Selenium Effects on Oxidative Stress-Induced Calcium Signaling Pathways in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a neurological disorder in which oxidative stress and reactive oxygen species productions are proposed to be involved in its pathogenesis. Despite considerable advancement in Selenium’s (Se) molecular biology and metabolism, we do not know much about the cell type-specific pattern of Se distribution in the brain of PD humans and experimental animals. Although, there is plenty of evidence around the role of Se deficiency in PD’s pathogenesis impacting lipid peroxidation and reducing glutathione (GSH) and glutathione peroxidase (GPX). It has been suggested that Se has an inducible role in selenium-dependent GPX activity in PD animals and humans. However, calcium as a second messenger regulates the neuron cells’ essential activities, but its overloading leads to cellular oxidative stress and apoptosis. Therefore, Se’s antioxidant role can affect calcium signaling and alleviate its complications. There are signs of Se and Selenoproteins incorporation in protecting stress oxidative in various pathways. In conclusion, there is convincing proof for the crucial role of Se and Calcium in PD pathogenesis.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12291-022-01031-1.

Introduction

Although the brain occupies less than 2% of the body’s mass, it has the most metabolical function among all body organs [1]. However, according to its great metabolic activity, it is significantly defenseless to peroxidation [2]; also, lack of antioxidant enzyme activities in the brain increases oxidative stress within specific neurons [3]. Antioxidant enzymes have an essential role in the pathogenesis of neurodegenerative disorders characterized by neuronal inflammation and neuronal death among the aging population, including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar dementia, and Multiple Sclerosis (MS) [4–6]. PD, however, is a progressive neurodegenerative disorder affecting patients’ motor functions while causing non-motor symptoms ranging from cognitive impairment to gastrointestinal problems [7] [8–10]. The molecular basis underlying neurodegenerative diseases’ pathogenesis is increasingly being exposed, such as aggregation of unfolded or misfolded proteins [11], dysfunction of the ubiquitin-proteasome system [12, 13], and changing metal homeostasis (especially Calcium Signaling) [14].

Calcium (Ca²⁺), as a second messenger, regulates the neuron cells’ essential activities and participates in depolarization signals and synaptic activities. During neurodegenerative disorders, neurons’ ability to maintain an adequate energy level might compromise Ca²⁺ homeostasis. Numerous theories have been proposed to describe the role of Ca signaling in PD. Still, it has been shown that the autonomous activities of neurons, which are sustained by their specific Cav1.3 L-type channel subunits, are responsible for the basal metabolic stress [15].

On the other hand, precise trace element balance is vital for a healthy nervous system and neuronal susceptibility to excitability. Numerous articles proposed that Selenium (Se) may play a crucial role in developing PD [16, 17]. Se is an ingredient of several antioxidant enzymes such as thioredoxin reductase (TrxR) and glutathione peroxidase (GPX) [18], and its biological role has been mainly attributed to its presence as the 21st amino acid, selenocysteine (Sec) [19–21]. Se also plays a crucial role in the stress oxidative defense system through its inherent antioxidant activity, though this element’s function is not clear yet.

Even in Se deficiency, the brain has the most significant superiority to intake Se [22]. Besides, the antioxidant activity of particular selenoproteins is of distinct interest in neurodegeneration disorders [23]. This article reviews the current data and essential theories regarding Selenium’s effects on oxidative Stress-induced molecular pathways through calcium signaling in PD.

Oxidative stress

The reactive species production is one of the uncontrolled damaging biomolecules’ principles, such as DNA, lipids, proteins, and carbohydrates or altered metal homeostasis [24]. Numerous of these processes are series reactions beginning by a radical species delivered to full target biomolecules [25–28]. Two main types of free radical species are reactive oxygen species (ROS) and reactive nitrogen species (NO) [29]. ROS includes hydrogen peroxide (H₂O₂), hydroxyl radical (^•OH), and Superoxide (O₂^•−) [30].

