function of the proteasome machinery, impairing normal protein degradation and results in the degeneration of motor neurons [21]. 2.2. Oxidative stress mediates neurodegenerative diseases

4. Lipophilic antioxidants as biomarkers in neurodegenerative diseases

In neurodegenerative diseases, misfolded proteins result in the ROS toxicity to neurons. For example, ROS is generated during the process of Aβ aggregation by activating pro-oxidative enzyme NADPH-dependent oxidase [22] and reducing divalent metal ions (Fe2+, Cu2+) [23]. This accumulation of ROS results in lipid peroxidation and subsequently generates cytotoxic 4-hydroxynonenal (HNE) [24]. HNE impairs membrane Ca2+ pumps and increases Ca2+ influx through voltagedependent and ligand-gated calcium channels [25], contributing to excessive intracellular Ca2+ load and subsequent neurotoxicity [26]. ROS also mediates Aβ-induced impairment in long-term potentiation (LTP). LTP was impaired in wild-type hippocampal slices treated with exogenous Aβ and in slices from aAPP/PS1 mutant AD mouse model [27]. In PD, exposure of dopaminergic neurons to HNE-αSYN, a posttranslational modifications of αSYN caused by oxidative stress, triggers the production of intracellular ROS that precedes neuronal cell death [17]. In addition, oxidative stress reduces the clearance of Aβ and αSYN by inducing microglial senescence [28] and affecting ubiquitin-proteasome system and mitophagy [29]. Substantial evidence has shown a role for oxidative damage in the pathogenesis of HD [19, 30]. Accumulation of HTT decreases the expression of the antioxidant protein PRX1, while overexpression of PRX1 suppresses HTT-induced toxicity [31]. Various missense mutations of TDP-43 are identified in patients with ALS [32]. Mutant TDP-43 leads to lipid peroxidation, oxidative damage and mitochondrial dysfunction [33]. Overexpression of TDP-43 also up-regulates markers for oxidative stress, apoptosis, and necrosis [34].

4.1. Vitamin A and carotenoids Vitamin A and provitamin A carotenoid are considered to be antioxidant compounds. Low serum and plasma levels of vitamin A [61, 63, 82–87], α-carotene, [63, 85, 86, 88], β-carotene [83–85, 87–90], lycopene [63, 82, 83, 85, 88] and lutein [63, 88] in AD patients have been reported in several studies, whereas other studies have shown the conflicting results in plasma α-carotene [84, 98], β-carotene [86, 100], lycopene [86, 89, 90], and lutein [85] levels of AD (Table 1). Increased cognitive decline was inversely correlated with serum vitamin A level in the elderly [91]. A higher plasma concentration of β-carotene was also associated with better memory performance in the elderly [92]. Higher blood levels of lutein and lycopene were also significantly associated with a decrease risk of AD [93, 94]. Lower plasma level of vitamin A level has been reported in PD patients (Table 1) [82]. Serum levels of α- and β-carotenes and lycopene were reduced and inversely correlated with the Hoehn and Yahr stage and UPDRS motor score in PD patients [95]. 4.2. Vitamin E Vitamin E, a major lipophilic antioxidant in the brain [96], protects lipids against oxidative stress. Low levels of vitamin E have been observed in the CSF of AD patients [97], but another two did not find the differences [98, 99]. A number of studies demonstrate low levels of vitamin E in the blood of AD patients compared to controls [61, 63, 82, 83, 85–88, 90, 97, 100], whereas other studies reported no difference [89, 98, 99, 101–105] (Table 1). The level of plasma vitamin E was significantly lower in PD patients [68] (Table 1). However, conflicting results in PD have also been reported [103, 105–107].

3. Lipid peroxidation as biomarkers in neurodegenerative diseases Lipid peroxidation has been shown to induce disturbance in membrane organization and functional loss/modification of proteins and DNA. F2-isoprostanes are products of free radical damage to arachidonic acid (AA) [35]. F3-isoprostanes are the products of EPA peroxidation and neuroprostanes are generated analogously from docosahexaenoic acid (DHA) [36]. A number of studies have demonstrated increased levels of lipid peroxidation markers, such as isoprostanes [37,

4.3. Coenzyme Q10 Coenzyme Q10 (CoQ10), also known as ubiquinone is a component of the electron transport chain [108]. It is located in the inner membrane of mitochondria and plays a major role in ATP synthesis [108]. 80

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Table 1 Lipophilic antioxidant as potential biomarkers in neurodegenerative diseases. Candidate marker

Disease

Origin

Change

Reference

Vitamin A

AD PD AD AD PD AD AD PD AD AD PD AD AD AD AD AD AD PD PD AD HD PD PD

Blood Blood Blood Blood Blood Blood Blood Blood Blood Blood Blood Blood Blood Blood Blood CSF CSF Blood Blood Blood Blood Blood Platelet

↓ (versus NC) ↓ (versus NC) ↓ (versus NC) ≅ (versus NC) ↓ (versus NC) ↓ (versus NC) ≅ (versus NC) ↓ (versus NC) ↓ (versus NC) ≅ (versus NC) ↓ (versus NC) ↓ (versus NC) ≅ (versus NC) ↓ (versus NC) ≅ (versus NC) ↓ (versus NC) ≅ (versus NC) ↓ (versus NC) ≅ (versus NC) ≅ (versus NC) ↓ (versus NC) ↑ (versus NC) ↑ (versus NC)

[61, 63, 82–87] [82] [63, 85, 86, 88] [84, 98] [95] [83–85, 87–90] [86, 100] [95] [63, 82, 83, 85, 88] [86, 89, 90] [95] [63, 88] [85] [61, 63, 82, 83, 85–88, 90, 97, 100] [89, 98, 99, 101–105] [97] [98, 99] [68] [103, 105–107] [89, 90, 110] [113] [112] [111]

α-Carotene

β-Carotene

Lycopene

Lutein Vitamin E

CoQ10 Oxidized CoQ10/total CoQ10

AD: Alzheimer's disease; CoQ10: coenzyme Q10; CSF: cerebrospinal fluid; HE: Huntington's disease; NC: normal control; PD: Parkinson’s disease; ↑: up-regulation; ↓: down-regulation; ≅: unchanged.

mice [115]. Carotenoids protect lipid membranes through free radical entrapment and oxidation interference [116]. In a randomised doubleblind placebo-controlled study, treatment with astaxanthin, a xanthophyll carotenoid with highly potent anti-peroxidative activity, displayed improved multiple domains of cognitive function in healthy subjects with age-related forgetfulness [117, 118]. However, supplementary with multi-carotinoids did not improve cognitive function in AD patients [119]. Likewise, oral supplementation with lutein/zeaxanthin had no statistically significant effect on cognitive function in a double-blind randomized clinical trial [120]. In the N-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP; a parkinsonism-inducing neurotoxin)-induced mouse model of PD, pretreatment with β-carotene or lutein demonstrated neuroprotective effects against MPTP-induced neurotoxicity [121–123]. Lycopene, another carotenoid compound, reduces oxidative stress and cognitive decline in a rotenone-induced rat model of PD [124]. Rats deprived of vitamin A developed atrophy and muscular weakness mainly in the hind limbs and a marked loss of spinal cord motor neurons [125]. Epidemiological studies have demonstrated significant risk reduction of PD in individuals who consume foods containing carotenoids and β-carotene compared to the control group [126]. Although epidemiolgical studies in AD and PD have suggested the beneficial risk reduction of and vitamin A/carotenoids, more clinical investigations are warranted to clarify their role in treating neurodegenerative diseases.

CoQ10 is also a scavenger of free radicals and has antioxidant activity which protects mitochondrial and lipid membranes against the ROS generated during oxidative phosphorylation [109]. Lower levels of serum CoQ10 and a lower ratio of CoQ10/total cholesterol were found in one study to be associated with an increased risk of developing dementia in the general population. However, other studies showed no significant differences in serum CoQ10 level between AD patients or vascular dementia and the control population [110]. Moreover, population-based cross-sectional studies found that there were no differences in serum CoQ10 level between demented patients and controls [89, 90] (Table 1). Percentages of oxidized CoQ10 in total CoQ10 level in platelets [111] and plasma [112] of PD patients were significantly higher compared with controls (Table 1). Similarly, HD patients had marked lower serum level of CoQ10 than controls (Table 1), indicating a lower anti-oxidant capacity [113]. 5. Potential application of lipophilic antioxidants in treating neurodegenerative diseases 5.1. Vitamin A and carotenoids Vitamin A and carotenoids have shown anti-oxidative, cell protective, and anti-aggregative effects in in vitro and in vivo models. However, there is a lack of robust clinical trials exploring the use of vitamin A or carotenoids in the treatment of neurodegenerative diseases. Increasing evidence suggests that Vitamin A deficiency contributes to the pathogenesis of AD. Serum Vitamin A deficiency is correlated with cognitive decline in the elderly [91]. Marginal vitamin A deficiency promotes beta-site APP cleaving enzyme 1 (BACE1)mediated Aβ production and neuritic plaque formation, and therefore exacerbates memory deficits in APP/PS1 double-transgenic mice. Supplementing a therapeutic dose of vitamin A ameliorated the marginal vitamin A deficiency-induced memory deficits [91]. Vitamin A has previously been demonstrated to cause inhibitory effects on the oligomerization of Aβ [114]. Eight-week intraperitoneal treatment with vitamin A decreases brain Aβ deposition and tau phosphorylation in APP/ PS1 transgenic mice [115]. Furthermore, vitamin A-treatment decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory in APP/PS1

