Vitamins in Treatment of Parkinson’s Disease: History
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Sandeep S
,
Manas Ranjan Sahu
,
Linchi Rani
,
Arun S. Kharat
,
Amal Chandra Mondal

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer’s disease. Pathophysiologically, it is characterized by intracytoplasmic aggregates of α-synuclein protein in the Lewy body and loss of dopaminergic neurons from substantia nigra pars compacta and striatum regions of the brain. Although the exact mechanism of neurodegeneration is not fully elucidated, it has been reported that environmental toxins such as MPTP, rotenone, paraquat, and MPP+ induce oxidative stress, which is one of the causative factors for it. There is no complete cure. However, the indispensable role of oxidative stress in mediating PD indicates that antioxidant therapy could be a possible therapeutic strategy against the disease. The deficiency of vitamins has been extensively co-related to PD. Dietary supplementation of vitamins with antioxidant, anti-inflammatory, anti-apoptotic, and free radical scavenging properties could be the potential neuroprotective therapeutic strategy. 

  • Parkinson’s disease
  • oxidative stress
  • neurodegeneration

1. Vitamin A

Vitamin A (retinol) is a major antioxidant in the diet and is abundant in fish, meat, dairy products, and plants. During the development of the central nervous system, vitamin A regulates the expression of genes involved in brain development and controls neural tube patterning and neuronal differentiation [1]. Several studies have shown the neuroprotective effects of vitamin A in PD. In vitro studies have shown that retinoic acid, the biologically active form of vitamin A, protects against 6-OHDA and 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity via activating protein kinase B (Akt) signaling, decreasing p53 levels and increasing Bcl-2 activation [2]. It has been demonstrated that the administration of retinoic acid reduced PD-related motor impairment and elevated dopamine (DA) levels. Furthermore, it prevented the loss of DA-ergic neurons in several rat PD models [2]. Vitamin A and its derivatives function by activating retinoid receptors, specifically the retinoic acid receptor (RAR) and retinoid X receptor (RXR). These receptors, in turn, inhibit the activation of Nur77, a pro-apoptotic protein, thus protecting DA-ergic neurodegeneration [2][3]. Furthermore, vitamin A treatment lowers the serum levels of various proinflammatory cytokines, such as TNF-α, Interleukin (IL)-1β, and Iba-1, alleviating neuroinflammation in the 6-OHDA-induced PD model [4]. The immunomodulatory effect of retinoic acid is carried out via inactivation of receptor-advanced glycation-end (RAGE) products, key regulators of p38 mitogen-activated protein kinase/nuclear factor kappa B (p38MAPK/NF-κB)-associated inflammatory cytokine production during PD [3]. Contrary to the above findings, some studies have also shown that vitamin A promotes oxidative stress, resulting in cell death. Treatment of neuronal cells with vitamin A, at a concentration above the cellular physiologically available concentration, elevated α-synuclein phosphorylation, and increased oxidative stress level leading to progression of neuronal death [5].

2. Vitamin B Family

2.1. Vitamin B1

Vitamin B1 (thiamine) is commonly found in organ meat, egg, fish, lean pork, beef, legumes, wheat germ and whole grain, and nuts [6]. Thiamine uptake occurs in the body’s small intestine by two transporters named THTR1 and THTR2. Thiamine deficiency (TD) is associated with an increased risk of PD. In PD patients, there is a decrease in the level of α-ketoglutarate dehydrogenase complex (an enzyme associated with TD) in the SNpc region of the brain. This reduction is correlated with degeneration severity [6]. Patients suffering from Parkinsonism dementia have shown a decrease in the activity of thiamine triphosphate (TPP), a metabolically active form of thiamine, in the frontal cortex region of the brain [7]. Genetic alterations in thiamine metabolism also cause neurological diseases such as PD, which can be treated with a high dose of vitamin B1 [8]. The low dietary vitamin B1 intake in two to eight years before diagnosing PD is associated with olfactory dysfunction, a non-motor symptom related to increased risk of PD [9]. These findings suggest that deficiency of vitamin B1 promotes neuronal death, leading to increased risk for PD, and supplementation of the same may ameliorate pathological changes associated with PD. A clinical study on PD patients found that high doses of vitamin B1 improve motor symptoms from 31.3% to 77.3% of the Unified Parkinson’s Disease Rating Scale (UPDRS) in PD patients receiving no other anti-Parkinson therapy [8]. It has also been demonstrated that elevated plasma thiamine is associated with a reduced risk of mild cognitive impairment (MCI) in male PD patients [10]. Clinical studies have shown a significant improvement in the motor and non-motor symptoms in PD patients when administered daily 100–200 mg doses of thiamine intramuscularly [8]. Mechanistically, the PD ameliorative effects of B1 are mediated through the regulation of apoptotic signaling pathway involving the anti-apoptotic protein Bcl-2 and the pro-apoptotic protein p53 in the neuronal cells. Further, vitamin B1 also inhibits the GSK-3β activation associated neuroinflammatory responses, including activation of astrocytes in the PD brain [7]. Though significant studies have highlighted the beneficial role of vitamin B1 supplementation in the management of PD, the outcomes of the clinical study are inconsistent. Therefore, careful re-evaluation of vitamin B1 doses and combination of nutrients and the route of administration should be considered in the clinical studies [6]. Though regular dietary intake of vitamin B1 may reduce the risk of PD, research is needed to elucidate the therapeutic potential of vitamin B1 against PD.