Besides, NO is generated endogenously through the reduction of l-arginine to l‐citrulline via three nitric oxide synthase (NOS) isoforms: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS) [31]. As a neurotransmitter and neuromodulator, NO protects against Microglia penetration to the brain and alerts for threatening neuronal cells [32, 33]. Microglia enhances NO generation via iNOS/NO signaling and increases calcium entrance throughout transient-receptor-potential-vanilloid type-II (TRPV II) channels via PKG/PI3K dependent pathway [34]. Besides, microglia generates H₂O₂ and cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). These cytokines induce more ROSand iNOS production and excess NO radicals in microglia [35]. The cytokines also activate nNOS, phospholipase A2, and calpains (a member of the Ca²⁺-stimulated proteinases family), turning xanthine dehydrogenase into xanthine oxidase and producing O₂ and H₂O₂ [36–38]. Furthermore, the intracellular Ca²⁺ elevation prevents mitochondrial functions with the production of mitochondrial O₂. Thus, excess superoxide radicals react with NO radicals to produce peroxynitrite, contributing to neuronal damage in neurodegenerative disorders [39–41].

Oxidative stress and PD

Experimental evidence has shown that oxidative stress leads to PD, but the process related to neuronal degeneration in substantia nigra pars compacta (SNc) remained unknown [42].

Degeneration of SNc is advanced in PD patients, and only late-stage components of pathogenesis are detectable. The Glutathione (GSH) level in advanced PD is lower than age‐matched control tissues [43], which probably indicates that impairments of the antioxidant system in PD may be related to the vulnerability of the SNc to oxidative mechanisms [44]. However, the cause of losing nigral GSH is not understood clearly yet. Nevertheless, a hypothesis shows that the loss of nigral GSH is not due to an impairment of GSH synthesis and defects of enzyme systems in the GSH oxidation-reduction cycle; but is due to leakage of impaired GSH, which still preserved its function. Furthermore, the formation of the glutamyl and cysteinyl peptides of GSH with dopamine occurs and can be detected in PD patients’ brains. Noticeably, converting these peptides to molecular species prevents mitochondrial activity, which might be toxic to dopaminergic cells. Whatever is the reason for the losing GSH, it makes cells more vulnerable to toxin actions and potentiates the toxic impacts of glial cell activation toward dopaminergic neurons [45, 46].

Except for GSH levels, there is no evidence demonstrating that oxidative stress can initiate cell death in PD. However, oxidative stress is present in measurable quantities when the neuronal loss is marked [47], and it may be linked to other processes related to cell death, including mitochondrial impairment, inflammation, and the toxic effects of NO [48, 49]. Through inhibition of oxidative stress, prevention of apoptotic cell death is possible, whether as a direct or indirect mediated alteration; therefore, dopaminergic cells are supplied by various protective mechanisms [50]. Still, dopaminergic cells may be overcome by an extra oxidative load, and protective mechanisms’ failure may allow endogenous oxidative processes to damaged cells [51–53].

In conclusion, the evidence for the role of oxidative stress in PD is overwhelming, and it can lead to rising oxidative damage in the SNc. Oxidative stress, however, is not separated from other components of dopaminergic cell degeneration. The basic nature of free radicals production and the protective mechanisms interfere with the nigral cell degeneration process [54].

Role of Calcium in PD

Calcium (Ca²⁺) is one of the second messengers that regulate cells’ essential activities [55]. Developing various pathways to couple the Ca2 + signal to their biochemical functions is vital to neurons [56].

Remarkably, Ca²⁺ contributes to activity-dependent modulation of synaptic transmission in the brain [57]. During neurodegenerative disorders, neurons’ ability to keep enough energy can affect Ca²⁺ homeostasis [41]. In PD, multiple neurodegeneration symptoms result from mitochondria malfunctions due to toxins’ particular effects on the respiratory chain and genetic mutations [58, 59]. Notwithstanding these effects, a distinctive feature of PD is the selective loss of dopaminergic neurons in SNc [60]. Recently it has been demonstrated that innate autonomous dopaminergic neuron activity, which their particular L-type voltage-gated calcium channel Cav1.3 subunit is responsible for the oxidative stress under physiological conditions, compensated by mitochondrial buffering. However, oxidative stress overcomes the protective mechanisms when mitochondrial functions become compromised, and the neurodegenerative process will appear [15].