5.2. Vitamin E Lower α-tocopherol levels in plasma might contribute to the cognition impairment in older Chinese adults [127] and higher levels of serum γ-tocopherol and tocotrienol are associated with lower risk of development of cognitive impairment in a follow-up study in Finnish cohort of healthy older adults [128]. An association between increased vitamin E intake and a decreased risk of developing AD or cognitive decline was revealed in several epidemiological studies [129–134], whereas other three studies did not show this association [135–137]. Nevertheless, a meta-analysis suggests that vitamin E exhibits a pronounced protective effect of lowering the risk of AD [138]. Several clinical trials of lipophilic antioxidants have been performed in treating neurodegenerative diseases (Table 2). In a double-blind, randomized 81

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protected mice against MPTP-induced degeneration of nigrostriatal pathway [156]. Clinically, one early study demonstrated slowing of functional decline in early PD patients using CoQ10 treatment and another one showed mild symptomatic benefit of CoQ10 treatment [157, 158] (Table 2). However, recent studies cannot support the effect of disease modification on PD by CoQ10 [159–162] (Table 2). Furthermore, a meta-analysis did not show the superiority of CoQ10 to placebo in terms of motor symptoms improving in PD [163]. Three studies showed neuroprotective effects of CoQ10 in HD mouse models [164–166], but such effect was not seen in another [167]. In a randomized double blinded control trial, high dose (2400 mg/day) of CoQ10 did not have a significant effect on slowing decline in total functional capacity or time to death in HD patients compared to the control group [168] (Table 2). CoQ10 administration in ALS patients did not appear to slow the progression of disease in a double blinded randomized control trial [169] (Table 2).

Table 2 Clinical trials of lipophilic antioxidants in treating neurodegenerative diseases Disease

Number of patients (treatment/placebo)

Follow-up

Daily dose

Effect

reference

Vitamine AD AD AD AD AD PD HD

E 169 (85/84) 280 (140/140) 516 (257/259) 70 (40/30) 33 (19/14) 400 (202/199) 73 (40/33)

2 years 2.5 years 3 years 6 months 6 months 2 years 1 year

2000IU 2000IU 2000IU 2000IU 800IU 2000IU 3000IU

Beneficial Beneficial No No No No Beneficial

[139] [140] [144] [143] [142] [149] [150]

Coenzyme Q10 (CoQ10) PD 28 (14/14) PD 80 (64/16)

4 weeks 16 months

Beneficial Beneficiala

[158] [157]

PD

600 (397/203)

16 months

No

[162]

PD PD PD HD ALS

64 (36/28) 131 (64/67) 142 (71/71) 609 (303/306) 80 (40/40)

96 weeks 3 months 1 year 60 months 9 months

360mg 3001200mg 12002400mg 300mg 300mg 2400mg 2400mg 2700mg

No No No No No

[161] [160] [159] [168] [169]

Docosahexaenoic acid (DHA) AD 402 (238/164)

18 months

2g

No

[180]

Eicosapentaenoic acid (EPA) HD 8 (4/4) HD 83 (39/44) HD 184 (97/87)

6 months 12 months 6 months

2g 2g 2g

Beneficial Beneficial No

[187] [186] [188]

5.4. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) DHA and EPA belong to a family of the n-3 polyunsaturated fatty acids. DHA and EPA modulate gene expression coding for oxidative metabolism and mitochondrial biogenesis in the brain [170]. Epidemiological studies demonstrated that a low intake of n-3 polyunsaturated fatty acids is associated with an increased risk of developing AD [171–179]. However, a double-blind randomized control trial found that DHA did not slow the rate of cognitive and functional decline in patients with AD [180] (Table 2). DHA exerts neuroprotective effects in MPTP-induced rat and mouse models for PD [181–184]. A study in primates demonstrated a significant reduction in levodopainduced dyskinesia in animals treated with DHA [185]. However, no clinical studies investigating the neuroprotective effects of DHA in the prevention of developing PD exist. Two small clinical studies on HD suggest beneficial effects of EPA on neuropsychological and motor functions [186, 187] (Table 2). However, a large multicenter randomized controlled trial concluded that EPA did not clinically improve neurological symptoms in HD patients [188] (Table 2). An observational study reported that a diet rich in n-3 polyunsaturated fatty acids may lower the risk of developing ALS [189], but a conflicting result was observed in another study whereby it was seen to worsen the condition and accelerate disease progression in the ALS mouse model [190]. Thus more trials are needed to validate the appropriateness of 3-polyunsaturated fatty acids as a part of the treatment for ALS.

AD: Alzheimer’s disease; ALS: Amyotrophic lateral sclerosis; HD: Huntington’s disease; PD: Parkinson’s disease a In the group with coenzyme Q10 1200 mg treatment.

controlled trial using a placebo, patients treated with vitamin E showed delay in developing dementia compared to the control group [139] (Table 2). Among patients with mild to moderate AD, treatment with vitamin E resulted in slower functional decline compared to the placebo group [140] (Table 2). A study showed the treatment combination of vitamin E and C is better than vitamin E alone in reducing plasma lipoprotein oxidation in AD patients [141]. However, other studies could not replicate the beneficial effects of vitamin E in AD patients [142–144] (Table 2). The effect of vitamin E on PD has also been examined in several epidemiological studies. One study has shown inverse association of the amount of Vitamin E consumption with PD incidence [145]. In contrast, two population-based studies did not recapitulate the association between the intake of vitamin E and risk of PD [146, 147]. Long-term treatment with vitamin E may delay the use of levodopa in PD patients [148]. However, in another study, vitamin E intake was not shown to cause a delay in the speed of neuronal degeneration and intellectual decline or a decrease in the death rate of PD patients [149] (Table 2). While only a handful of studies exist exploring the therapeutic effects of vitamin E in HD and ALS, vitamin E may still potentially play an important role in the therapeutic strategy of HD and ALS. This is highlighted in one study where treatment with vitamin E in early-staged HD patients delayed motor decline [150] (Table 2). Although vitamin E did not extend the lifespan of patients with ALS, those who took vitamin E had a decreased risk of progressing from mild to severe disease [151].

6. Conclusion remarks Various biomarkers of oxidation are currently being investigated and developed for aiding in the early detection of neurodegenerative diseases, predicting its progression and testing the therapeutic efficacy. Currently, the challenge of finding such biomarkers of neurodegenerative diseases lies in the lack of trials evaluating multiple biomarkers in the context of either cohort studies or randomized control trials. There is currently no clinical trials clearly demonstrate that a specific antioxidant intervention prevents disease progression or decreases risk with modification of biomarkers, it is therefore imperative that further and more robust clinical trials are carried out such as in the context of a wider population, elimination of confounding factors and application of useful biomarkers as surrogate endpoints, in order to develop new or improved therapeutic strategies for neurodegenerative diseases. Although lipophilic antioxidants are found abundantly in various diets, it is important to highlight that their bioavailability may be influenced by several factors. These include structure instability, poor solubility, inefficient permeability, gastro-intestinal degradation, first-pass metabolism, and interaction with other drugs [191]. Owing to the aforementioned pharmaceutical properties, the doses of supplement tablets containing antioxidants may not be optimum for neuroprotection. Novel drug delivery approaches by chemical modifications [192, 193],

5.3. Coenzyme Q10 (CoQ10) CoQ10 improved the behavioral performance and cognitive functions in AD transgenic mice [152, 153], whereas it had no effect on CSF biomarkers linked to Aβ or tauopathy and on cognitive function in AD patients [154]. A study using metallothionein knock out as the PD mouse model has shown neuroprotective effects of CoQ10 [155]. Administration of nanomicellar formulation of CoQ10 significantly 82

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water-soluble inclusion complexes [194, 195], liposomes [196], nanoparticles [197, 198] and gel-based systems [199] would be helpful in delivering the lipophilic antioxidants via an oral or intravenous route. Multidisciplinary approaches will be required to further our understanding of the complex relationships among oxidation, antioxidants and neurodegenerative diseases.

