Benefits of Vitamins in the Treatment of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the elderly, which is clinically characterized by bradykinesia, resting tremor, abnormal posture balance, and hypermyotonia. Currently, the pathogenic mechanism of PD remains unclear. Numerous clinical studies as well as animal and cell experiments have found a certain relationship between the vitamin family and PD. The antioxidant properties of vitamins and their biological functions of regulating gene expression may be beneficial for the treatment of PD. Current clinical evidence indicates that proper supplementation of various vitamins can reduce the incidence of PD in the general population and improve the clinical symptoms of patients with PD; nevertheless, the safety of regular vitamin supplements still needs to be highlighted. Vitamin supplementation may be an effective adjuvant treatment for PD. In this review, we summarized the biological correlations between vitamins and PD as well as the underlying pathophysiological mechanisms. Additionally, we elaborated the therapeutic potentials of vitamins for PD.

1. Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder following Alzheimer’s disease. Clinically, PD is characterized by resting tremor, hypermyotonia, postural instability, and bradykinesia [1]. Additionally, patients with PD can also manifest with nonmotor symptoms, such as cognitive decline, olfactory dysfunction, constipation, sleep disorders, and autonomic symptoms [2], and these nonmotor symptoms usually occur prior to the onset of motor symptoms [3]. PD severely affects the quality of life of the individual with the disease and also creates a great burden on the caregivers. The typical pathological hallmark of PD is degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and eosinophilic inclusion bodies (Lewy bodies) in the remaining neurons, which is the major contributor to the deficiency of dopamine in the basal ganglia [4, 5]. The exact pathogenetic mechanisms of PD is not yet fully understood. Current theories regard PD as a multifactorial disease, involving various genetic and environmental factors, among which mitochondrial dysfunction and oxidative stress play an important role in the pathogenesis and development of PD [6, 7]. The treatment for PD is challenging, and the existing therapeutic strategies can only relieve clinical symptoms but fail to control the progression of PD.

Vitamins are natural bioactive products with antioxidant properties, which are necessities for maintaining the normal functions of human organisms. Essential vitamins cannot be endogenously synthesized in the organism and therefore must be obtained through the diet. Clinically, vitamin deficiency is quite common, especially in infants and elderly. Vitamins are generally divided into fat-soluble variants (vitamins A, D, E, and K) and water-soluble variants (vitamins B and C). The former mainly bind to cellular nuclear receptors and affect the expression of specific genes [8]. The latter mainly constitute a cofactor for the enzyme, affecting the enzymatic activity [9].

Numerous clinical studies as well as animal and cell experiments have found a certain relationship between the vitamin family and PD [10]. The antioxidant properties of vitamins and their biological functions of regulating gene expression may be beneficial for the treatment of PD. Current clinical evidence indicates that proper supplementation of various vitamins can reduce the incidence of PD in the general population and improve the clinical symptoms of patients with PD; nevertheless, the safety of regular vitamin supplements still needs to be highlighted. Vitamin supplementation may represent an effective adjuvant treatment for PD. In this review, we summarized the biological correlations between vitamins and PD as well as the underlying pathophysiological mechanisms. Additionally, we elaborated the therapeutic potentials of vitamins for PD.

2. The Pathogenesis of Oxidative Stress in PD

Oxidative stress refers to the imbalance between the oxidation system and antioxidant system, resulting in excessive accumulation of oxidative substances, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) [11]. ROS include superoxide anion radical (O₂^-), hydroxyl radical (OH^-), and hydrogen peroxide (H₂O₂); RNS include nitric oxide (NO), nitrogen dioxide (NO₂), and peroxynitrite (ONOO^-). The antioxidant system mainly consists of two subtypes: (1) enzymatic antioxidant system, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and (2) nonenzymatic antioxidant system, including vitamin C, vitamin E, glutathione, melatonin, alpha-lipoic acid, carotenoids, and trace elements copper, zinc, and selenium.

Oxidative stress plays an important physiological role in the organism. For example, phagocytic cells kill pathogenic microorganisms, participate in detoxification and enzymatic reactions, and synthesize some essential biologically active substances. Meanwhile, it can as well cause damage to the body, such as cell membrane destruction, protein denaturation, and nucleic acid changes.

There is increasing evidence that oxidative stress represents a pathophysiological characteristic of PD, and the production of reactive oxygen species can result in neuronal death [12, 13]. The mitochondrial respiratory chain is regarded as the major source of ROS [14]. Additionally, previous studies have found that mitochondrial dysfunction exists in the substantia nigra of patients with PD [15]. Reduced glutathione (GSH) can enhance the production of ROS and RNS [16], and oxidation of dopamine and dopamine metabolites such as 3,4-dihydroxyphenylacetic acid (DOPAC) can inhibit the activity of complex I [17]. These findings indicate that the downstream metabolites of dopamine may make dopamine neurons more susceptible. Moreover, iron accumulation in the substantia nigra is common in patients with PD, leading to overproduction of hydrogen peroxide and molecular oxygen in the Fenton reaction from Fe²⁺ to Fe³⁺; hydrogen peroxide generates a highly toxic hydroxyl radical through the Haber-Weiss reaction in the presence of Fe²⁺, which causes severe oxidative damage to the cellular components [18]. From the above, the oxidant stress is closely associated with the pathogenesis of PD. Oxidative stress can cause neuronal loss through some underlying intracellular damage, such as protein aggregation, mitochondrial dysfunction, and DNA rupture. Therefore, antioxidant damage has become a potential target for the treatment of PD.

3. Vitamin B and PD

The B family of vitamins is water-soluble, which includes thiamine (vitamin B₁), riboflavin (vitamin B₂), niacin (vitamin B₃), pantothenic acid (vitamin B₅), pyridoxine (vitamin B₆), biotin (vitamin B₇), folate (vitamin B₉), and cobalamin (vitamin B₁₂) [19]. These vitamins play an important role as enzyme cofactors in multiple biochemical pathways in all tissues, such as regulating metabolism, improving the function of the immune system and nervous system, and promoting cell growth and division [20].

Almost all of these B family vitamins are essential variants dependent on diet supply, except niacin which can also be synthesized from tryptophan. Vitamin B deficiencies are frequent in the children, elderly, vegetarians, pregnant women, and patients with gastrointestinal diseases. Recently, the association with vitamin B and PD is getting more and more attention. Herein, we use vitamin B₃ as a representative to discuss the relationship between vitamin B and PD.

3.1. Vitamin B₃

Nicotinamide is the active form of niacin, and it is the precursor of coenzymes NADH and NADPH, which are essential for over 200 enzymatic reactions in the organism, especially the production of adenosine triphosphate (ATP). Meat, fish, and wheat are generally rich in nicotinamide, while vegetables have a low nicotinamide content [21]. Deficiency of nicotinamide/niacin can lead to pellagra, causing dermatitis, diarrhea, and depression [22]. Nicotinamide has neuroprotective and antioxidant functions at low doses but exhibits neurotoxicity, especially dopaminergic toxicity, at high doses [23]. Fukushima also suggests that excessive nicotinamide is related to the development of PD [24]; excessive nicotinamide can induce overproduction of 1-methylnicotinamide (MNA), which is increased in patients with PD [25]. In an in vitro study, Griffin et al. found that low-dose nicotinamide (10 mM) has a significant effect on inducing differentiation from embryonic stem cells into neurons; however, higher doses (>20 mM) of nicotinamide induce cytotoxicity and cell death [26]. The definitive protective dose of vitamin B₃ still needs further researches.

3.2. Possible Neuroprotective Mechanisms of Vitamin B₃ in PD

Firstly, numerous studies have demonstrated that mitochondrial dysfunction and cellular energy failure are pathophysiological features of PD. Nicotinamide participates in the biosynthesis of nicotinamide adenine dinucleotide (NAD; oxidized form: NAD⁺; reduced form: NADH) via various metabolic pathways [27]. NADH is an essential cofactor assisting the tetrahydrobiopterin functioning in tyrosine hydroxylase, which can hydroxylate tyrosine and produce dopamine; NADH deficiency is common in PD [28].