The gradient of specific ions, i.e., Na⁺, K⁺, Ca²⁺, and Cl⁻, between extracellular and intracellular, leads to alteration of membrane potential toward positive values and causes action potentials which most neurons react to these small changes [61]. The diversity depends on the differential expression of voltage-dependent channels, including voltage-dependent Ca²⁺, voltage-activated K⁺, Ca²⁺-activated K⁺ currents, etc. [62]. SNc neurons involve Cav1.3 L-type Ca²⁺ channels [63]. These channels generate a Ca²⁺ influx that has the advantage of dopamine production [64]. Also, during physiological pace-making enhanced, Ca²⁺ entry create oxidative stress in mitochondria by enhanced ROS production [65].

On the other hand, high alpha-synuclein (α-syn, a misfolded protein that aggregates in the brain and leads to PD) disrupts cellular/ mitochondrial Ca²⁺ homeostasis by enhancing membrane permeability to the ions [66]. The loss of α-syn function (attributed to overexpression, silencing, or mutations) induces endoplasmic reticulum (ER)–mitochondria interaction by reduction of their tethering; Thus, α-syn losing impairs mitochondrial Ca²⁺ homeostasis, which is leading to PD progression (represented in the figure) [67].

Fig. 1.

schematic view of Se effects on calcium signaling, stress oxidative and antioxidant system

SNc neurons involve Cav1.3 L-type Ca²⁺ channels. These channels generate Ca²⁺ influx that has the advantage of dopamine production. During physiological pace-making enhanced Ca²⁺ entry create oxidative stress in mitochondria by enhanced ROS production. On the other hand, High levels of α-syn disrupt cellular/ mitochondrial Ca²⁺ homeostasis. Oxidative stress causes Ca²⁺ influx into the cytoplasm from the extracellular environment and the ER through the cell membrane and channels. Increasing the Ca²⁺ level in the cytoplasm induces Ca²⁺ influx into mitochondria and nuclei. In mitochondria, Ca²⁺ impairs metabolism to induce cell death. In nuclei, Ca²⁺ modulates gene transcription and nucleases to control apoptosis.

The effect of oxidative stress on calcium signaling

ROS and NO species can be used as a messenger in normal cell functions [68]. Nevertheless, at oxidative stress levels, they can impair normal pathways. Such an alteration is primarily mediated by Ca²⁺ Signaling [69].

Oxidative stress causes Ca²⁺ influx into the cytoplasm from the extracellular environment and the Endoplasmic reticulum (ER) through the cell membrane and channels. Increasing the Ca²⁺ level in the cytoplasm induces Ca²⁺ influx into mitochondria and nuclei [70]. In mitochondria, Ca²⁺ impairs metabolism to cause cell death, but Ca²⁺ modulates gene transcription and nucleases in nuclei to control apoptosis [71]. Since oxidative stress is associated with PD, understanding how oxidants and antioxidants alter Ca²⁺ signaling help to understand the process of neurodegeneration and may lead to strategies for prevention; one of the essential antioxidants can be Se.

Selenium intake and metabolism in PD

Selenium (Se) is a micronutrient that enters into the food chain through plants, and its concentration modifies according to the available Se level of the soil [72]. Se can be in two forms of organic and inorganic. The most common inorganic types of Se are Selenite and Selenate, found in animal and plant tissues. On the other hand, the major organic forms are Selenomethionine and Se-methyl selenocysteine, found in selenium-enriched plants such as cerebral grains, grassland legumes, and wild leaks [73–75]. Selenite and selenate are converted into Sec. Besides, selenomethionine (dietary) combines in the body protein instead of methionine, then converts to Sect. [76]. Selenium compounds catabolize to the hydrogen selenide and methylate, finally secrete in the breath as dimethyl-selenide or urine as trimethyl-selenonium [77].