[27] T. Ma, C.A. Hoeffer, H. Wong, C.A. Massaad, P. Zhou, C. Iadecola, M.P. Murphy, R.G. Pautler, E. Klann, Amyloid β-induced impairments in hippocampal synaptic plasticity are rescued by decreasing mitochondrial superoxide, J. Neurosci. 31 (2011) 5589–5595. [28] G.J. Harry, Microglia during development and aging, Pharmacol. Ther. 139 (2013) 313–326. [29] K.S.P. McNaught, P. Jenner, Proteasomal function is impaired in substantia nigra in Parkinson's disease, Neurosci. Lett. 297 (2001) 191–194. [30] S.E. Browne, M.F. Beal, Oxidative damage in Huntington's disease pathogenesis, Antioxid. Redox Signal. 8 (2006) 2061–2073. [31] A. Pitts, K. Dailey, J.T. Newington, A. Chien, R. Arseneault, T. Cann, L.M. Thompson, R.C. Cumming, Dithiol-based compounds maintain expression of antioxidant protein peroxiredoxin 1 that counteracts toxicity of mutant huntingtin, J. Biol. Chem. 287 (2012) 22717–22729. [32] E.L. Scotter, H.J. Chen, C.E. Shaw, TDP-43 proteinopathy and ALS: insights into disease mechanisms and therapeutic targets, Neurotherapeutics 12 (2015) 352–363. [33] W. Duan, X. Li, J. Shi, Y. Guo, Z. Li, C. Li, Mutant TAR DNA-binding protein-43 induces oxidative injury in motor neuron-like cell, Neuroscience 169 (2010) 1621–1629. [34] R.J. Braun, C. Sommer, D. Carmona-Gutierrez, C.M. Khoury, J. Ring, S. Büttner, F. Madeo, Neurotoxic 43-kDa TAR DNA-binding protein (TDP-43) triggers mitochondrion-dependent programmed cell death in yeast, J. Biol. Chem. 286 (2011) 19958–19972. [35] J.D. Morrow, A.R. Tapper, W.E. Zackert, J. Yang, S.C. Sanchez, T.J. Montine, L.J. Roberts, Formation of novel isoprostane-like compounds from docosahexaenoic acid, in: K.V. Honn, L.J. Marnett, S. Nigam, E.A. Dennis (Eds.), Eicosanoids and other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, vol. 4, Springer US, Boston, MA, 1999, pp. 343–347. [36] E. Miller, A. Morel, L. Saso, J. Saluk, Isoprostanes and neuroprostanes as biomarkers of oxidative stress in neurodegenerative diseases, Oxid. Med. Cell. Longev. 572491 (2014). [37] J. Nourooz-Zadeh, E.H. Liu, B. Yhlen, E.E. Anggard, B. Halliwell, F4-isoprostanes as specific marker of docosahexaenoic acid peroxidation in Alzheimer's disease, J. Neurochem. 72 (1999) 734–740. [38] D. Pratico, M.Y. Lee, J.Q. Trojanowski, J. Rokach, G.A. Fitzgerald, Increased F2isoprostanes in Alzheimer's disease: evidence for enhanced lipid peroxidation in vivo, FASEB J. 12 (1998) 1777–1783. [39] E.E. Reich, W.R. Markesbery, L.J. Roberts, L.L. Swift, J.D. Morrow, T.J. Montine, Brain regional quantification of F-ring and D-/E-ring isoprostanes and neuroprostanes in Alzheimer's disease, Am. J. Pathol. 158 (2001) 293–297. [40] T.T. Reed, W.M. Pierce, W.R. Markesbery, D.A. Butterfield, Proteomic identification of HNE-bound proteins in early Alzheimer disease: Insights into the role of lipid peroxidation in the progression of AD, Brain Res. 1274 (2009) 66–76. [41] W. Völkel, T. Sicilia, A. Pähler, W. Gsell, T. Tatschner, K. Jellinger, F. Leblhuber, P. Riederer, W.K. Lutz, M.E. Götz, Increased brain levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer's disease, Neurochem. Int. 48 (2006) 679–686. [42] R.J. Castellani, G. Perry, S.L. Siedlak, A. Nunomura, S. Shimohama, J. Zhang, T. Montine, L.M. Sayre, M.A. Smith, Hydroxynonenal adducts indicate a role for lipid peroxidation in neocortical and brainstem Lewy bodies in humans, Neurosci. Lett. 319 (2002) 25–28. [43] J. Lee, B. Kosaras, S.J. Del Signore, K. Cormier, A. McKee, R.R. Ratan, N.W. Kowall, H. Ryu, Modulation of lipid peroxidation and mitochondrial function by nordihydroguaiaretic acid (NDGA) improves neuropathology in Huntington’s disease mice, Acta Neuropathol. 121 (2011) 487–498. [44] A. Yoritaka, N. Hattori, K. Uchida, M. Tanaka, E.R. Stadtman, Y. Mizuno, Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease, Proc. Natl. Acad. Sci. U. S. A. 93 (1996) 2696–2701. [45] D.T. Dexter, C.J. Carter, F.R. Wells, F. Javoy-Agid, Y. Agid, A. Lees, P. Jenner, C.D. Marsden, Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease, J. Neurochem. 52 (1989) 381–389. [46] S.E. Browne, R.J. Ferrante, M.F. Beal, Oxidative stress in Huntington's disease, Brain Pathol. 9 (1999) 147–163. [47] N. Stoy, G.M. Mackay, C.M. Forrest, J. Christofides, M. Egerton, T.W. Stone, L.G. Darlington, Tryptophan metabolism and oxidative stress in patients with Huntington's disease, J. Neurochem. 93 (2005) 611–623. [48] W.R. Markesbery, R.J. Kryscio, M.A. Lovell, J.D. Morrow, Lipid peroxidation is an early event in the brain in amnestic mild cognitive impairment, Ann. Neurol. 58 (2005) 730–735. [49] C.D. Aluise, R.A. Sowell, D.A. Butterfield, Peptides and proteins in plasma and cerebrospinal fluid as biomarkers for the prediction, diagnosis, and monitoring of therapeutic efficacy of Alzheimer's disease, Biochim. Biophys. Acta 1782 (2008) 549–558. [50] M.L. Selley, D.R. Close, S.E. Stern, The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease, Neurobiol. Aging 23 (2002) 383–388. [51] L.T. McGrath, B.M. McGleenon, S. Brennan, D. McColl, I.S. Mc, A.P. Passmore, Increased oxidative stress in Alzheimer's disease as assessed with 4-hydroxynonenal but not malondialdehyde, QJM 94 (9) (2001) 485–490. [52] M.A. Lovell, W.D. Ehmann, M.P. Mattson, W.R. Markesbery, Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer's disease, Neurobiol. Aging 18 (1997) 457–461. [53] M.L. Selley, (E)-4-hydroxy-2-nonenal may be involved in the pathogenesis of Parkinson's disease, Free Radic. Biol. Med. 25 (1998) 169–174.

Acknowledgements This work was supported by CMRPG3F136 and 3G052 from Chang Gung Memorial Hospital, Taoyuan, Taiwan. References [1] B.P. Tu, J.S. Weissman, Oxidative protein folding in eukaryotes: mechanisms and consequences, J. Cell Biol. 164 (2004) 341–346. [2] M.S. Cooke, R. Olinski, M.D. Evans, Does measurement of oxidative damage to DNA have clinical significance? Clin. Chim. Acta 365 (2006) 30–49. [3] Q. Kong, C.L.G. Lin, Oxidative damage to RNA: mechanisms, consequences, and diseases, Cell. Mol. Life Sci. 67 (2010) 1817–1829. [4] T. Finkel, N.J. Holbrook, Oxidants, oxidative stress and the biology of ageing, Nature 408 (2000) 239–247. [5] V. Lobo, A. Patil, A. Phatak, N. Chandra, Free radicals, antioxidants and functional foods: Impact on human health, Pharmacogn. Rev. 4 (2010) 118–126. [6] H.W. Querfurth, F.M. LaFerla, Alzheimer's disease, N. Engl. J. Med. 362 (2010) 329–344. [7] G.G. Glenner, C.W. Wong, Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein, Biochem. Biophys. Res. Commun. 122 (1984) 1131–1135. [8] C.L. Masters, G. Simms, N.A. Weinman, G. Multhaup, B.L. McDonald, K. Beyreuther, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proc. Natl. Acad. Sci. U. S. A. 82 (1985) 4245–4249. [9] P.R. Turner, K. O’Connor, W.P. Tate, W.C. Abraham, Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory, Prog. Neurobiol. 70 (2003) 1–32. [10] C. Priller, T. Bauer, G. Mitteregger, B. Krebs, H.A. Kretzschmar, J. Herms, Synapse formation and function is modulated by the amyloid precursor protein, J. Neurosci. 26 (2006) 7212–7221. [11] N.M. Hooper, Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein, Biochem. Soc. Trans. 33 (2005) 335–338. [12] F. Checler, Processing of the beta-amyloid precursor protein and its regulation in Alzheimer's disease, J. Neurochem. 65 (1995) 1431–1444. [13] I. Grundke-Iqbal, K. Iqbal, Y.C. Tung, M. Quinlan, H.M. Wisniewski, L.I. Binder, Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology, Proc. Natl. Acad. Sci. U. S. A. 83 (1986) 4913–4917. [14] E.D. Roberson, K. Scearce-Levie, J.J. Palop, F. Yan, I.H. Cheng, T. Wu, H. Gerstein, G.-Q. Yu, L. Mucke, Reducing endogenous tau ameliorates amyloid ß-induced deficits in an Alzheimer's disease mouse model, Science 316 (2007) 750–754. [15] A.E. Lang, A.M. Lozano, Parkinson's disease. First of two parts, N. Engl. J. Med. 339 (1998) 1044–1053. [16] M. Zhou, S. Xu, J. Mi, K. Uéda, P. Chan, Nuclear translocation of alpha-synuclein increases susceptibility of MES23.5 cells to oxidative stress, Brain Res. 1500 (Suppl C) (2013) 19–27. [17] W. Xiang, J.C.M. Schlachetzki, S. Helling, J.C. Bussmann, M. Berlinghof, T.E. Schäffer, K. Marcus, J. Winkler, J. Klucken, C.M. Becker, Oxidative stressinduced posttranslational modifications of alpha-synuclein: Specific modification of alpha-synuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity, Mol. Cell. Neurosci. 54 (Suppl C) (2013) 71–83. [18] The Huntington's Disease Collaborative Research Group, A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes, Cell 72 (1993) 971–983. [19] C.M. Chen, Mitochondrial dysfunction, metabolic deficits, and increased oxidative stress in Huntington's disease, Chang Gung Med. J. 34 (2011) 135–152. [20] A. Al-Chalabi, A. Jones, C. Troakes, A. King, S. Al-Sarraj, L.H. van den Berg, The genetics and neuropathology of amyotrophic lateral sclerosis, Acta Neuropathol. 124 (2012) 339–352. [21] R. Bonafede, R. Mariotti, ALS Pathogenesis and Therapeutic Approaches: The role of mesenchymal stem cells and extracellular vesicles, Front. Cell. Neurosci. 11 (2017) 80. [22] C. Behl, J.B. Davis, R. Lesley, D. Schubert, Hydrogen peroxide mediates amyloid β protein toxicity, Cell 77 (1994) 817–827. [23] T. Lynch, R.A. Cherny, A.I. Bush, Oxidative processes in Alzheimer's disease: the role of Aβ-metal interactions, Exp. Gerontol. 35 (2000) 445–451. [24] R. Mark, K. Hensley, D. Butterfield, M. Mattson, Amyloid beta-peptide impairs ionmotive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death, J. Neurosci. 15 (1995) 6239–6249. [25] M.P. Mattson, S.L. Chan, Neuronal and glial calcium signaling in Alzheimer’s disease, Cell Calcium 34 (2003) 385–397. [26] M. Arundine, M. Tymianski, Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity, Cell Calcium 34 (2003) 325–337.