Secondly, NADH is indispensable for the physiological function of mitochondrial complex I in ATP synthesis, and the corresponding dysfunction is involved in PD patients and animal models [15, 29, 30]. Nicotinamide mononucleotide (NMN) constitutes one of the key precursors of NAD⁺. In previous in vitro studies, the scholars have established a cellular model of PD using rotenone-treated PC12 cells, and they found the NMN (0.1 mM or 1 mM) treatment was associated with a significantly higher survival rate in the rotenone-treated (0.5 μm) PC12 cells. NMN is assumed to enhance the intracellular levels of NAD⁺ and ATP in the cellular model of PD [31].

In addition, nicotinamide can act a neuroprotective role by inhibiting the oxidative stress. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced mouse models of PD, nicotinamide (500 mg/kg) was injected before subacute (30 mg/kg/d for 5 days) MPTP administration. This study showed that cotreatment with MPTP and nicotinamide significantly improved the locomotor activity compared to single-agent treatment with MPTP. Nicotinamide administration significantly attenuated the MPTP-induced dopamine depletion ( vs. ). Meanwhile, nicotinamide pretreatment markedly inhibited MPTP-induced lactate dehydrogenase (LDH) and NOS activities, which prevented the oxidative stress and alleviated the oxidative damage.

Sirtuins (SIRTs) are NAD⁺-dependent protein deacetylases involved in vital biological processes [32]. Recently, sirtuin 5 (SIRT5) has received considerable attention. Liu et al. investigated the role of SIRT5 in MPTP-induced mouse PD models [33]. They found that deletion of SIRT5 exacerbated motor deficits, nigrostriatal dopaminergic degeneration in the compact part of substantia nigra (SNc), and mitochondrial antioxidant activities in the PD models. These findings provide new insight into the therapeutic strategies for PD. However, the protective effects of nicotinamide are still controversial, and further researches are needed to clarify the biological function of vitamin B₃ in PD.

3.3. Clinical Studies regarding Vitamin B₃ in PD

Current existing clinical studies have shown that a high-niacin diet can reduce the risk of PD [34, 35]. A previous case report also demonstrated that oral niacin (500 mg twice daily for three months) significantly improved rigidity and bradykinesia in a patient with idiopathic PD, though the original purpose was to treat hypertriglyceridemia; after the cessation of oral niacin due to obvious adverse effects (unacceptable nightmares and skin rash), the symptoms of rigidity and bradykinesia relapsed [36]. However, other studies failed to notice the remarkable clinical efficacy [37, 38]. Therefore, more clinical observations are warranted to verify the efficacy as well as side effects of niacin in PD.

4. Vitamin C and PD

Vitamin C (ascorbic acid) is another water-soluble, essential vitamin, which is widely distributed in various tissues. This nutriment is abundant in vegetables, fresh fruits, and animal livers. Vitamin C contains two molecular subforms in organisms: the reduced form (ascorbic acid (AA)) and the oxidized form (dehydroascorbic acid (DHA)). Deficiency of vitamin C is common, especially in children and elderly. A long-term lack of vitamin C can cause scurvy. Vitamin C is very important for the physiological function of the nervous system and the antioxidant function by inhibiting oxidative stress, reducing lipid peroxidation, and scavenging free radicals [39]. Moreover, it is also involved in many nonoxidative stress processes, such as synthesis of collagen, cholesterol, carnitine, catecholamines, amino acids, and some peptide hormones [40, 41].

Dopamine metabolism can produce oxidative stress products, which in return induce accumulation of abnormal proteins in PD [42]. Vitamin C has potentials for the treatment of PD considering the following reasons. Firstly, vitamin C is mainly distributed in areas that are rich in neurons [43, 44]. Secondly, vitamin C can be transported to the brain by SVCT2 (vitamin C transporter type 2) [45], and DHA can be transported to the brain by GLUT1 (glucose transporter type 1) and GLUT3 (glucose transporter type 3) [46].

4.1. Possible Neuroprotective Mechanisms of Vitamin C in PD

There is evidence that ascorbic acid can protect against both levodopa toxicity and the MPTP neurotoxicity [47, 48]. Vitamin C can increase the production of dihydroxyphenylalanine (DOPA). Seitz et al. noted overproduction of DOPA in a dose-dependent manner after incubation of the human neuroblastoma cell line SK-N-SH with ascorbic acid (100-500 mM) for 2 hours. Additionally, the gene expression of tyrosine hydroxylase increased threefold after incubation with ascorbic acid (200 mM) for 5days. The scholars speculated that ascorbic acid may be effective in the treatment of early-stage PD [49].

Vitamin C can improve the absorption of levodopa in elderly PD patients with a poor levodopa bioavailability [50]. Previous studies showed that ascorbic acid can reduce the levodopa dosage under the premise of equal efficacy [51]. Combination of anti-PD drugs and vitamin C may be more effective for alleviating the symptoms of PD.

Vitamin C is essential for the brain development. A study showed that ascorbic acid treatment can promote a 10-fold increase of dopaminergic differentiation in CNS precursor cells derived from the E12 rat mesencephalon [52]. Soon after, another in vitro study also reported that AA can stimulate the CNS precursor cells differentiating into CNS neurons and glia [53]. Recently, He et al. proposed that vitamin C can greatly enhance the embryonic midbrain neural stem cells differentiating into midbrain dopaminergic neurons in vitro. Vitamin C induces the gain of 5-hydroxymethylcytosine (5HMC) and loss of H3K27m3 in dopaminergic phenotype gene promoters, which are catalysed by ten-eleven translocation 1 methylcytosine dioxygenase 1 (TET1) and histone H3K27 demethylase (JMJD3), respectively. However, subsequent TET1 and JMJD3 knockdown/inhibition experiments did not show this effect of vitamin C, and the epigenetic role of vitamin C may be associated with the midbrain dopaminergic neuron development [54, 55].

4.2. Clinical Studies regarding Vitamin C in PD

Although vitamin C has many potential positive effects on PD, the serum level of vitamin C in patients with PD remains controversial [56, 57]. Noteworthily, the vitamin C level in lymphocytes has been found significantly lower in patients with severe PD [58]. Theoretically, vitamin C supplementation may be beneficial for the treatment of PD. A cohort study involving 1036 patients with PD supported this hypothesis, which found that dietary vitamin C intake significantly reduced the risk of PD, but this effect is invalid for a 4-year-lag analysis [59]. Controversially, many studies did not support that vitamin C supplementation can reduce the risk of PD [10, 60, 61]. We speculate this contradiction may be related to the timing of vitamin application.

5. Vitamin E and PD

Vitamin E is a fat-soluble vitamin with high antioxidant properties. Natural vitamin E includes two subgroups: tocopherols and tocotrienols; and they can further be divided into four lipophilic molecules, respectively: α-, β-, γ-, and δ-tocopherol (αT, βT, γT, and δT) and α-, β-, γ-, and δ-tocotrienol (αTE, βTE, γTE, and δTE). The major difference between tocopherols and tocotrienols is the side chain. Tocopherols have a saturated phytyl tail, while tocotrienols possess an unsaturated isoprenoid side chain [62]. Because of this unsaturated side chain, the tocotrienol is superior to the tocopherol as an antioxidant by increasing the molecular mobility through lipid membranes and by accepting electrons readily. Overt vitamin E deficiency is relatively rare, mainly in infants and premature babies.

In addition to its potent antioxidant capacity, vitamin E is involved in many physiological processes such as immune function [63], cognitive function, physical performance [64, 65], and regulation of gene expression. In humans, deficiency of vitamin E is clinically characterized by peripheral neuropathy, ataxia, and anemia [66, 67].