The total level of Se is approximately low in the human brain, but the brain can retain its Se even at prolonged times of insufficient dietary Se consumption [22, 78]. However, Se levels in various adult human brain areas differ. Gray matter areas have higher Se concentrations; the highest level belongs to putamen (1,093 ng/g dry weight) [79], but white matter regions tend to have lower Se levels (283 ng/g in Corpus callosum) [80]. Besides, Se-dependent enzymes, including Glutathione peroxidase (GPX) and thioredoxin system, are involved in all brain and nervous system parts [81]. The etiological role of Se remained unknown yet. However, evidence revealed that Se protects against ROS-induced cell damage [82]. The proposed mechanisms are principally within the function of selenoenzymes and selenoproteins [83]. Here we focus on the effects of Se in PD. Very high or deficient levels of Se might contribute to the pathogenesis of PD because this imbalance increases oxidative stress levels. Se is involved in the antioxidant system; it plays a unique role in PD’s pathogenesis [84]. Nowadays, several population-based types of research that have studied the relationship between Se and PD acclaimed that Se could be used as an independent biomarker for diagnosing PD [85–87]. Therefore, Se’s very high and low body levels may increase the oxidative stress level and contribute to PD’s pathogenesis. In this way, Gellein et al. demonstrated that the Se levels of serum samples collected after patients’ diagnosis with PD (73.0 µg/l) is lower than pre-diagnostic proportions (109.8 µg/l) [88]. Also, a research by Maass et al. on the Se level of CSF shows a higher level in PD patients (9.4 µg/l) in comparison with the control group (5.9 µg/l) [89] while, Zhao et al. acclaimed that lower range of plasma Se may reduce the risk of PD [90]. In this regard, Shahar et al. have shown in a long-term study that the level of plasma Se was not associated with PD risk but undoubtedly correlated to performance-based assessments in neurological task coordination and motor speed [91].

In addition to all this, some selenoproteins, such as SelP and GPX4, have been reported to be involved in PD’s physiopathology, which we discuss them.

Effects of Selenium on Calcium Signaling

GSH is used as a substrate to synthesize the Se-dependent GPX enzyme. [92]. If the free radical generation increases equivalent to GPX enzyme activities, GSH levels decrease [93]. Researchers have shown a reduction in Ca²⁺ release in GSH depleted neurons, although N-acetylcysteine induces protective effects on Ca²⁺ release and oxidative stress in GSH depleted neurons. Besides, GSH and GPX play a crucial role in protecting cells from ROS, which is formed from the mitochondrial respiratory chain pathways [94]. Se administration in animals and humans indicates an increased GSH and GPX activity level and detoxifies reactive intermediates throughout its antioxidant role [95–97]. Hence, Se may also have protective effects on the oxidative values, Ca²⁺ release, and apoptosis in the neurons [98, 99]. Excessive free radicals due to oxidative stress may fundamentally stimulate voltage-gated Ca²⁺ channels [100]. Also, oxidative stress-induced stimulation of other ion channels leads to the calcium influx into the cytosol and induces depolarization in mitochondria that may eventually cause free radical generation. neurons display Ca²⁺ ion-selective channel-dependent ROS generation and Ca²⁺ influx following cytosolic GSH depletion[101]. Besides, evidence reveals that cytosolic GSH depletion causes lipid peroxidation, which attenuates GPX activity. A rise in cytoplasmic Ca²⁺ may enhance mitochondrial ROS formation during the depolarization of mitochondria. In response to a high level of cytosolic Ca²⁺ through activation of Ca²⁺ cation channels, it may provoke Ca²⁺-induced respiratory impairment, potentiate free radical production, inflict structural damage to mitochondria, and ultimately apoptotic cell death if antioxidants do not inhibit the Ca²⁺ influx [102]. In this regard, H₂O₂ triggers apoptotic pathways with antioxidant properties, and Se induces a protective effect on apoptotic pathways (represented in the figure) [103].

Indeed, oxidative stress and impairments in the release of Ca²⁺ induced by H₂O₂ could be improved by Se. The investigations support the neuroprotective effects of Se. It may be used in treating neurons dependent on disorders as an antioxidant element.

Selenium supplementations effects on PD.

Due to multiple studies, an Insufficient supply of Se to antioxidant enzymes in the brain may contribute to neurodegeneration pathophysiology; therefore, supplementations may potentially slow neurodegeneration by reducing oxidative stress via increasing GPX levels which is a crucial factor for the reduction of oxidative stress [104]. A piece of research has shown that administration of selenium selenite (0.1, 0.2, and 0.3 mg/kg- ip.) for a week upregulates the antioxidant status and lowers dopamine depletion, elevates GPX activity, relieves lipid peroxidation, and improves motor function of the 6-hydroxydopamine (6-OHDA) induced PD rats models. Thus, Se, as an essential micronutrient, slows neurodegeneration progress in PD [105]. Also, a considerable impairment of MPTP dopaminergic neurotransmission might reverse by Se administration (3 mg/kg) in C57BL mice [106].