83

Clinica Chimica Acta 485 (2018) 79–87

K.-H. Chang et al.

[54] E.P. Simpson, Y.K. Henry, J.S. Henkel, R.G. Smith, S.H. Appel, Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden, Neurology 62 (2004) 1758–1765. [55] R.G. Smith, Y.K. Henry, M.P. Mattson, S.H. Appel, Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis, Ann. Neurol. 44 (1998) 696–699. [56] F. Sinem, K. Dildar, E. Gokhan, B. Melda, Y. Orhan, M. Filiz, The serum protein and lipid oxidation marker levels in Alzheimer's disease and effects of cholinesterase inhibitors and antipsychotic drugs therapy, Curr. Alzheimer Res. 7 (2010) 463–469. [57] C. Cecchi, C. Fiorillo, S. Sorbi, S. Latorraca, B. Nacmias, S. Bagnoli, P. Nassi, G. Liguri, Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer's patients, Free Radic. Biol. Med. 33 (2002) 1372–1379. [58] S. Martin-Aragon, P. Bermejo-Bescos, J. Benedi, E. Felici, P. Gil, J.M. Ribera, A.M. Villar, Metalloproteinase's activity and oxidative stress in mild cognitive impairment and Alzheimer's disease, Neurochem. Res. 34 (2009) 373–378. [59] A. Casado, M. Encarnacion Lopez-Fernandez, M. Concepcion Casado, R. de La Torre, Lipid peroxidation and antioxidant enzyme activities in vascular and Alzheimer dementias, Neurochem. Res. 33 (2008) 450–458. [60] J. Greilberger, C. Koidl, M. Greilberger, M. Lamprecht, K. Schroecksnadel, F. Leblhuber, D. Fuchs, K. Oettl, Malondialdehyde, carbonyl proteins and albumindisulphide as useful oxidative markers in mild cognitive impairment and Alzheimer's disease, Free Radic. Res. 42 (2008) 633–638. [61] I. Bourdel-Marchasson, M.C. Delmas-Beauvieux, E. Peuchant, S. Richard-Harston, A. Decamps, B. Reignier, J.P. Emeriau, M. Rainfray, Antioxidant defences and oxidative stress markers in erythrocytes and plasma from normally nourished elderly Alzheimer patients, Age Ageing 30 (2001) 235–241. [62] H. Aybek, F. Ercan, D. Aslan, T. Sahiner, Determination of malondialdehyde, reduced glutathione levels and APOE4 allele frequency in late-onset Alzheimer's disease in Denizli, Turkey, Clin. Biochem. 40 (2007) 172–176. [63] M.C. Polidori, P. Mecocci, Plasma susceptibility to free radical-induced antioxidant consumption and lipid peroxidation is increased in very old subjects with Alzheimer disease, J. Alzheimers Dis. 4 (2002) 517–522. [64] R. Ozcankaya, N. Delibas, Malondialdehyde, superoxide dismutase, melatonin, iron, copper, and zinc blood concentrations in patients with Alzheimer disease: cross-sectional study, Croat. Med. J. 43 (2002) 28–32. [65] A. Sharma, P. Kaur, B. Kumar, S. Prabhakar, K.D. Gill, Plasma lipid peroxidation and antioxidant status of Parkinson's disease patients in the Indian population, Parkinsonism Relat. Disord. 14 (2008) 52–57. [66] T.V. Ilic, M. Jovanovic, A. Jovicic, M. Tomovic, Oxidative stress indicators are elevated in de novo Parkinson's disease patients, Funct. Neurol. 14 (1999) 141–147. [67] J. Sanyal, S.K. Bandyopadhyay, T.K. Banerjee, S.C. Mukherjee, D.P. Chakraborty, B.C. Ray, V.R. Rao, Plasma levels of lipid peroxides in patients with Parkinson's disease, Eur. Rev. Med. Pharmacol. Sci. 13 (2009) 129–132. [68] C.M. Chen, J.L. Liu, Y.R. Wu, Y.C. Chen, H.S. Cheng, M.L. Cheng, D.T.Y. Chiu, Increased oxidative damage in peripheral blood correlates with severity of Parkinson's disease, Neurobiol. Dis. 33 (2009) 429–435. [69] C.M. Chen, Y.R. Wu, M.L. Cheng, J.L. Liu, Y.M. Lee, P.W. Lee, B.W. Soong, D.T.Y. Chiu, Increased oxidative damage and mitochondrial abnormalities in the peripheral blood of Huntington’s disease patients, Biochem. Biophys. Res. Commun. 359 (2007) 335–340. [70] M. Pena-Sanchez, G. Riveron-Forment, T. Zaldivar-Vaillant, A. Soto-Lavastida, J. Borrero-Sanchez, G. Lara-Fernandez, E.M. Esteban-Hernandez, Z. Hernandez-Diaz, A. Gonzalez-Quevedo, I. Fernandez-Almirall, C. Perez-Lopez, Y. Castillo-Casanas, O. Martinez-Bonne, A. Cabrera-Rivero, L. Valdes-Ramos, R. Guerra-Badia, R. Fernandez-Carriera, M.C. Menendez-Sainz, S. Gonzalez-Garcia, Association of status redox with demographic, clinical and imaging parameters in patients with Huntington's disease, Clin. Biochem. 48 (2015) 1258-1263. [71] H. Blasco, G. Garcon, F. Patin, C. Veyrat-Durebex, J. Boyer, D. Devos, P. Vourc'h, C.R. Andres, P. Corcia, Panel of Oxidative Stress and Inflammatory Biomarkers in ALS: A Pilot Study, Can. J. Neurol. Sci. 44 (2017) 90–95. [72] A. Baillet, V. Chanteperdrix, C. Trocme, P. Casez, C. Garrel, G. Besson, The role of oxidative stress in amyotrophic lateral sclerosis and Parkinson's disease, Neurochem. Res. 35 (2010) 1530–1537. [73] B. Gokce Cokal, M. Yurtdas, S. Keskin Guler, H.N. Gunes, C. Atac Ucar, B. Aytac, Z.E. Durak, T.K. Yoldas, I. Durak, H.C. Cubukcu, Serum glutathione peroxidase, xanthine oxidase, and superoxide dismutase activities and malondialdehyde levels in patients with Parkinson's disease, Neurol. Sci. 38 (2017) 425–431. [74] J.A. Molina, F.J. Jimenez-Jimenez, P. Fernandez-Calle, L. Lalinde, J.M. Tenias, M. Pondal, A. Vazquez, R. Codoceo, Serum lipid peroxides in patients with Parkinson's disease, Neurosci. Lett. 136 (1992) 137–140. [75] T.J. Montine, M.F. Beal, M.E. Cudkowicz, H. O’Donnell, R.A. Margolin, L. McFarland, A.F. Bachrach, W.E. Zackert, L.J. Roberts, J.D. Morrow, Increased CSF F2-isoprostane concentration in probable AD, Neurology 52 (1999) 562. [76] T.J. Montine, K.S. Montine, W. McMahan, W.R. Markesbery, J.F. Quinn, J.D. Morrow, F2-isoprostanes in Alzheimer and other neurodegenerative diseases, Antioxid. Redox Signal. 7 (2005) 269–275. [77] T.J. Montine, M.F. Beal, D. Robertson, M.E. Cudkowicz, I. Biaggioni, H. O'Donnell, W.E. Zackert, L.J. Roberts, J.D. Morrow, Cerebrospinal fluid F2-isoprostanes are elevated in Huntington's disease, Neurology 52 (1999) 1104–1105. [78] R.C.S. Seet, C.Y.J. Lee, E.C.H. Lim, J.J.H. Tan, A.M.L. Quek, W.L. Chong, W.F. Looi, S.H. Huang, H. Wang, Y.H. Chan, B. Halliwell, Oxidative damage in Parkinson disease: Measurement using accurate biomarkers, Free Rad. Biol. Med. 48 (2010) 560–566. [79] M.C. Irizarry, Y. Yao, B.T. Hyman, J.H. Growdon, D. Pratico, Plasma F2A

[80]

[81]

[82]

[83]

[84]

[85] [86]

[87]

[88]

[89]

[90]

[91]

[92]

[93] [94]

[95]

[96]

[97]

[98]

[99] [100]

[101]

[102]

[103]

[104]

[105]