5.1. Possible Neuroprotective Mechanisms of Vitamin E in PD

Unilateral 6-hydroxydopamine (6-OHDA) injections into the striatum can cause circling behaviours and biochemical abnormalities in rats. Cadet et al. found that pretreatment with either D-alpha-tocopherol or all-racemic-alpha-tocopherol significantly attenuated these pathological changes [68]. Roghani and Behzadi [69] and Sharma and Nehru [70] also demonstrated the similar phenomenon in 6-OHDA-induced PD models and in rotenone-induced PD models, respectively. However, some studies have shown that vitamin E did not completely protect dopaminergic neurons from MPTP-mediated damage in PD models [71, 72]. The protective effects of vitamin E may be achieved through preventing oxidative stress in cells and inhibiting apoptosis. Moreover, one study has found that tocotrienol participates not only in antioxidant stress but also in estrogen receptor beta (ERβ) signal transduction [73]. Then, Nakaso’s team demonstrated a protective effect of vitamin E via this signaling pathway. Firstly, they reported that γ-tocotrienol/δ-tocotrienol exerts neuroprotective effects through the ERβ-PI3K/Akt signaling pathways in SH-SY5Y cells by resisting 1-methyl-4-phenylpyridiniumion- (MPP⁺-) induced toxicity [74]. Secondly, they verified this mechanism in a mouse model of PD. Meanwhile, they found δ-tocotrienol administration can reduce the loss of dopaminergic neurons in the substantia nigra and ER inhibitors can attenuate this neuroprotective effect [75]. These findings indicate vitamin E may be potential therapeutic agents for PD.

5.2. Clinical Studies regarding Vitamin E in PD

The DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) experiment is a multicentre-controlled clinical trial to investigate the long-term efficacy of treatment with deprenyl and/or copherol (vitamin E) and to explore whether it is possible to extend the time before the application of levodopa treatment. At 28 US and Canadian sites, 800 eligible patients with untreated early-stage PD were enrolled in DATATOP and randomized to four groups: (1) deprenyl 10 mg/d, (2) copherol 2000 IU/d, (3) placebo-controlled, and (4) deprenyl 10 mg/d and copherol 2000 IU/d. Deprenyl can delay the development of functional disorders, delay the application of levodopa, and improve motor symptoms, but vitamin E is disappointing [76]. Similarly, another two population-based studies also did not find the association between vitamin E intake and risk of PD [10, 77].

However, a large community-based study showed that high intake of dietary vitamin E (10 mg/day) may reduce the occurrence of PD [78]. Another pilot trail suggests that long-term treatment with vitamin E may delay the use of levodopa in patients with PD [79]. Further research is needed to verify these results.

Although there seems to be no difference in the level of alpha-tocopherol (vitamin E) in serum, cerebrospinal fluid, and brains between PD and normal controls [80–82], there is evidence showing that high-dose vitamin E (2000 IU/day) can significantly elevate the vitamin E level in cerebrospinal fluid [83]. At present, the protective mechanism of vitamin E in PD is still unclear and may be related to the strong antioxidant effect of vitamin E. Further research is needed to determine whether vitamin E can be used as a potential treatment for PD.

6. Vitamin D and PD

Vitamin D, a steroid hormone, is crucial for calcium homeostasis and skeletal health. This nutriment mainly includes two forms: vitamin D₂ and vitamin D₃; the latter is endogenously produced when skin is exposed to UV-B rays from the sun. Both of the above forms are inactive, and they are transformed into the active form 1,25-dihydroxy vitamin D3 (1,25-(OH)₂-D₃) after being hydroxylated twice [84, 85]. 1,25-(OH)₂-D₃ were secreted into the blood system by the kidney, having a direct effect on gene regulation by binding to the nuclear vitamin D receptor (VDR) [86, 87]. Vitamin D deficiency is prevalent at all ages, especially in elderly. Vitamin D not only regulates the calcium homeostasis and skeletal health but also regulates the physiological and pathological processes, such as cell proliferation and differentiation, immunomodulatory, and antioxidative stress [88–90]. Children with a lack of vitamin D may suffer from rickets, and adults may develop osteomalacia. Additionally, vitamin D deficiency is also associated with cardiovascular diseases, muscle weakness, diabetes mellitus, cancers, and multiple sclerosis [91]. The relationship between vitamin D and PD has gradually attracted attention [92].

6.1. Possible Neuroprotective Mechanisms of Vitamin D in PD

VDR belongs to the intranuclear receptor superfamily, composing of eight coding exons and three alternative 5 noncoding exons, spanning over 105 kb, on chromosome 12 [93]. The most widely studied biallelic polymorphic sites are BsmI, TaqI, ApaI, and FokI. Substantial researches have been carried out to explore the relationship between these allelic variations and PD. Kim et al. detected VDR gene BsmI polymorphisms in over 300 Korean individuals (85 PD and 231 controls). The frequency of VDR genotype bb was significantly increased in the PD patients (84.7%) than that in the controls (72.7%). The bb genotype was more common in PD patients with postural instability and gait difficulty than in the PD patients with tremor (94.3% vs. 75.6%) [94]. A meta-analysis showed that VDR BsmI and FokI polymorphisms were associated with the risk of PD [95], and VDR FokI genotype was associated with the severity and cognitive decline of PD [96, 97]. Muscular and motor impairments, which can seriously affect the motor behaviour, were found in the VDR-knockout mice [98], indicating that vitamin D may be involved in the pathogenesis of PD.

Glial cell line-derived neurotrophic factor (GDNF) is a protein that is essential for the maintenance and survival of dopaminergic neurons and can inhibit microglial activation [99]. Many animal studies showed that 1,25-(OH)₂-D₃ could enhance the endogenous GDNF expression in vitro and in vivo and inhibit the glial cell activation to protect dopaminergic neurons from immune inflammation [100–102].

Vitamin D₃ can protect dopaminergic neurons against 6-hydroxydopamine-mediated neurotoxicity and improve the motor performance in the 6-hydroxydopamine-induced PD rat [103]. It may be related to vitamin D’s properties of inhibiting oxidative stress and decreasing the production of reactive oxygen species and free radicals [104]. In addition, endothelial dysfunction may be associated with low vitamin D levels in patients with PD [105]. The definitive correlations between vitamin D and PD require more researches.

6.2. Clinical Studies regarding Vitamin D in PD

Substantial epidemiological and clinical studies suggest that vitamin D has a positive effect on PD. In a cohort study, over 7000 Finnish’s serum samples were collected for measuring the 25-hydroxy vitamin D level, and meanwhile, the occurrence of PD was instigated over a 30-year follow-up period. The results showed that individuals with higher serum vitamin D concentrations had a lower risk of PD [106]. Evatt et al. also noted consistent findings [107].

As mentioned above, vitamin D₃ can be endogenously synthesized upon sunlight exposure in the skin. In a large case-control study of Danish men, involving 3819 PD patients and 19,282 controls, the scholars proposed that men working outdoors have a lower risk of PD [108]. Another nationwide ecologic study in France also suggests that vitamin D levels are negatively correlated with the risk of PD, but this result needs taking ages into account [109]. Wang et al. not only demonstrated a positive correlation between serum 25-hydroxy vitamin D and sunlight exposure but also noted that lower serum levels of 25-hydroxy vitamin D and sunlight exposure can increase the risk of PD [110].

Furthermore, PD patients with lower 25-hydroxy vitamin D levels may exhibit more severe symptoms compared with normal controls [111, 112]. Unsurprisingly, a randomized, double-blind, placebo-controlled trial found that vitamin D₃ supplementation (1200 IU/day for 12 months) significantly prevented the deterioration of PD [113].

7. Conclusion

In summary, vitamins may play a protective role in PD. Among the fat-soluble vitamins, we briefly summarized the effects of vitamin E and vitamin D. At present, although many studies have shown that vitamin E supplementation can reduce the risk of Parkinson’s disease (Table 1), the DATATOP study has showed that vitamin E supplementation is ineffective in Parkinson’s disease (Table 2). Many noninterventional studies found that the high levels of serum vitamin D can reduce the risk of PD (Table 1), and several clinical intervention trials also proposed that vitamin D supplementation can attenuate the deterioration of the Parkinson’s disease and reduce the occurrence of fractures in patients with PD (Table 2). Among the water-soluble vitamins, we elaborated the functions of vitamin B₃ and vitamin C. There is still a paucity of clinical evidence for determining the pros and cons of vitamin B₃ in PD (Table 2). Vitamin C is vital to the human organism, and it can improve levodopa absorption in elderly PD patients (Table 2); current epidemiological evidence is still insufficient to establish a correlation between the serum level or dietary intakes of vitamin C and the risk of PD (Table 1). Although there have been many researches on the relationship between vitamins and PD (Tables 1–3), there is still lack of a clinical intervention trial explicitly confirming that vitamin supplementation can reduce the incidence of PD and prevent the progression of the disease. Moreover, the individual physical and chemical properties, absorption rate, and bioavailability of vitamins may affect the efficacy. Further studies are still needed to clarify the potentials of vitamins for the treatment of PD.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Authors’ Contributions

Xiuzhen Zhao and Ming Zhang equally contributed to this study.