In this regard, another study on experimental male Wistar rats of PQ-induced PD shows that Se (11.18 µg/L in the drinking water) maintains locomotor activity and leukocytes’ DNA integrity. Also, there is no change in DNA damage proportion in brain cells throughout the experimental groups [107]. However, this protective effect of Se on dopamine in animal models of PD was strengthened by the results of the research performed by Zafar et al., who used the 6-OHDA to induce the PD model in rats [105]. Additionally, a report of an experiment using embryonic stem cells transplantation in rats’ brains submitted to a model of 6-OHDA-induced PD explained that Se could also protect against inflammation generated in this treatment [108]. Although the outcomes of these investigations are pretty relevant, it is noticeable that these researchers have investigated the effects of the Se in experimental PD models, which differ in some aspects from PD occurring naturally. Thus, further studies are required to conclude the results to humans [109, 110].

Besides, Human studies on investigations of Se supplementation for PD are lacking. However, evidence indicates that either a deficiency or overabundance of Se might contribute to neurodegeneration, or conversely, PD pathology might impair Se mobilization in neurons. The Recommended Dietary Allowance (RDA) for Se is 70 µg /day, and the Institute of Medicine has established a Tolerable Upper Intake Level for Se at 400 mg/day [111]. Hence, meeting the RDA without excess may be cautious.

Selenoproteins in the brain

As mentioned above, Se is well maintained in the brain, even in prolonged dietary Se deficiency [22], and its functions carry out by selenoproteins [23] which are expressed in the brain; still, many questions remained about their roles in neuronal function [112]. GPX expression in glial cells will rise surrounding the damaged area in PD, consistent with its protective role against oxidative damage [113]. Besides, selenoproteins represent antioxidant activities and promote neuronal cell survival in the brain [112]. Researchers revealed the differential expression of brain selenoproteins in a mouse model of PD [114]. While 17 selenoproteins are downregulated, and none of them is upregulated in the SNc, mixed patterns of induced and suppressed expression of selenoprotein mRNAs in the cerebellum, cortex, hippocampus, and pons exist. Thus, most selenoproteins in SNc play critical roles in modulating PD [115, 116]. This idea is supported by physiological evidence generated from mouse models with innovative manipulations of selenoprotein genes.

Glutathione peroxidase (GPX)

All cells, including those of the brain, generate hydrogen peroxide, which induces oxidative stress in cells. Polyunsaturated fatty acids (PUFAs) in the brain are also subject to peroxidation, leading to cell membrane damage [117]. It is thought that the most crucial hydrogen peroxide removing enzyme in the brain is GPX, containing 20% of the total Se in the brain [118]. GPX removes hydrogen peroxide by coupling its reduction to water or alcohols with GSH oxidation [119]. The product, oxidized glutathione (GSSG), consists of two GSH linked by a disulfide bridge and can be transformed back to GSH by glutathione reductases. GPX can act on peroxides of fatty acids, changing them to alcohol [120].

GPX1 is localized in Lewy bodies [119], and its overexpression decreases the loss of tyrosine hydroxylase-positive dopaminergic neurons in SNc in mice PD models [121]. It was observed that Gpx1−/− mice intraperitoneally injected with high levels of paraquat (a quaternary nitrogen herbicide, highly toxic for humans) died within 4–6 h with severe motor symptoms and increased oxidation of proteins, lipids, NADH, and NADPH in the liver and lungs, as compared to wild-type mice that survived three days [122, 123]. Moreover, Gpx1-/- mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine face dopamine depletion and exhibit high 3-nitrotyrosine production in the striatum [124]. Hence, GPX1 can be protective at normal levels and advantageous when overexpressed to maintain dopaminergic neurons, implicating this H2O2-decomposing selenoprotein in protecting against PD in exposure to certain environmental neurotoxins within redox transition.