84

isoprostane levels in Alzheimer's and Parkinson's disease, Neurodegener. Dis. 4 (2007) 403–405. H. Mitsumoto, R.M. Santella, X. Liu, M. Bogdanov, J. Zipprich, H.C. Wu, J. Mahata, M. Kilty, K. Bednarz, D. Bell, P.H. Gordon, M. Hornig, M. Mehrazin, A. Naini, M.F. Beal, P. Factor-Litvak, Oxidative stress biomarkers in sporadic ALS, Amyotroph. Lateral Scler. 9 (2008) 177–183. Y. Yoshida, A. Yoshikawa, T. Kinumi, Y. Ogawa, Y. Saito, K. Ohara, H. Yamamoto, Y. Imai, E. Niki, Hydroxyoctadecadienoic acid and oxidatively modified peroxiredoxins in the blood of Alzheimer's disease patients and their potential as biomarkers, Neurobiol. Aging 30 (2009) 174–185. C.J. Foy, A.P. Passmore, M.D. Vahidassr, I.S. Young, J.T. Lawson, Plasma chainbreaking antioxidants in Alzheimer's disease, vascular dementia and Parkinson's disease, QJM 92 (1999) 39–45. C. Jeandel, M.B. Nicolas, F. Dubois, F. Nabet-Belleville, F. Penin, G. Cuny, Lipid peroxidation and free radical scavengers in Alzheimer's disease, Gerontology 35 (1989) 275–282. F.J. Jimenez-Jimenez, J.A. Molina, F. de Bustos, M. Orti-Pareja, J. Benito-Leon, A. Tallon-Barranco, T. Gasalla, J. Porta, J. Arenas, Serum levels of beta-carotene, alpha-carotene and vitamin A in patients with Alzheimer's disease, Eur. J. Neurol. 6 (1999) 495–497. P. Mecocci, M. Polidori, A. Cherubini, et al., Lymphocyte oxidative DNA damage and plasma antioxidants in alzheimer disease, Arch. Neurol. 59 (2002) 794–798. P. Rinaldi, M.C. Polidori, A. Metastasio, E. Mariani, P. Mattioli, A. Cherubini, M. Catani, R. Cecchetti, U. Senin, P. Mecocci, Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease, Neurobiol. Aging 24 (2003) 915–919. Z. Zaman, S. Roche, P. Fielden, P.G. Frost, D.C. Niriella, A.C. Cayley, Plasma concentrations of vitamins A and E and carotenoids in Alzheimer's disease, Age Ageing 21 (1992) 91–94. K. Mullan, M.A. Williams, C.R. Cardwell, B. McGuinness, P. Passmore, G. Silvestri, J.V. Woodside, G.J. McKay, Serum concentrations of vitamin E and carotenoids are altered in Alzheimer's disease: A case-control study, Alzheimers. Dement. Trans. Res. Clin. Interv. 3 (2017) 432–439. C.A.F. Von Arnim, F. Herbolsheimer, T. Nikolaus, R. Peter, H.K. Biesalski, A.C. Ludolph, M. Riepe, G. Nagel, Dietary antioxidants and dementia in a population-based case-control study among older people in South Germany, J. Alzheimer's Dis. 31 (2012) 717–724. L. Giavarotti, K.A. Simon, L.A. Azzalis, F.L.A. Fonseca, A.F. Lima, M.C.V. Freitas, M.K.C. Brunialti, Salom, A.A.V.S. Moscardi, M. Monta, L.R. Ramos, V. Junqueira, Mild systemic oxidative stress in the subclinical stage of Alzheimer's disease, Oxid. Med. Cell. Longev. 2013 (2013) 8. J. Zeng, L. Chen, Z. Wang, Q. Chen, Z. Fan, H. Jiang, Y. Wu, L. Ren, J. Chen, T. Li, W. Song, Marginal vitamin A deficiency facilitates Alzheimer's pathogenesis, Acta Neuropathol. 133 (2017) 967–982. W.J. Perrig, P. Perrig, H.B. Stähelin, The relation between antioxidants and memory performance in the old and very old, J. Am. Geriatr. Soc. 45 (1997) 718–724. J. Min, K. Min, Serum lycopene, lutein and zeaxanthin, and the risk of Alzheimer's disease mortality in older adults, Dement. Geriatr. Cogn. Dis. 37 (2014) 246–256. C. Feart, L. Letenneur, C. Helmer, C. Samieri, W. Schalch, S. Etheve, C. Delcourt, J.F. Dartigues, P. Barberger-Gateau, Plasma carotenoids are inversely associated with dementia risk in an elderly French cohort, J. Gerontol. A. Biol. Sci. Med. Sci. 71 (2016) 683–688. J.H. Kim, J. Hwang, E. Shim, E.J. Chung, S.H. Jang, S.B. Koh, Association of serum carotenoid, retinol, and tocopherol concentrations with the progression of Parkinson's Disease, Nutr. Res. Pract. 11 (2017) 114–120. T. Metcalfe, D.M. Bowen, D.P. Muller, Vitamin E concentrations in human brain of patients with Alzheimer's disease, fetuses with Down's syndrome, centenarians, and controls, Neurochem. Res. 14 (1989) 1209–1212. F.J. Jiménez-Jiménez, F. de Bustos, J.A. Molina, J. Benito-León, A. TallónBarranco, T. Gasalla, M. Ortí-Pareja, F. Guillamón, J.C. Rubio, J. Arenas, R. Enríquez-de-Salamanca, Cerebrospinal fluid levels of alpha-tocopherol (vitamin E) in Alzheimer's disease, J. Neural Transm. 104 (1997) 703–710. S. Schippling, A. Kontush, S. Arlt, C. Buhmann, H.J. Sturenburg, U. Mann, T. Muller-Thomsen, U. Beisiegel, Increased lipoprotein oxidation in Alzheimer's disease, Free Radic. Biol. Med. 28 (2000) 351–360. J. Quinn, J. Suh, M.M. Moore, J. Kaye, B. Frei, Antioxidants in Alzheimer's diseasevitamin C delivery to a demanding brain, J. Alzheimers. Dis. 5 (2003) 309–313. A.J. Sinclair, A.J. Bayer, J. Johnston, C. Warner, S.R. Maxwell, Altered plasma antioxidant status in subjects with Alzheimer's disease and vascular dementia, Int. J. Geriatr. Psychiatry 13 (1998) 840–845. K.E. Charlton, T.L. Rabinowitz, L.N. Geffen, M.A. Dhansay, Lowered plasma vitamin C, but not vitamin E, concentrations in dementia patients, J. Nutr. Health Aging 8 (2004) 99–107. D. Ryglewicz, M. Rodo, P.K. Kunicki, M. Bednarska-Makaruk, A. Graban, W. Lojkowska, H. Wehr, Plasma antioxidant activity and vascular dementia, J. Neurol. Sci. 203–204 (2002) 195–197. P. Fernandez-Calle, J.A. Molina, F.J. Jimenez-Jimenez, A. Vazquez, M. Pondal, P.J. Garcia-Ruiz, D.G. Urra, J. Domingo, R. Codoceo, Serum levels of alpha-tocopherol (vitamin E) in Parkinson's disease, Neurology 42 (1992) 1064–1066. S. Riviere, I. Birlouez-Aragon, F. Nourhashemi, B. Vellas, Low plasma vitamin C in Alzheimer patients despite an adequate diet, Int. J. Geriatr. Psychiatry 13 (1998) 749–754. J.E. Ahlskog, R.J. Uitti, P.A. Low, G.M. Tyce, K.K. Nickander, R.C. Petersen, E. Kokmen, No evidence for systemic oxidant stress in Parkinson's or Alzheimer's disease, Mov. Disord. 10 (1995) 566–573.

Clinica Chimica Acta 485 (2018) 79–87

K.-H. Chang et al.