Acknowledgments

This work was supported by the crosswise project from the Ministry of Science and Technology of Jilin Province (Grant No. 3R2168713428) and the Natural Science Foundation of Jilin Province (Grant No. 20180101154JC).

References

1. W. R. Gibb and A. J. Lees, “The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease,” Journal of Neurology, Neurosurgery, and Psychiatry, vol. 51, no. 6, pp. 745–752, 1988. View at: Publisher Site | Google Scholar
2. T. K. Khoo, A. J. Yarnall, G. W. Duncan et al., “The spectrum of nonmotor symptoms in early Parkinson disease,” Neurology, vol. 80, no. 3, pp. 276–281, 2013. View at: Publisher Site | Google Scholar
3. R. B. Postuma, D. Aarsland, P. Barone et al., “Identifying prodromal Parkinson’s disease: pre-motor disorders in Parkinson’s disease,” Movement Disorders, vol. 27, no. 5, pp. 617–626, 2012. View at: Publisher Site | Google Scholar
4. P. Goswami, N. Joshi, and S. Singh, “Neurodegenerative signaling factors and mechanisms in Parkinson’s pathology,” Toxicology In Vitro, vol. 43, pp. 104–112, 2017. View at: Publisher Site | Google Scholar
5. M. G. Spillantini, M. L. Schmidt, V. M. Y. Lee, J. Q. Trojanowski, R. Jakes, and M. Goedert, “α-Synuclein in Lewy bodies,” Nature, vol. 388, no. 6645, pp. 839-840, 1997. View at: Publisher Site | Google Scholar
6. E. Hattingen, J. Magerkurth, U. Pilatus et al., “Phosphorus and proton magnetic resonance spectroscopy demonstrates mitochondrial dysfunction in early and advanced Parkinson’s disease,” Brain, vol. 132, no. 12, pp. 3285–3297, 2009. View at: Publisher Site | Google Scholar
7. W. D. Parker Jr, J. K. Parks, and R. H. Swerdlow, “Complex I deficiency in Parkinson’s disease frontal cortex,” Brain Research, vol. 1189, pp. 215–218, 2008. View at: Publisher Site | Google Scholar
8. D. Sánchez-Hernández, G. H. Anderson, A. N. Poon et al., “Maternal fat-soluble vitamins, brain development, and regulation of feeding behavior: an overview of research,” Nutrition Research, vol. 36, no. 10, pp. 1045–1054, 2016. View at: Publisher Site | Google Scholar
9. J. Chawla and D. Kvarnberg, “Hydrosoluble vitamins,” Handbook of Clinical Neurology, vol. 120, pp. 891–914, 2014. View at: Publisher Site | Google Scholar
10. S. M. Zhang, M. A. Hernan, H. Chen, D. Spiegelman, W. C. Willett, and A. Ascherio, “Intakes of vitamins E and C, carotenoids, vitamin supplements, and PD risk,” Neurology, vol. 59, no. 8, pp. 1161–1169, 2002. View at: Publisher Site | Google Scholar
11. H. Sies, C. Berndt, and D. P. Jones, “Oxidative stress,” Annual Review of Biochemistry, vol. 86, no. 1, pp. 715–748, 2017. View at: Publisher Site | Google Scholar
12. L. V. Kalia and A. E. Lang, “Parkinson’s disease,” The Lancet, vol. 386, no. 9996, pp. 896–912, 2015. View at: Publisher Site | Google Scholar
13. J. Blesa, I. Trigo-Damas, A. Quiroga-Varela, and V. R. Jackson-Lewis, “Oxidative stress and Parkinson’s disease,” Frontiers in Neuroanatomy, vol. 9, p. 91, 2015. View at: Publisher Site | Google Scholar
14. M. P. Murphy, “How mitochondria produce reactive oxygen species,” The Biochemical Journal, vol. 417, no. 1, pp. 1–13, 2009. View at: Publisher Site | Google Scholar
15. A. H. Schapira, J. M. Cooper, D. Dexter, P. Jenner, J. B. Clark, and C. D. Marsden, “Mitochondrial complex I deficiency in Parkinson’s disease,” The Lancet, vol. 333, no. 8649, p. 1269, 1989. View at: Publisher Site | Google Scholar
16. J. Sian, D. T. Dexter, A. J. Lees et al., “Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia,” Annals of Neurology, vol. 36, no. 3, pp. 348–355, 1994. View at: Publisher Site | Google Scholar
17. M. R. Gluck and G. D. Zeevalk, “Inhibition of brain mitochondrial respiration by dopamine and its metabolites: implications for Parkinson’s disease and catecholamine-associated diseases,” Journal of Neurochemistry, vol. 91, no. 4, pp. 788–795, 2004. View at: Publisher Site | Google Scholar
18. D. J. Hare and K. L. Double, “Iron and dopamine: a toxic couple,” Brain, vol. 139, no. 4, pp. 1026–1035, 2016. View at: Publisher Site | Google Scholar
19. H. E. Sauberlich, “Implications of nutritional status on human biochemistry, physiology, and health,” Clinical Biochemistry, vol. 17, no. 2, pp. 132–142, 1984. View at: Publisher Site | Google Scholar
20. K. Mikkelsen, L. Stojanovska, K. Tangalakis, M. Bosevski, and V. Apostolopoulos, “Cognitive decline: a vitamin B perspective,” Maturitas, vol. 93, pp. 108–113, 2016. View at: Publisher Site | Google Scholar
21. W. Gehring, “Nicotinic acid/niacinamide and the skin,” Journal of Cosmetic Dermatology, vol. 3, no. 2, pp. 88–93, 2004. View at: Publisher Site | Google Scholar
22. D. Surjana and D. L. Damian, “Nicotinamide in dermatology and photoprotection,” Skinmed, vol. 9, no. 6, pp. 360–365, 2011. View at: Google Scholar
23. A. Williams and D. Ramsden, “Nicotinamide: a double edged sword,” Parkinsonism & Related Disorders, vol. 11, no. 7, pp. 413–420, 2005. View at: Publisher Site | Google Scholar
24. T. Fukushima, “Niacin metabolism and Parkinson’s disease,” Environmental Health and Preventive Medicine, vol. 10, no. 1, pp. 3–8, 2005. View at: Publisher Site | Google Scholar
25. K. Aoyama, K. Matsubara, M. Kondo et al., “Nicotinamide-N-methyltransferase is higher in the lumbar cerebrospinal fluid of patients with Parkinson’s disease,” Neuroscience Letters, vol. 298, no. 1, pp. 78–80, 2001. View at: Publisher Site | Google Scholar
26. S. M. Griffin, M. R. Pickard, R. P. Orme, C. P. Hawkins, and R. A. Fricker, “Nicotinamide promotes neuronal differentiation of mouse embryonic stem cells in vitro,” Neuroreport, vol. 24, no. 18, pp. 1041–1046, 2013. View at: Publisher Site | Google Scholar
27. S. Imai, “Nicotinamide phosphoribosyltransferase (Nampt): a link between NAD biology, metabolism, and diseases,” Current Pharmaceutical Design, vol. 15, no. 1, pp. 20–28, 2009. View at: Publisher Site | Google Scholar
28. S. M. Pearl, M. D. Antion, G. D. Stanwood, J. D. Jaumotte, G. Kapatos, and M. J. Zigmond, “Effects of NADH on dopamine release in rat striatum,” Synapse, vol. 36, no. 2, pp. 95–101, 2000. View at: Publisher Site | Google Scholar
29. Y. Mizuno, S. Ohta, M. Tanaka et al., “Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease,” Biochemical and Biophysical Research Communications, vol. 163, no. 3, pp. 1450–1455, 1989. View at: Publisher Site | Google Scholar
30. W. J. Nicklas, I. Vyas, and R. E. Heikkila, “Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine,” Life Sciences, vol. 36, no. 26, pp. 2503–2508, 1985. View at: Publisher Site | Google Scholar
31. L. Lu, L. Tang, W. Wei et al., “Nicotinamide mononucleotide improves energy activity and survival rate in an in vitro model of Parkinson’s disease,” Experimental and Therapeutic Medicine, vol. 8, no. 3, pp. 943–950, 2014. View at: Publisher Site | Google Scholar