GPX4 has a substrate preference toward phospholipid hydroperoxides and is a crucial regulator of ferroptosis, a form of necrotic cell death characterized by iron-dependent lipid peroxidation [125]. Recent researchers acclaimed that Se renders the most critical neuroprotective role of GPX4 and its peroxidase activity [126]. Using a knock-in mouse model by replacing the selenocysteine residue of GPX4 with cysteine has shown accelerated neurodegeneration. Therefore, the oxidoreductase activity of GPX4 is essential in the protection against neurodegeneration [126]. While there is not any clear link between GPX4 and PD, such a view is supported by studies employing biochemical and cellular approaches. Evidence implicates GPX4 co-localizes with neuromelanin in SNc, and its level is increased in dystrophic axons and cortex of the PD brain [127]; GPX4 expression is raised against the separation of PARK7 (DJ-1) from its mRNA in response to oxidative stress [128]; oxidized dopamine is a covalent target mitochondrial GPX4 and diminishes its activity in dopaminergic neurons [129] leading to a progression of PD.

On the other hand, ROS couple with calcium signaling throughout the glutathione cycle [130]. Ca²⁺ activates NADPH oxidase to generate ROS via binding to the enzyme’s EF-hand, regulated by Ca²⁺ dependent phosphorylation. Besides, the Ca²⁺ increases NADPH level by stimulating NAD kinase and providing a substrate for NADPH oxidase [131]. In this regard, there is a hypothesis that GPX as an antioxidant might increase to prevent the excessive generation of GSH and ameliorate the oxidative stress induced by Ca²⁺. For proving this idea, more information and research are needed.

Selenoprotein P

SelP, the major plasma selenoprotein, is produced by the liver as a glycoprotein, contains ten selenocysteine residues secreted either into plasma or interstitial fluid, supplied Se to tissues, and plays a role as a survival factor for neuronal cells [132]. SelP synthesis is regulated by a highly sophisticated system containing transcriptional, translational, and post-translational levels depending on Se availability [133, 134]. There are restricted data on the transcriptional regulation of SelP expression and transcription factors that indicate activated FoxO (forkhead box, class O) affects SelP expression. Thus, SelP expression may regulate by FoxO transcription factors and involve in the cellular response to stressful stimuli, such as oxidative stress [135–138].

The expression of FoxO genes is involved in stress resistance through regulating cell cycle progression, incorporating proteins to DNA repair, or activating antioxidant enzymes [139–141]. Serine/threonine kinase (AKT) - protein kinase B (PKB/AKT) is activated via phosphoinositide 3-kinases (PI3K) through various growth factors and hormones, including insulin; then it phosphorylates FoxO proteins [142, 143]. The protection from FoxO translocation-induced death is dependent on calcium signaling and calcium/calmodulin-dependent protein kinase IV. FoxO shuttling modulation may represent a mechanism that affects cell death processes through nuclear calcium signaling responses [144].

On the other hand, ROS can affect PKB/AKT signaling by preventing FoxO-dependent transcriptional activation, leading to Akt-dependent phosphorylation, so inactivate and translocate FoxO into the cytoplasm [145, 146]. The same effects have been revealed to result from insulin-mimetic signals obtained by the exposure of cells to stressful stimuli, such as Se [147–150]. The high level of Se increases ROS generation [151], and ROS can inhibit SelP production through disruption of PKB/AKT phosphorylation on PV interneurons in the hippocampus, inferior colliculus, medial septum, red nucleus, thalamic reticular nucleus, cerebellum, and choroid plexus in the brain [152].

Conclusions

Cav1.3 L-type Ca²⁺ channels produce Ca²⁺ influx, which is essential in releasing dopamine. Ca²⁺ entrance can lead to oxidative stress in mitochondria through ROS production. Also, Oxidative stress causes Ca²⁺ influx into the cytoplasm from the extracellular environment and the ER and increases the Ca²⁺ level in the cytoplasm, which in turn induces Ca²⁺ influx into mitochondria and nuclei and impairs their functions to cause cell death. Also, High levels of α-syn disrupt cellular/ mitochondrial Ca²⁺ homeostasis and again lead to cell death. In conclusion, Se induced a protective impact on oxidative stress and suppressed the neurons’ apoptosis throughout Ca²⁺ release regulation. Furthermore, oxidative stress and changes in intracellular Ca²⁺ release improved by Se. Thus, our review study supports the neuroprotective role of Se as an antioxidant agent, which might be effective in treating neurodegenerative disorders, especially PD.

Electronic Supplementary Material

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Declarations

Conflict of interest

The authors declare that there is no conflict of interest.