Alzheimer disease, Alzheimer. Dis. Assoc. Disord. 12 (1998) 121–126. [132] M.J. Engelhart, M.I. Geerlings, A. Ruitenberg, J.C. van Swieten, A. Hofman, J.C. Witteman, M.M. Breteler, Dietary intake of antioxidants and risk of Alzheimer disease, JAMA 287 (2002) 3223–3229. [133] M.C. Morris, D.A. Evans, J.L. Bienias, C.C. Tangney, D.A. Bennett, N. Aggarwal, R.S. Wilson, P.A. Scherr, Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study, JAMA 287 (2002) 3230–3237. [134] P.P. Zandi, J.C. Anthony, A.S. Khachaturian, S.V. Stone, D. Gustafson, J.T. Tschanz, M.C. Norton, K.A. Welsh-Bohmer, J.C. Breitner, G. Cache County Study, Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study, Arch. Neurol. 61 (2004) 82–88. [135] S.L. Gray, M.L. Anderson, P.K. Crane, J.C. Breitner, W. McCormick, J.D. Bowen, L. Teri, E. Larson, Antioxidant vitamin supplement use and risk of dementia or Alzheimer's disease in older adults, J. Am. Geriatr. Soc. 56 (2008) 291–295. [136] K.H. Masaki, K.G. Losonczy, G. Izmirlian, D.J. Foley, G.W. Ross, H. Petrovitch, R. Havlik, L.R. White, Association of vitamin E and C supplement use with cognitive function and dementia in elderly men, Neurology 54 (2000) 1265–1272. [137] J.A. Luchsinger, M.X. Tang, S. Shea, R. Mayeux, Antioxidant vitamin intake and risk of Alzheimer disease, Arch. Neurol. 60 (2003) 203–208. [138] F.J. Li, L. Shen, H.F. Ji, Dietary intakes of vitamin E, vitamin C, and beta-carotene and risk of Alzheimer's disease: a meta-analysis, J. Alzheimers Dis. 31 (2012) 253–258. [139] M. Sano, C. Ernesto, R.G. Thomas, M.R. Klauber, K. Schafer, M. Grundman, P. Woodbury, J. Growdon, C.W. Cotman, E. Pfeiffer, L.S. Schneider, L.J. Thal, A Controlled Trial of Selegiline, Alpha-Tocopherol, or Both as Treatment for Alzheimer's Disease, N. Engl. J. Med. 336 (1997) 1216–1222. [140] M.W. Dysken, M. Sano, S. Asthana, J.E. Vertrees, M. Pallaki, M. Llorente, S. Love, G.D. Schellenberg, J.R. McCarten, J. Malphurs, S. Prieto, P. Chen, D.J. Loreck, G. Trapp, R.S. Bakshi, J.E. Mintzer, J.L. Heidebrink, A. Vidal-Cardona, L.M. Arroyo, A.R. Cruz, S. Zachariah, N.W. Kowall, M.P. Chopra, S. Craft, S. Thielke, C.L. Turvey, C. Woodman, K.A. Monnell, K. Gordon, J. Tomaska, Y. Segal, P.N. Peduzzi, P.D. Guarino, Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial, JAMA 311 (2014) 33–44. [141] A. Kontush, U. Mann, S. Arlt, A. Ujeyl, C. Luhrs, T. Muller-Thomsen, U. Beisiegel, Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer's disease, Free Radic. Biol. Med. 31 (2001) 345–354. [142] A. Lloret, M.C. Badia, N.J. Mora, F.V. Pallardo, M.D. Alonso, J. Vina, Vitamin E paradox in Alzheimer's disease: it does not prevent loss of cognition and may even be detrimental, J. Alzheimers Dis. 17 (2009) 143–149. [143] M. Onofrj, A. Thomas, A.L. Luciano, D. Iacono, A. Di Rollo, G. D'Andreamatteo, A. Di Iorio, Donepezil versus vitamin E in Alzheimer's disease: Part 2: mild versus moderate-severe Alzheimer's disease, Clin. Neuropharmacol. 25 (2002) 207–215. [144] R.C. Petersen, R.G. Thomas, M. Grundman, D. Bennett, R. Doody, S. Ferris, D. Galasko, S. Jin, J. Kaye, A. Levey, E. Pfeiffer, M. Sano, C.H. van Dyck, L.J. Thal, G. Alzheimer's Disease Cooperative Study, Vitamin E and donepezil for the treatment of mild cognitive impairment, N. Engl. J. Med. 352 (2005) 2379–2388. [145] M.C. de Rijk, M.M. Breteler, J.H. den Breeijen, L.J. Launer, D.E. Grobbee, F.G. van der Meche, A. Hofman, Dietary antioxidants and Parkinson disease. The Rotterdam Study, Arch. Neurol. 54 (1997) 762–765. [146] G. Logroscino, K. Marder, L. Cote, M.X. Tang, S. Shea, R. Mayeux, Dietary lipids and antioxidants in Parkinson's disease: a population-based, case-control study, Ann. Neurol. 39 (1996) 89–94. [147] S.M. Zhang, M.A. Hernán, H. Chen, D. Spiegelman, W.C. Willett, A. Ascherio, Intakes of vitamins E and C, carotenoids, vitamin supplements, and PD risk, Neurology 59 (2002) 1161–1169. [148] S. Fahn, A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson's disease, Ann. Neurol. 32 (Suppl) (1992) S128–S132. [149] The Parkinson Study Group, Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease, N. Engl. J. Med. 328 (1993) 176–183. [150] C.E. Peyser, M. Folstein, G.A. Chase, S. Starkstein, J. Brandt, J.R. Cockrell, F. Bylsma, J.T. Coyle, P.R. McHugh, S.E. Folstein, Trial of d-alpha-tocopherol in Huntington's disease, Am. J. Psychiatry 152 (1995) 1771–1775. [151] C. Desnuelle, M. Dib, C. Garrel, A. Favier, A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group, Amyotroph, Lateral Scler. Other Motor Neuron Disord. 2 (2001) 9–18. [152] C. Elipenahli, C. Stack, S. Jainuddin, M. Gerges, L. Yang, A. Starkov, M.F. Beal, M. Dumont, Behavioral improvement after chronic administration of coenzyme Q10 in P301S transgenic mice, J. Alzheimers Dis. 28 (2012) 173–182. [153] M. Dumont, K. Kipiani, F. Yu, E. Wille, M. Katz, N.Y. Calingasan, G.K. Gouras, M.T. Lin, M.F. Beal, Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer's disease, J. Alzheimers Dis. 27 (2011) 211–223. [154] D.R. Galasko, E. Peskind, C.M. Clark, J.F. Quinn, J.M. Ringman, G.A. Jicha, C. Cotman, B. Cottrell, T.J. Montine, R.G. Thomas, P. Aisen, S. Alzheimer's Disease Cooperative, Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures, Arch. Neurol. 69 (2012) 836–841. [155] S.K. Sharma, H. El Refaey, M. Ebadi, Complex-1 activity and 18F-DOPA uptake in genetically engineered mouse model of Parkinson's disease and the neuroprotective role of coenzyme Q10, Brain Res. Bull. 70 (2006) 22–32. [156] M. Sikorska, P. Lanthier, H. Miller, M. Beyers, C. Sodja, B. Zurakowski, S. Gangaraju, S. Pandey, J.K. Sandhu, Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant

[106] A. Federico, C. Battisti, P. Formichi, M.T. Dotti, Plasma levels of vitamin E in Parkinson's disease, J. Neural Transm. Suppl 45 (1995) 267–270. [107] G. Nicoletti, L. Crescibene, M. Scornaienchi, L. Bastone, A. Bagalà, I.D. Napoli, M. Caracciolo, A. Quattrone, Plasma levels of vitamin E in Parkinson's disease, Arch. Gerontol. Geriatr. 33 (2001) 7–12. [108] K.S. Lokendra, L. Jianxin, B. Yidong, Mitochondrial respiratory complex I: structure, function and implication in human diseases, Curr. Med. Chem. 16 (2009) 1266–1277. [109] A.W. Linnane, M. Kios, L. Vitetta, Coenzyme Q10 – Its role as a prooxidant in the formation of superoxide anion/hydrogen peroxide and the regulation of the metabolome, Mitochondrion 7 (Suppl) (2007) S51–S61. [110] F. de Bustos, J.A. Molina, F.J. Jiménez-Jiménez, A. García-Redondo, C. GómezEscalonilla, J. Porta-Etessam, A. Berbel, M. Zurdo, B. Barcenilla, G. Parrilla, R. Enriquez-de-Salamanca, J. Arenas, Serum levels of coenzyme Q10 in patients with Alzheimer's disease, J. Neural Transm. 107 (2000) 233–239. [111] M.E. Gotz, A. Gerstner, R. Harth, A. Dirr, B. Janetzky, W. Kuhn, P. Riederer, M. Gerlach, Altered redox state of platelet coenzyme Q10 in Parkinson's disease, J. Neural Transm. 107 (2000) 41–48. [112] M. Sohmiya, M. Tanaka, N.W. Tak, M. Yanagisawa, Y. Tanino, Y. Suzuki, K. Okamoto, Y. Yamamoto, Redox status of plasma coenzyme Q10 indicates elevated systemic oxidative stress in Parkinson's disease, J. Neurol. Sci. 223 (2004) 161–166. [113] J. Andrich, C. Saft, M. Gerlach, B. Schneider, A. Arz, W. Kuhn, T. Muller, Coenzyme Q10 serum levels in Huntington's disease, J. Neural Transm. Suppl 68 (2004) 111–116. [114] J. Takasaki, K. Ono, Y. Yoshiike, M. Hirohata, T. Ikeda, A. Morinaga, A. Takashima, M. Yamada, Vitamin A has anti-oligomerization effects on amyloidbeta in vitro, J. Alzheimers Dis. 27 (2011) 271–280. [115] Y. Ding, A. Qiao, Z. Wang, J.S. Goodwin, E.S. Lee, M.L. Block, M. Allsbrook, M.P. McDonald, G.H. Fan, Retinoic acid attenuates β-amyloid deposition and rescues memory deficits in an Alzheimer's disease transgenic mouse model, J. Neurosci. 28 (2008) 11622–11634. [116] S.A. Paiva, R.M. Russell, Beta-carotene and other carotenoids as antioxidants, J. Am. Coll. Nutr. 18 (1999) 426–433. [117] M. Katagiri, A. Satoh, S. Tsuji, T. Shirasawa, Effects of astaxanthin-rich Haematococcus pluvialis extract on cognitive function: a randomised, doubleblind, placebo-controlled study, J. Clin. Biochem. Nutr. 51 (2012) 102–107. [118] A. Satoh, S. Tsuji, Y. Okada, N. Murakami, M. Urami, K. Nakagawa, M. Ishikura, M. Katagiri, Y. Koga, T. Shirasawa, Preliminary clinical evaluation of toxicity and efficacy of a new astaxanthin-rich haematococcus pluvialis extract, J. Clin. Biochem. Nutr. 44 (2009) 280–284. [119] J.M. Nolan, E. Loskutova, A. Howard, R. Mulcahy, R. Moran, J. Stack, M. Bolger, R.F. Coen, J. Dennison, K.O. Akuffo, N. Owens, R. Power, D. Thurnham, S. Beatty, The impact of supplemental macular carotenoids in Alzheimer's disease: a randomized clinical trial, J. Alzheimers Dis. 44 (2015) 1157–1169. [120] E.Y. Chew, T.E. Clemons, E. Agron, L.J. Launer, F. Grodstein, P.S. Bernstein, Agerelated eye disease study 2 research, effect of omega-3 fatty acids, lutein/zeaxanthin, or other nutrient supplementation on cognitive function: the AREDS2 randomized clinical trial, JAMA 314 (2015) 791–801. [121] J. Nataraj, T. Manivasagam, A.J. Thenmozhi, M.M. Essa, Lutein protects dopaminergic neurons against MPTP-induced apoptotic death and motor dysfunction by ameliorating mitochondrial disruption and oxidative stress, Nutr. Neurosci. 19 (2016) 237–246. [122] T.L. Perry, V.W. Yong, R.M. Clavier, K. Jones, J.M. Wright, J.G. Foulks, R.A. Wall, Partial protection from the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6tetrahydropyridine by four different antioxidants in the mouse, Neurosci. Lett. 60 (1985) 109–114. [123] V.W. Yong, T.L. Perry, A.A. Krisman, Depletion of glutathione in brainstem of mice caused by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is prevented by antioxidant pretreatment, Neurosci. Lett. 63 (1986) 56–60. [124] H. Kaur, S. Chauhan, R. Sandhir, Protective Effect of lycopene on oxidative stress and cognitive decline in rotenone induced model of Parkinson’s disease, Neurochem. Res. 36 (2011) 1435–1443. [125] J. Corcoran, P.L. So, M. Maden, Absence of retinoids can induce motoneuron disease in the adult rat and a retinoid defect is present in motoneuron disease patients, J. Cell Sci. 115 (2002) 4735–4741. [126] Y. Miyake, W. Fukushima, K. Tanaka, S. Sasaki, C. Kiyohara, Y. Tsuboi, T. Yamada, T. Oeda, T. Miki, N. Kawamura, N. Sakae, H. Fukuyama, Y. Hirota, M. Nagai, G. Fukuoka Kinki Parkinson's Disease Study, Dietary intake of antioxidant vitamins and risk of Parkinson's disease: a case–control study in Japan, Eur. J. Neurol. 18 (2011) 106–113. [127] L. Yuan, J. Liu, W. Ma, L. Dong, W. Wang, R. Che, R. Xiao, Dietary pattern and antioxidants in plasma and erythrocyte in patients with mild cognitive impairment from China, Nutrition 32 (2016) 193–198. [128] F. Mangialasche, A. Solomon, I. Kareholt, B. Hooshmand, R. Cecchetti, L. Fratiglioni, H. Soininen, T. Laatikainen, P. Mecocci, M. Kivipelto, Serum levels of vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults, Exp. Gerontol. 48 (2013) 1428–1435. [129] L.L. Basambombo, P.H. Carmichael, S. Cote, D. Laurin, Use of vitamin E and C supplements for the prevention of cognitive decline, Ann. Pharmacother. 51 (2017) 118–124. [130] E.E. Devore, F. Grodstein, F.J. van Rooij, A. Hofman, M.J. Stampfer, J.C. Witteman, M.M. Breteler, Dietary antioxidants and long-term risk of dementia, Arch. Neurol. 67 (2010) 819–825. [131] M.C. Morris, L.A. Beckett, P.A. Scherr, L.E. Hebert, D.A. Bennett, T.S. Field, D.A. Evans, Vitamin E and vitamin C supplement use and risk of incident