32. L. Yang, X. Ma, Y. He et al., “Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors,” Science China Life Sciences, vol. 60, no. 3, pp. 249–256, 2017. View at: Publisher Site | Google Scholar
33. L. Liu, C. Peritore, J. Ginsberg, J. Shih, S. Arun, and G. Donmez, “Protective role of SIRT5 against motor deficit and dopaminergic degeneration in MPTP-induced mice model of Parkinson’s disease,” Behavioural Brain Research, vol. 281, pp. 215–221, 2015. View at: Publisher Site | Google Scholar
34. P. A. Fall, M. Fredrikson, O. Axelson, and A. K. Granérus, “Nutritional and occupational factors influencing the risk of Parkinson’s disease: a case-control study in southeastern Sweden,” Movement Disorders, vol. 14, no. 1, pp. 28–37, 1999. View at: Publisher Site | Google Scholar
35. W. Hellenbrand, H. Boeing, B. P. Robra et al., “Diet and Parkinson’s disease. II: a possible role for the past intake of specific nutrients. Results from a self-administered food-frequency questionnaire in a case-control study,” Neurology, vol. 47, no. 3, pp. 644–650, 1996. View at: Publisher Site | Google Scholar
36. J. M. Alisky, “Niacin improved rigidity and bradykinesia in a Parkinson’s disease patient but also caused unacceptable nightmares and skin rash—a case report,” Nutritional Neuroscience, vol. 8, no. 5-6, pp. 327–329, 2005. View at: Publisher Site | Google Scholar
37. R. D. Abbott, G. Webster Ross, L. R. White et al., “Environmental, life-style, and physical precursors of clinical Parkinson’s disease: recent findings from the Honolulu-Asia Aging Study,” Journal of Neurology, vol. 250, Supplement 3, pp. iii30–iii39, 2003. View at: Publisher Site | Google Scholar
38. C. C. Johnson, J. M. Gorell, B. A. Rybicki, K. Sanders, and E. L. Peterson, “Adult nutrient intake as a risk factor for Parkinson’s disease,” International Journal of Epidemiology, vol. 28, no. 6, pp. 1102–1109, 1999. View at: Publisher Site | Google Scholar
39. H. M. Oudemans-van Straaten, A. M. E. Spoelstra-de Man, and M. C. de Waard, “Vitamin C revisited,” Critical Care, vol. 18, no. 4, p. 460, 2014. View at: Publisher Site | Google Scholar
40. I. B. Chatterjee, A. K. Majumder, B. K. Nandi, and N. Subramanian, “Synthesis and some major functions of vitamin C in animals,” Annals of the New York Academy of Sciences, vol. 258, pp. 24–47, 1975. View at: Publisher Site | Google Scholar
41. G. Grosso, R. Bei, A. Mistretta et al., “Effects of vitamin C on health: a review of evidence,” Frontiers in Bioscience, vol. 18, pp. 1017–1029, 2013. View at: Google Scholar
42. E. Belluzzi, M. Bisaglia, E. Lazzarini, L. C. Tabares, M. Beltramini, and L. Bubacco, “Human SOD2 modification by dopamine quinones affects enzymatic activity by promoting its aggregation: possible implications for Parkinson’s disease,” PLoS One, vol. 7, no. 6, article e38026, 2012. View at: Publisher Site | Google Scholar
43. I. N. Mefford, A. F. Oke, and R. N. Adams, “Regional distribution of ascorbate in human brain,” Brain Research, vol. 212, no. 1, pp. 223–226, 1981. View at: Publisher Site | Google Scholar
44. K. Milby, A. Oke, and R. N. Adams, “Detailed mapping of ascorbate distribution in rat brain,” Neuroscience Letters, vol. 28, no. 1, pp. 15–20, 1982. View at: Publisher Site | Google Scholar
45. S. N. Hansen, P. Tveden-Nyborg, and J. Lykkesfeldt, “Does vitamin C deficiency affect cognitive development and function?” Nutrients, vol. 6, no. 9, pp. 3818–3846, 2014. View at: Publisher Site | Google Scholar
46. K. Hosoya, G. Nakamura, S. I. Akanuma, M. Tomi, and M. Tachikawa, “Dehydroascorbic acid uptake and intracellular ascorbic acid accumulation in cultured Müller glial cells (TR-MUL),” Neurochemistry International, vol. 52, no. 7, pp. 1351–1357, 2008. View at: Publisher Site | Google Scholar
47. B. Pardo, M. A. Mena, S. Fahn, and J. G. de Yébenes, “Ascorbic acid protects against levodopa-induced neurotoxicity on a catecholamine-rich human neuroblastoma cell line,” Movement Disorders, vol. 8, no. 3, pp. 278–284, 1993. View at: Publisher Site | Google Scholar
48. H. Sershen, M. E. A. Reith, A. Hashim, and A. Lajtha, “Protection against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine neurotoxicity by the antioxidant ascorbic acid,” Neuropharmacology, vol. 24, no. 12, pp. 1257–1259, 1985. View at: Publisher Site | Google Scholar
49. G. Seitz, S. Gebhardt, J. F. Beck et al., “Ascorbic acid stimulates DOPA synthesis and tyrosine hydroxylase gene expression in the human neuroblastoma cell line SK-N-SH,” Neuroscience Letters, vol. 244, no. 1, pp. 33–36, 1998. View at: Publisher Site | Google Scholar
50. H. Nagayama, M. Hamamoto, M. Ueda, C. Nito, H. Yamaguchi, and Y. Katayama, “The effect of ascorbic acid on the pharmacokinetics of levodopa in elderly patients with Parkinson disease,” Clinical Neuropharmacology, vol. 27, no. 6, pp. 270–273, 2004. View at: Publisher Site | Google Scholar
51. W. Sacks and G. M. Simpson, “Letter: ascorbic acid in levodopa therapy,” Lancet, vol. 1, no. 7905, p. 527, 1975. View at: Google Scholar
52. J. Yan, L. Studer, and R. D. G. McKay, “Ascorbic acid increases the yield of dopaminergic neurons derived from basic fibroblast growth factor expanded mesencephalic precursors,” Journal of Neurochemistry, vol. 76, no. 1, pp. 307–311, 2001. View at: Publisher Site | Google Scholar
53. J. Y. Lee, M. Y. Chang, C. H. Park et al., “Ascorbate-induced differentiation of embryonic cortical precursors into neurons and astrocytes,” Journal of Neuroscience Research, vol. 73, no. 2, pp. 156–165, 2003. View at: Publisher Site | Google Scholar
54. X. B. He, M. Kim, S. Y. Kim et al., “Vitamin C facilitates dopamine neuron differentiation in fetal midbrain through TET1- and JMJD3-dependent epigenetic control manner,” Stem Cells, vol. 33, no. 4, pp. 1320–1332, 2015. View at: Publisher Site | Google Scholar
55. N. Wulansari, E. H. Kim, Y. A. Sulistio, Y. H. Rhee, J. J. Song, and S. H. Lee, “Vitamin C-induced epigenetic modifications in donor NSCs establish midbrain marker expressions critical for cell-based therapy in Parkinson’s disease,” Stem Cell Reports, vol. 9, no. 4, pp. 1192–1206, 2017. View at: Publisher Site | Google Scholar
56. P. Férnandez-Calle, F. J. Jiménez-Jiménez, J. A. Molina et al., “Serum levels of ascorbic acid (vitamin C) in patients with Parkinson’s disease,” Journal of the Neurological Sciences, vol. 118, no. 1, pp. 25–28, 1993. View at: Publisher Site | Google Scholar
57. K. Sudha, A. V. Rao, S. Rao, and A. Rao, “Free radical toxicity and antioxidants in Parkinson’s disease,” Neurology India, vol. 51, no. 1, pp. 60–62, 2003. View at: Google Scholar
58. K. Ide, H. Yamada, K. Umegaki et al., “Lymphocyte vitamin C levels as potential biomarker for progression of Parkinson’s disease,” Nutrition, vol. 31, no. 2, pp. 406–408, 2015. View at: Publisher Site | Google Scholar