85

Clinica Chimica Acta 485 (2018) 79–87

K.-H. Chang et al.

(2002) 2619–2624. [171] B.M. van Gelder, M. Tijhuis, S. Kalmijn, D. Kromhout, Fish consumption, n−3 fatty acids, and subsequent 5-y cognitive decline in elderly men: the Zutphen Elderly Study, Am. J. Clin. Nutr. 85 (2007) 1142–1147. [172] P. Barberger-Gateau, C. Raffaitin, L. Letenneur, C. Berr, C. Tzourio, J.F. Dartigues, A. Alpérovitch, Dietary patterns and risk of dementia, the Three-City cohort study, Neurology 69 (2007) 1921–1930. [173] E. Nurk, C.A. Drevon, H. Refsum, K. Solvoll, S.E. Vollset, O. Nygård, H.A. Nygaard, K. Engedal, G.S. Tell, A.D. Smith, Cognitive performance among the elderly and dietary fish intake: the Hordaland Health Study, Am. J. Clin. Nutr. 86 (2007) 1470–1478. [174] T.L. Huang, P.P. Zandi, K.L. Tucker, A.L. Fitzpatrick, L.H. Kuller, L.P. Fried, G.L. Burke, M.C. Carlson, Benefits of fatty fish on dementia risk are stronger for those without APOE ε4, Neurology 65 (2005) 1409–1414. [175] M.C. Morris, D.A. Evans, C.C. Tangney, J.L. Bienias, R.S. Wilson, Fish consumption and cognitive decline with age in a large community study, Arch. Neurol. 62 (2005) 1849–1853. [176] S. Kalmijn, M.P. van Boxtel, M. Ocke, W.M. Verschuren, D. Kromhout, L.J. Launer, Dietary intake of fatty acids and fish in relation to cognitive performance at middle age, Neurology 62 (2004) 275–280. [177] M.C. Morris, D.A. Evans, J.L. Bienias, C.C. Tangney, D.A. Bennett, R.S. Wilson, N. Aggarwal, J. Schneider, Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease, Arch. Neurol. 60 (2003) 940–946. [178] S. Kalmijn, L.J. Launer, A. Ott, J.C. Witteman, A. Hofman, M.M. Breteler, Dietary fat intake and the risk of incident dementia in the Rotterdam Study, Ann. Neurol. 42 (1997) 776–782. [179] S. Kalmijn, E.J. Feskens, L.J. Launer, D. Kromhout, Polyunsaturated fatty acids, antioxidants, and cognitive function in very old men, Am. J. Epidemiol. 145 (1997) 33–41. [180] J.F. Quinn, R. Raman, R.G. Thomas, K. Yurko-Mauro, E.B. Nelson, C. Van Dyck, J.E. Galvin, J. Emond, C.R. Jack, M. Weiner, L. Shinto, P.S. Aisen, Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial, JAMA 304 (2010) 1903–1911. [181] G. Tanriover, Y. Seval-Celik, O. Ozsoy, G. Akkoyunlu, F. Savcioglu, G. Hacioglu, N. Demir, A. Agar, The effects of docosahexaenoic acid on glial derived neurotrophic factor and neurturin in bilateral rat model of parkinson's disease, Folia Histochem. Cytobiol. 48 (2010) 434–441. [182] O. Ozsoy, Y. Seval-Celik, G. Hacioglu, P. Yargicoglu, R. Demir, A. Agar, M. Aslan, The influence and the mechanism of docosahexaenoic acid on a mouse model of Parkinson’s disease, Neurochem. Int. 59 (2011) 664–670. [183] M. Bousquet, K. Gue, V. Emond, P. Julien, J.X. Kang, F. Cicchetti, F. Calon, Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease, J. Lipid Res. 52 (2011) 263–271. [184] M. Bousquet, M. Saint-Pierre, C. Julien, J.N. Salem, F. Cicchetti, F. Calon, Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson’s disease, FASEB J. 22 (2008) 1213–1225. [185] P. Samadi, L. Grégoire, C. Rouillard, P.J. Bédard, T. Di Paolo, D. Lévesque, Docosahexaenoic acid reduces levodopa-induced dyskinesias in 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine monkeys, Ann. Neurol. 59 (2006) 282–288. [186] B.K. Puri, B.R. Leavitt, M.R. Hayden, C.A. Ross, A. Rosenblatt, J.T. Greenamyre, S. Hersch, K.S. Vaddadi, A. Sword, D.F. Horrobin, M. Manku, H. Murck, Ethyl-EPA in Huntington disease: A double-blind, randomized, placebo-controlled trial, Neurology 65 (2005) 286–292. [187] B.K. Puri, G.M. Bydder, S.J. Counsell, B.J. Corridan, A.J. Richardson, J.V. Hajnal, C. Appel, H.M. McKee, K.S. Vaddadi, D.F. Horrobin, MRI and neuropsychological improvement in Huntington disease following ethyl-EPA treatment, NeuroReport 13 (2002) 123–126. [188] J.J. Ferreira, A. Rosser, D. Craufurd, F. Squitieri, N. Mallard, B. Landwehrmeyer, Ethyl-eicosapentaenoic acid treatment in Huntington's disease: A placebo-controlled clinical trial, Mov. Disord. 30 (2015) 1426–1429. [189] K.C. Fitzgerald, E.J. O'Reilly, G.J. Falcone, M.L. McCullough, Y. Park, L.N. Kolonel, A. Ascherio, Dietary omega-3 polyunsaturated fatty acid intake and risk for amyotrophic lateral sclerosis, JAMA Neurol. 71 (2014) 1102–1110. [190] P.K. Yip, C. Pizzasegola, S. Gladman, M.L. Biggio, M. Marino, M. Jayasinghe, F. Ullah, S.C. Dyall, A. Malaspina, C. Bendotti, A. Michael-Titus, The omega-3 fatty acid eicosapentaenoic acid accelerates disease progression in a model of amyotrophic lateral sclerosis, PLoS one 8 (2013) e61626. [191] D.V. Ratnam, D.D. Ankola, V. Bhardwaj, D.K. Sahana, M.N.V.R. Kumar, Role of antioxidants in prophylaxis and therapy: A pharmaceutical perspective, J. Control. Release 113 (2006) 189–207. [192] J.S. Armstrong, M. Whiteman, P. Rose, D.P. Jones, The Coenzyme Q10 Analog Decylubiquinone inhibits the redox-activated mitochondrial permeability transition: role of mitochondrial respiratory complex III, J Biol. Chem. 278 (2003) 49079–49084. [193] H.J. Youk, E. Lee, M.K. Choi, Y.J. Lee, H.C. Jun, S.H. Kim, C.H. Lee, S.J. Lim, Enhanced anticancer efficacy of α-tocopheryl succinate by conjugation with polyethylene glycol, J Control. Release 107 (2005) 43–52. [194] R. Ficarra, S. Tommasini, D. Raneri, M.L. Calabrò, M.R. Di Bella, C. Rustichelli, M.C. Gamberini, P. Ficarra, Study of flavonoids/β-cyclodextrins inclusion complexes by NMR, FT-IR, DSC, X-ray investigation, J. Pharm. Biomed. Anal. 29 (2002) 1005–1014. [195] D.V. Bangalore, W. McGlynn, D.D. Scott, Effect of β-Cyclodextrin in Improving the Correlation between Lycopene Concentration and ORAC Values, J. Agric. Food Chem. 53 (2005) 1878–1883. [196] T. Minko, A. Stefanov, V. Pozharov, Selected Contribution: Lung hypoxia:

treatment in Parkinson's disease, Neurobiol. Aging 35 (2014) 2329–2346. [157] C.W. Shults, D. Oakes, K. Kieburtz, M.F. Beal, R. Haas, S. Plumb, J.L. Juncos, J. Nutt, I. Shoulson, J. Carter, K. Kompoliti, J.S. Perlmutter, S. Reich, M. Stern, R.L. Watts, R. Kurlan, E. Molho, M. Harrison, M. Lew, G. Parkinson Study, Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline, Arch. Neurol. 59 (2002) 1541–1550. [158] T. Müller, T. Büttner, A.-F. Gholipour, W. Kuhn, Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson's disease, Neurosci. Lett. 341 (2003) 201–204. [159] A randomized clinical trial of coenzyme Q < sub > 10 < /sub > and GPI-1485 in early Parkinson disease, Neurology 68 (2007) 20–28. [160] A. Storch, W.H. Jost, P. Vieregge, J. Spiegel, W. Greulich, J. Durner, T. Muller, A. Kupsch, H. Henningsen, W.H. Oertel, G. Fuchs, W. Kuhn, P. Niklowitz, R. Koch, B. Herting, H. Reichmann, Q.S.G. German Coenzyme, Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease, Arch. Neurol. 64 (2007) 938–944. [161] A. Yoritaka, S. Kawajiri, Y. Yamamoto, T. Nakahara, M. Ando, K. Hashimoto, M. Nagase, Y. Saito, N. Hattori, Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson's disease, Parkinsonism Relat. Disord. 21 (2015) 911–916. [162] Q.E.I. Parkinson Study Group, M.F. Beal, D. Oakes, I. Shoulson, C. Henchcliffe, W.R. Galpern, R. Haas, J.L. Juncos, J.G. Nutt, T.S. Voss, B. Ravina, C.M. Shults, K. Helles, V. Snively, M.F. Lew, B. Griebner, A. Watts, S. Gao, E. Pourcher, L. Bond, K. Kompoliti, P. Agarwal, C. Sia, M. Jog, L. Cole, M. Sultana, R. Kurlan, I. Richard, C. Deeley, C.H. Waters, A. Figueroa, A. Arkun, M. Brodsky, W.G. Ondo, C.B. Hunter, J. Jimenez-Shahed, A. Palao, J.M. Miyasaki, J. So, J. Tetrud, L. Reys, K. Smith, C. Singer, A. Blenke, D.S. Russell, C. Cotto, J.H. Friedman, M. Lannon, L. Zhang, E. Drasby, R. Kumar, T. Subramanian, D.S. Ford, D.A. Grimes, D. Cote, J. Conway, A.D. Siderowf, M.L. Evatt, B. Sommerfeld, A.N. Lieberman, M.S. Okun, R.L. Rodriguez, S. Merritt, C.L. Swartz, W.R. Martin, P. King, N. Stover, S. Guthrie, R.L. Watts, A. Ahmed, H.H. Fernandez, A. Winters, Z. Mari, T.M. Dawson, B. Dunlop, A.S. Feigin, B. Shannon, M.J. Nirenberg, M. Ogg, S.A. Ellias, C.A. Thomas, K. Frei, I. Bodis-Wollner, S. Glazman, T. Mayer, R.A. Hauser, R. Pahwa, A. Langhammer, R. Ranawaya, L. Derwent, K.D. Sethi, B. Farrow, R. Prakash, I. Litvan, A. Robinson, A. Sahay, M. Gartner, V.K. Hinson, S. Markind, M. Pelikan, J.S. Perlmutter, J. Hartlein, E. Molho, S. Evans, C.H. Adler, A. Duffy, M. Lind, L. Elmer, K. Davis, J. Spears, S. Wilson, M.A. Leehey, N. Hermanowicz, S. Niswonger, H.A. Shill, S. Obradov, A. Rajput, M. Cowper, S. Lessig, D. Song, D. Fontaine, C. Zadikoff, K. Williams, K.A. Blindauer, J. Bergholte, C.S. Propsom, M.A. Stacy, J. Field, D. Mihaila, M. Chilton, E.Y. Uc, J. Sieren, D.K. Simon, L. Kraics, A. Silver, J.T. Boyd, R.W. Hamill, C. Ingvoldstad, J. Young, K. Thomas, S.K. Kostyk, J. Wojcieszek, R.F. Pfeiffer, M. Panisset, M. Beland, S.G. Reich, M. Cines, N. Zappala, J. Rivest, R. Zweig, L.P. Lumina, C.L. Hilliard, S. Grill, M. Kellermann, P. Tuite, S. Rolandelli, U.J. Kang, J. Young, J. Rao, M.M. Cook, L. Severt, K. Boyar, A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit, JAMA Neurol. 71 (2014) 543–552. [163] Z.G. Zhu, M.X. Sun, W.L. Zhang, W.W. Wang, Y.M. Jin, C.L. Xie, The efficacy and safety of coenzyme Q10 in Parkinson's disease: a meta-analysis of randomized controlled trials, Neurol. Sci. 38 (2017) 215–224. [164] M.A. Hickey, C. Zhu, V. Medvedeva, N.R. Franich, M.S. Levine, M.F. Chesselet, Evidence for behavioral benefits of early dietary supplementation with CoEnzymeQ10 in a slowly progressing mouse model of Huntington's disease, Mol. Cell. Neurosci. 49 (2012) 149–157. [165] L. Yang, N.Y. Calingasan, E.J. Wille, K. Cormier, K. Smith, R.J. Ferrante, M.F. Beal, Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson's and Huntington's diseases, J. Neurochem. 109 (2009) 1427–1439. [166] R.J. Ferrante, O.A. Andreassen, A. Dedeoglu, K.L. Ferrante, B.G. Jenkins, S.M. Hersch, M.F. Beal, Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease, J. Neurosci. 22 (2002) 1592–1599. [167] L.B. Menalled, M. Patry, N. Ragland, P.A. Lowden, J. Goodman, J. Minnich, B. Zahasky, L. Park, J. Leeds, D. Howland, E. Signer, A.J. Tobin, D. Brunner, Comprehensive behavioral testing in the R6/2 mouse model of Huntington's disease shows no benefit from CoQ10 or minocycline, PLoS One 5 (2010) e9793. [168] A. McGarry, M. McDermott, K. Kieburtz, E.A. de Blieck, F. Beal, K. Marder, C. Ross, I. Shoulson, P. Gilbert, W.M. Mallonee, M. Guttman, J. Wojcieszek, R. Kumar, M.S. LeDoux, M. Jenkins, H.D. Rosas, M. Nance, K. Biglan, P. Como, R.M. Dubinsky, K.M. Shannon, P. O'Suilleabhain, K. Chou, F. Walker, W. Martin, V.L. Wheelock, E. McCusker, J. Jankovic, C. Singer, J. Sanchez-Ramos, B. Scott, O. Suchowersky, S.A. Factor, D.S. Higgins Jr., E. Molho, F. Revilla, J.N. Caviness, J.H. Friedman, J.S. Perlmutter, A. Feigin, K. Anderson, R. Rodriguez, N.R. McFarland, R.L. Margolis, E.S. Farbman, L.A. Raymond, V. Suski, S. Kostyk, A. Colcher, L. Seeberger, E. Epping, S. Esmail, N. Diaz, W.L. Fung, A. Diamond, S. Frank, P. Hanna, N. Hermanowicz, L.S. Dure, M. Cudkowicz, C.I. Huntington Study Group, Coordinators, A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease, Neurology 88 (2017) 152–159. [169] P. Kaufmann, J.L. Thompson, G. Levy, R. Buchsbaum, J. Shefner, L.S. Krivickas, J. Katz, Y. Rollins, R.J. Barohn, C.E. Jackson, E. Tiryaki, C. Lomen-Hoerth, C. Armon, R. Tandan, S.A. Rudnicki, K. Rezania, R. Sufit, A. Pestronk, S.P. Novella, T. Heiman-Patterson, E.J. Kasarskis, E.P. Pioro, J. Montes, R. Arbing, D. Vecchio, A. Barsdorf, H. Mitsumoto, B. Levin, Q.S. Group, Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III, Ann. Neurol. 66 (2009) 235–244. [170] K. Kitajka, L.G. Puskás, Á. Zvara, L. Hackler, G. Barceló-Coblijn, Y.K. Yeo, T. Farkas, The role of n-3 polyunsaturated fatty acids in brain: Modulation of rat brain gene expression by dietary n-3 fatty acids, Proc. Natl. Acad. Sci. U. S. A. 99

86

Clinica Chimica Acta 485 (2018) 79–87

K.-H. Chang et al. antioxidant and antiapoptotic effects of liposomal α-tocopherol, J. Appl. Physiol. 93 (2002) 1550–1560. [197] C.H. Hsu, Z. Cui, R.J. Mumper, M. Jay, Preparation and characterization of novel coenzyme Q(10) nanoparticles engineered from microemulsion precursors, AAPS PharmSciTech. 4 (2003) 24–35. [198] S.S. Kwon, Y.S. Nam, J.S. Lee, B.S. Ku, S.H. Han, J.Y. Lee, I.S. Chang, Preparation

and characterization of coenzyme Q10-loaded PMMA nanoparticles by a new emulsification process based on microfluidization, Colloids Surf. A Physicochem. Eng. Asp. 210 (2002) 95–104. [199] M. Ishida, H. Sakai, S. Sugihara, S. Aoshima, S. Yokoyama, M. Abe, Controlled release of vitamin E from thermo-responsive polymeric physico-gel, Chem. Pharm. Bull. 51 (2003) 1348–1349.

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