59. K. C. Hughes, X. Gao, I. Y. Kim et al., “Intake of antioxidant vitamins and risk of Parkinson’s disease,” Movement Disorders, vol. 31, no. 12, pp. 1909–1914, 2016. View at: Publisher Site | Google Scholar
60. Y. Miyake, W. Fukushima, K. Tanaka et al., “Dietary intake of antioxidant vitamins and risk of Parkinson’s disease: a case-control study in Japan,” European Journal of Neurology, vol. 18, no. 1, pp. 106–113, 2011. View at: Publisher Site | Google Scholar
61. F. Yang, A. Wolk, N. Håkansson, N. L. Pedersen, and K. Wirdefeldt, “Dietary antioxidants and risk of Parkinson’s disease in two population-based cohorts,” Movement Disorders, vol. 32, no. 11, pp. 1631–1636, 2017. View at: Publisher Site | Google Scholar
62. M. L. Colombo, “An update on vitamin E, tocopherol and tocotrienol-perspectives,” Molecules, vol. 15, no. 4, pp. 2103–2113, 2010. View at: Publisher Site | Google Scholar
63. A. Beharka, S. Redican, L. Leka, and S. N. Meydani, “[22] Vitamin E status and immune function,” Methods in Enzymology, vol. 282, pp. 247–263, 1997. View at: Publisher Site | Google Scholar
64. M. Cesari, M. Pahor, B. Bartali et al., “Antioxidants and physical performance in elderly persons: the Invecchiare in Chianti (InCHIANTI) study,” The American Journal of Clinical Nutrition, vol. 79, no. 2, pp. 289–294, 2004. View at: Publisher Site | Google Scholar
65. A. Cherubini, A. Martin, C. Andres-Lacueva et al., “Vitamin E levels, cognitive impairment and dementia in older persons: the InCHIANTI study,” Neurobiology of Aging, vol. 26, no. 7, pp. 987–994, 2005. View at: Publisher Site | Google Scholar
66. M. W. Clarke, J. R. Burnett, and K. D. Croft, “Vitamin E in human health and disease,” Critical Reviews in Clinical Laboratory Sciences, vol. 45, no. 5, pp. 417–450, 2008. View at: Publisher Site | Google Scholar
67. J. M. Aparicio, A. Bélanger-Quintana, L. Suárez et al., “Ataxia with isolated vitamin E deficiency: case report and review of the literature,” Journal of Pediatric Gastroenterology and Nutrition, vol. 33, no. 2, pp. 206–210, 2001. View at: Publisher Site | Google Scholar
68. J. L. Cadet, M. Katz, V. Jackson-Lewis, and S. Fahn, “Vitamin E attenuates the toxic effects of intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats: behavioral and biochemical evidence,” Brain Research, vol. 476, no. 1, pp. 10–15, 1989. View at: Publisher Site | Google Scholar
69. M. Roghani and G. Behzadi, “Neuroprotective effect of vitamin E on the early model of Parkinson’s disease in rat: behavioral and histochemical evidence,” Brain Research, vol. 892, no. 1, pp. 211–217, 2001. View at: Publisher Site | Google Scholar
70. N. Sharma and B. Nehru, “Beneficial effect of vitamin E in rotenone induced model of PD: behavioural, neurochemical and biochemical study,” Experimental Neurobiology, vol. 22, no. 3, pp. 214–223, 2013. View at: Publisher Site | Google Scholar
71. T. L. Perry, V. W. Yong, S. Hansen et al., “α-Tocopherol and β-carotene do not protect marmosets against the dopaminergic neurotoxicity of N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine,” Journal of the Neurological Sciences, vol. 81, no. 2-3, pp. 321–331, 1987. View at: Publisher Site | Google Scholar
72. C. Heim, W. Kolasiewicz, T. Kurz, and K. H. Sontag, “Behavioral alterations after unilateral 6-hydroxydopamine lesions of the striatum. Effect of alpha-tocopherol,” Polish Journal of Pharmacology, vol. 53, no. 5, pp. 435–448, 2001. View at: Google Scholar
73. R. Comitato, K. Nesaretnam, G. Leoni et al., “A novel mechanism of natural vitamin E tocotrienol activity: involvement of ERβ signal transduction,” American Journal of Physiology. Endocrinology and Metabolism, vol. 297, no. 2, pp. E427–E437, 2009. View at: Publisher Site | Google Scholar
74. K. Nakaso, N. Tajima, Y. Horikoshi et al., “The estrogen receptor β-PI3K/Akt pathway mediates the cytoprotective effects of tocotrienol in a cellular Parkinson’s disease model,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1842, no. 9, pp. 1303–1312, 2014. View at: Publisher Site | Google Scholar
75. K. Nakaso, Y. Horikoshi, T. Takahashi et al., “Estrogen receptor-mediated effect of δ-tocotrienol prevents neurotoxicity and motor deficit in the MPTP mouse model of Parkinson’s disease,” Neuroscience Letters, vol. 610, pp. 117–122, 2016. View at: Publisher Site | Google Scholar
76. “DATATOP: a multicenter controlled clinical trial in early Parkinson’s disease: Parkinson Study Group,” Archives of Neurology, vol. 46, no. 10, pp. 1052–1060, 1989. View at: Publisher Site | Google Scholar
77. G. Logroscino, K. Marder, L. Cote, M. X. Tang, S. Shea, and R. Mayeux, “Dietary lipids and antioxidants in Parkinson’s disease: a population-based, case-control study,” Annals of Neurology, vol. 39, no. 1, pp. 89–94, 1996. View at: Publisher Site | Google Scholar
78. M. C. de Rijk, M. M. Breteler, J. den Breeijen et al., “Dietary antioxidants and Parkinson disease. The Rotterdam Study,” Archives of Neurology, vol. 54, no. 6, pp. 762–765, 1997. View at: Publisher Site | Google Scholar
79. S. Fahn, “A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson’s disease,” Annals of Neurology, vol. 32, no. S1, pp. S128–S132, 1992. View at: Publisher Site | Google Scholar
80. P. Fernandez-Calle, J. A. Molina, F. J. Jimenez-Jimenez et al., “Serum levels of alpha-tocopherol (vitamin E) in Parkinson’s disease,” Neurology, vol. 42, no. 5, pp. 1064–1066, 1992. View at: Publisher Site | Google Scholar
81. D. T. Dexter, P. Jenner, R. J. Ward et al., “α-Tocopherol levels in brain are not altered in Parkinson’s disease,” Annals of Neurology, vol. 32, no. 4, pp. 591–593, 1992. View at: Publisher Site | Google Scholar
82. J. A. Molina, F. de Bustos, F. J. Jiménez-Jiménez et al., “Cerebrospinal fluid levels of alpha-tocopherol (vitamin E) in Parkinson’s disease,” Journal of Neural Transmission, vol. 104, no. 11-12, pp. 1287–1293, 1997. View at: Publisher Site | Google Scholar
83. G. T. Vatassery, S. Fahn, and M. A. Kuskowski, “Alpha tocopherol in CSF of subjects taking high-dose vitamin E in the DATATOP study: Parkinson Study Group,” Neurology, vol. 50, no. 6, pp. 1900–1902, 1998. View at: Publisher Site | Google Scholar
84. V. Kulda, “Vitamin D metabolism,” Vnitřní Lékařství, vol. 58, no. 5, pp. 400–404, 2012. View at: Google Scholar
85. S. Christakos, P. Dhawan, A. Verstuyf, L. Verlinden, and G. Carmeliet, “Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects,” Physiological Reviews, vol. 96, no. 1, pp. 365–408, 2016. View at: Publisher Site | Google Scholar
86. M. R. Haussler, G. K. Whitfield, I. Kaneko et al., “Molecular mechanisms of vitamin D action,” Calcified Tissue International, vol. 92, no. 2, pp. 77–98, 2013. View at: Publisher Site | Google Scholar
87. C. Carlberg and F. Molnar, “Vitamin D receptor signaling and its therapeutic implications: genome-wide and structural view,” Canadian Journal of Physiology and Pharmacology, vol. 93, no. 5, pp. 311–318, 2015. View at: Publisher Site | Google Scholar
88. S. Samuel and M. D. Sitrin, “Vitamin D’s role in cell proliferation and differentiation,” Nutrition Reviews, vol. 66, Supplement 2, no. 10, pp. S116–S124, 2008. View at: Publisher Site | Google Scholar
89. M. Myszka and M. Klinger, “The immunomodulatory role of vitamin D,” Postȩpy Higieny i Medycyny Doświadczalnej, vol. 68, pp. 865–878, 2014. View at: Publisher Site | Google Scholar
90. K. Kono, H. Fujii, K. Nakai et al., “Anti-oxidative effect of vitamin D analog on incipient vascular lesion in non-obese type 2 diabetic rats,” American Journal of Nephrology, vol. 37, no. 2, pp. 167–174, 2013. View at: Publisher Site | Google Scholar
91. O. Sahota, “Understanding vitamin D deficiency,” Age and Ageing, vol. 43, no. 5, pp. 589–591, 2014. View at: Publisher Site | Google Scholar
92. H. L. Newmark and J. Newmark, “Vitamin D and Parkinson’s disease—a hypothesis,” Movement Disorders, vol. 22, no. 4, pp. 461–468, 2007. View at: Publisher Site | Google Scholar
93. K. Köstner, N. Denzer, C. S. Müller, R. Klein, W. Tilgen, and J. Reichrath, “The relevance of vitamin D receptor (VDR) gene polymorphisms for cancer: a review of the literature,” Anticancer Research, vol. 29, no. 9, pp. 3511–3536, 2009. View at: Google Scholar
94. J. S. Kim, Y. I. Kim, C. Song et al., “Association of vitamin D receptor gene polymorphism and Parkinson’s disease in Koreans,” Journal of Korean Medical Science, vol. 20, no. 3, pp. 495–498, 2005. View at: Publisher Site | Google Scholar
95. C. Li, H. Qi, S. Wei et al., “Vitamin D receptor gene polymorphisms and the risk of Parkinson’s disease,” Neurological Sciences, vol. 36, no. 2, pp. 247–255, 2015. View at: Publisher Site | Google Scholar
96. M. Suzuki, M. Yoshioka, M. Hashimoto et al., “25-hydroxyvitamin D, vitamin D receptor gene polymorphisms, and severity of Parkinson’s disease,” Movement Disorders, vol. 27, no. 2, pp. 264–271, 2012. View at: Publisher Site | Google Scholar
97. N. M. Gatto, K. C. Paul, J. S. Sinsheimer et al., “Vitamin D receptor gene polymorphisms and cognitive decline in Parkinson’s disease,” Journal of the Neurological Sciences, vol. 370, pp. 100–106, 2016. View at: Publisher Site | Google Scholar
98. T. H. J. Burne, J. J. McGrath, D. W. Eyles, and A. Mackay-Sim, “Behavioural characterization of vitamin D receptor knockout mice,” Behavioural Brain Research, vol. 157, no. 2, pp. 299–308, 2005. View at: Publisher Site | Google Scholar
99. F. L. Campos, A. C. Cristovão, S. M. Rocha, C. P. Fonseca, and G. Baltazar, “GDNF contributes to oestrogen-mediated protection of midbrain dopaminergic neurones,” Journal of Neuroendocrinology, vol. 24, no. 11, pp. 1386–1397, 2012. View at: Publisher Site | Google Scholar
100. B. Sanchez, J. L. Relova, R. Gallego, I. Ben-Batalla, and R. Perez-Fernandez, “1, 25-Dihydroxyvitamin D3 administration to 6-hydroxydopamine-lesioned rats increases glial cell line-derived neurotrophic factor and partially restores tyrosine hydroxylase expression in substantia nigra and striatum,” Journal of Neuroscience Research, vol. 87, no. 3, pp. 723–732, 2009. View at: Publisher Site | Google Scholar
101. B. Sanchez, E. Lopez-Martin, C. Segura, J. L. Labandeira-Garcia, and R. Perez-Fernandez, “1, 25-Dihydroxyvitamin D₃ increases striatal GDNF mRNA and protein expression in adult rats,” Molecular Brain Research, vol. 108, no. 1-2, pp. 143–146, 2002. View at: Publisher Site | Google Scholar
102. J. S. Kim, S. Y. Ryu, I. Yun et al., “1α,25-Dihydroxyvitamin D3 protects dopaminergic neurons in rodent models of Parkinson’s disease through inhibition of microglial activation,” Journal of Clinical Neurology, vol. 2, no. 4, pp. 252–257, 2006. View at: Publisher Site | Google Scholar
103. J. Y. Wang, J. N. Wu, T. L. Cherng et al., “Vitamin D₃ attenuates 6-hydroxydopamine-induced neurotoxicity in rats,” Brain Research, vol. 904, no. 1, pp. 67–75, 2001. View at: Publisher Site | Google Scholar
104. W. Jang, H. J. Kim, H. Li et al., “1,25-Dyhydroxyvitamin D₃ attenuates rotenone-induced neurotoxicity in SH-SY5Y cells through induction of autophagy,” Biochemical and Biophysical Research Communications, vol. 451, no. 1, pp. 142–147, 2014. View at: Publisher Site | Google Scholar
105. J. H. Yoon, D. K. Park, S. W. Yong, and J. M. Hong, “Vitamin D deficiency and its relationship with endothelial dysfunction in patients with early Parkinson’s disease,” Journal of Neural Transmission (Vienna), vol. 122, no. 12, pp. 1685–1691, 2015. View at: Publisher Site | Google Scholar
106. P. Knekt, A. Kilkkinen, H. Rissanen, J. Marniemi, K. Sääksjärvi, and M. Heliövaara, “Serum vitamin D and the risk of Parkinson disease,” Archives of Neurology, vol. 67, no. 7, pp. 808–811, 2010. View at: Publisher Site | Google Scholar
107. M. L. Evatt, M. R. Delong, N. Khazai, A. Rosen, S. Triche, and V. Tangpricha, “Prevalence of vitamin d insufficiency in patients with Parkinson disease and Alzheimer disease,” Archives of Neurology, vol. 65, no. 10, pp. 1348–1352, 2008. View at: Publisher Site | Google Scholar
108. L. Kenborg, C. F. Lassen, B. Ritz et al., “Outdoor work and risk for Parkinson’s disease: a population-based case-control study,” Occupational and Environmental Medicine, vol. 68, no. 4, pp. 273–278, 2011. View at: Publisher Site | Google Scholar
109. A. Kravietz, S. Kab, L. Wald et al., “Association of UV radiation with Parkinson disease incidence: a nationwide French ecologic study,” Environmental Research, vol. 154, pp. 50–56, 2017. View at: Publisher Site | Google Scholar
110. J. Wang, D. Yang, Y. Yu, G. Shao, and Q. Wang, “Vitamin D and sunlight exposure in newly-diagnosed Parkinson’s disease,” Nutrients, vol. 8, no. 3, p. 142, 2016. View at: Publisher Site | Google Scholar
111. Y. Liu and B. S. Zhang, “Serum 25-hydroxyvitamin D predicts severity in Parkinson’s disease patients,” Neurological Sciences, vol. 35, no. 1, pp. 67–71, 2014. View at: Publisher Site | Google Scholar
112. I. Sleeman, T. Aspray, R. Lawson et al., “The role of vitamin D in disease progression in early Parkinson’s disease,” Journal of Parkinson's Disease, vol. 7, no. 4, pp. 669–675, 2017. View at: Publisher Site | Google Scholar
113. M. Suzuki, M. Yoshioka, M. Hashimoto et al., “Randomized, double-blind, placebo-controlled trial of vitamin D supplementation in Parkinson disease,” The American Journal of Clinical Nutrition, vol. 97, no. 5, pp. 1004–1013, 2013. View at: Publisher Site | Google Scholar
114. J. Xu, S. Q. Xu, J. Liang, Y. Lu, J. H. Luo, and J. H. Jin, “Protective effect of nicotinamide in a mouse Parkinson’s disease model,” Zhejiang Da Xue Xue Bao. Yi Xue Ban, vol. 41, no. 2, pp. 146–152, 2012. View at: Google Scholar
115. H. Jia, X. Li, H. Gao et al., “High doses of nicotinamide prevent oxidative mitochondrial dysfunction in a cellular model and improve motor deficit in a Drosophila model of Parkinson’s disease,” Journal of Neuroscience Research, vol. 86, no. 9, pp. 2083–2090, 2008. View at: Publisher Site | Google Scholar
116. D. W. Anderson, K. A. Bradbury, and J. S. Schneider, “Broad neuroprotective profile of nicotinamide in different mouse models of MPTP-induced parkinsonism,” The European Journal of Neuroscience, vol. 28, no. 3, pp. 610–617, 2008. View at: Publisher Site | Google Scholar
117. S. Khan, S. Jyoti, F. Naz et al., “Effect of L-ascorbic acid on the climbing ability and protein levels in the brain of Drosophila model of Parkinson’s disease,” The International Journal of Neuroscience, vol. 122, no. 12, pp. 704–709, 2012. View at: Publisher Site | Google Scholar
118. G. G. Ortiz, F. P. Pacheco-Moisés, V. M. Gómez-Rodríguez, E. D. González-Renovato, E. D. Torres-Sánchez, and A. C. Ramírez-Anguiano, “Fish oil, melatonin and vitamin E attenuates midbrain cyclooxygenase-2 activity and oxidative stress after the administration of 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine,” Metabolic Brain Disease, vol. 28, no. 4, pp. 705–709, 2013. View at: Publisher Site | Google Scholar
119. P. Pasbakhsh, N. Omidi, K. Mehrannia et al., “The protective effect of vitamin E on locus coeruleus in early model of Parkinson’s disease in rat: immunoreactivity evidence,” Iranian Biomedical Journal, vol. 12, no. 4, pp. 217–222, 2008. View at: Google Scholar
120. L. A. R. Lima, M. J. P. Lopes, R. O. Costa et al., “Vitamin D protects dopaminergic neurons against neuroinflammation and oxidative stress in hemiparkinsonian rats,” Journal of Neuroinflammation, vol. 15, no. 1, p. 249, 2018. View at: Publisher Site | Google Scholar
121. R. Calvello, A. Cianciulli, G. Nicolardi et al., “Vitamin D treatment attenuates neuroinflammation and dopaminergic neurodegeneration in an animal model of Parkinson’s disease, shifting M1 to M2 microglia responses,” Journal of Neuroimmune Pharmacology, vol. 12, no. 2, pp. 327–339, 2017. View at: Publisher Site | Google Scholar
122. H. Li, W. Jang, H. J. Kim et al., “Biochemical protective effect of 1,25-dihydroxyvitamin D₃ through autophagy induction in the MPTP mouse model of Parkinson’s disease,” Neuroreport, vol. 26, no. 12, pp. 669–674, 2015. View at: Publisher Site | Google Scholar
123. W. A. Cass, L. E. Peters, A. M. Fletcher, and D. M. Yurek, “Calcitriol promotes augmented dopamine release in the lesioned striatum of 6-hydroxydopamine treated rats,” Neurochemical Research, vol. 39, no. 8, pp. 1467–1476, 2014. View at: Publisher Site | Google Scholar
124. The Parkinson Study Group, “Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease,” The New England Journal of Medicine, vol. 328, no. 3, pp. 176–183, 1993. View at: Publisher Site | Google Scholar
125. M. Taghizadeh, O. R. Tamtaji, E. Dadgostar et al., “The effects of omega-3 fatty acids and vitamin E co-supplementation on clinical and metabolic status in patients with Parkinson’s disease: a randomized, double-blind, placebo-controlled trial,” Neurochemistry International, vol. 108, pp. 183–189, 2017. View at: Publisher Site | Google Scholar
126. Y. Sato, S. Manabe, H. Kuno, and K. Oizumi, “Amelioration of osteopenia and hypovitaminosis D by 1α-hydroxyvitamin D3 in elderly patients with Parkinson’s disease,” Journal of Neurology, Neurosurgery, and Psychiatry, vol. 66, no. 1, pp. 64–68, 1999. View at: Publisher Site | Google Scholar
127. D. King, J. R. Playfer, and N. B. Roberts, “Concentrations of vitamins A, C and E in elderly patients with Parkinson’s disease,” Postgraduate Medical Journal, vol. 68, no. 802, pp. 634–637, 1992. View at: Publisher Site | Google Scholar
128. J. E. Kim, E. Oh, J. Park, J. Youn, J. S. Kim, and W. Jang, “Serum 25-hydroxyvitamin D3 level may be associated with olfactory dysfunction in de novo Parkinson’s disease,” Journal of Clinical Neuroscience, vol. 57, pp. 131–135, 2018. View at: Publisher Site | Google Scholar
129. S. Shrestha, P. L. Lutsey, A. Alonso, X. Huang, T. H. Mosley Jr, and H. Chen, “Serum 25-hydroxyvitamin D concentrations in mid-adulthood and Parkinson’s disease risk,” Movement Disorders, vol. 31, no. 7, pp. 972–978, 2016. View at: Publisher Site | Google Scholar
130. C. H. Lin, K. H. Chen, M. L. Chen, H. I. Lin, and R. M. Wu, “Vitamin D receptor genetic variants and Parkinson’s disease in a Taiwanese population,” Neurobiology of Aging, vol. 35, no. 5, pp. 1212.e11–1212.e13, 2014. View at: Publisher Site | Google Scholar
131. D. Zhu, G. Y. Liu, Z. Lv, S. R. Wen, S. Bi, and W. Z. Wang, “Inverse associations of outdoor activity and vitamin D intake with the risk of Parkinson’s disease,” Journal of Zhejiang University Science B, vol. 15, no. 10, pp. 923–927, 2014. View at: Publisher Site | Google Scholar
132. M. S. Petersen, S. Bech, D. H. Christiansen, A. V. Schmedes, and J. Halling, “The role of vitamin D levels and vitamin D receptor polymorphism on Parkinson’s disease in the Faroe Islands,” Neuroscience Letters, vol. 561, pp. 74–79, 2014. View at: Publisher Site | Google Scholar
133. R. Török, N. Török, L. Szalardy et al., “Association of vitamin D receptor gene polymorphisms and Parkinson’s disease in Hungarians,” Neuroscience Letters, vol. 551, pp. 70–74, 2013. View at: Publisher Site | Google Scholar
134. Z. Lv, B. Tang, Q. Sun, X. Yan, and J. Guo, “Association study between vitamin d receptor gene polymorphisms and patients with Parkinson disease in Chinese Han population,” The International Journal of Neuroscience, vol. 123, no. 1, pp. 60–64, 2013. View at: Publisher Site | Google Scholar
135. A. L. Peterson, M. Mancini, and F. B. Horak, “The relationship between balance control and vitamin D in Parkinson’s disease-a pilot study,” Movement Disorders, vol. 28, no. 8, pp. 1133–1137, 2013. View at: Publisher Site | Google Scholar
136. M. L. Evatt, M. DeLong, M. Kumari et al., “High prevalence of hypovitaminosis D status in patients with early Parkinson disease,” Archives of Neurology, vol. 68, no. 3, pp. 314–319, 2011. View at: Publisher Site | Google Scholar
137. Y. Miyake, K. Tanaka, W. Fukushima et al., “Lack of association of dairy food, calcium, and vitamin D intake with the risk of Parkinson’s disease: a case-control study in Japan,” Parkinsonism & Related Disorders, vol. 17, no. 2, pp. 112–116, 2011. View at: Publisher Site | Google Scholar

Copyright

Copyright © 2019 Xiuzhen Zhao et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.