2.2. Vitamin B3

Niacin, or vitamin B3, is commonly present in foods including fish, meat, vegetables, and wheat [11]. Physiologically, it causes neural progenitors to differentiate into serotonergic and DA-ergic neurons [12]. The biological activity of vitamin B3 is mediated through the activation of a GPCR protein, GPR109A. Vitamin B3 supplementation has been shown to alleviate various symptoms associated with PD. In a Drosophila PD model, it has been shown that dietary supplementation with high doses of nicotinamide, an active form of vitamin B3, suppresses mitochondrial abnormalities and improves PD-associated motor deficits [13][14]. Additionally, it has also been shown that nicotinamide supplementation can prevent DA depletion and DA-ergic cell death in the SNpc region of the brain [15]. Further, clinical findings have revealed that vitamin B3 supplementation ameliorates neuroinflammation by modulating macrophage polarization from M1 (pro-inflammatory) to M2 (counter-inflammatory) in PD patients. Mechanistically, vitamin B3 promotes the biosynthesis of the classical enzyme cofactor nicotinamide adenine dinucleotide (NAD) and mediates the release of nicotinamide by poly-ADP ribosylation. This generates an anti-inflammatory response, which alleviates DA-ergic neurodegeneration caused by neuroinflammation [16][17][18]. These findings suggest that dietary supplementation with vitamin B3 may ameliorates oxidative stress and neuroinflammation, which would therefore prevent the death of DA-ergic neurons.

2.3. Vitamin B6

Vitamin B6 can either be obtained from a dietary source or synthesized by the microbiota of the human large intestine. Vitamin B6 and its metabolites play a vital role in different metabolic processes, including antioxidant effect, neurotransmitter and amino acid metabolism, synthesis of protein and polyamines, metabolism of lipids and carbohydrates, erythropoiesis, and mitochondrial function [19]. Multifactorial neurological disorders such as PD, Alzheimer’s disease (AD), autism, schizophrenia, and epilepsy are associated with intracellular deficiency of pyridoxal 5′-phosphate, the active form of vitamin B6 in the liver [20]. A single-cell whole genome expression profiling study from human SNpc in PD patients has observed a genetic variation in the pyridoxal kinase (PDXK) gene, which is involved in the metabolism of vitamin B6/DA, is associated with an increased risk of PD [21]. A deficiency of vitamin B6 causes status epilepticus and early-onset epilepsy in PD patients [22]. A case-controlled study in Japan involving 249 PD patients and 368 healthy controls reported that low dietary intake of vitamin B6 is correlated with an increased risk of PD [23]. In agreement with these findings, a population-based cohort study on 5289 participants over the age of 55 years in Rotterdam by L M L de Lau et al. found that high dietary intake of vitamin B6 was associated with a significantly reduced risk of PD [24]. These pieces of evidence indicate that dietary intake of vitamin B6 is indispensable for health and may have a neuroprotective effect against PD. However, further studies are needed to give more depth into the mechanism involved.

2.4. Vitamin B12

Vitamin B12 (cobalamin) commonly found in milk products, meat, and fish is one of the essential micronutrients which plays a crucial role in growth, nervous system, cognition, and chronic brain disorders [25]. Idiopathic PD (IPD) patients with hyperhomocysteinemia were observed to be deficient in vitamin B12, suggesting its association with Parkinsonian disorders [26]. Several studies have attempted to determine the relationship between vitamin B12 and PD. It has been shown that deficiency of vitamin B12 in PD patients is associated with cognitive impairment and gait impairment, rapid progression of disease, neuropathy, and rapid worsening of ambulatory capacity [27]. A population based-cohort study observed that PD patients with higher baseline level of vitamin B12 at PD diagnosis were associated with reduced risk of dementia [28]. A three-year longitudinal cohort study with 1741 individuals indicated that people receiving multivitamin (MVI) and B12 + MVI had a reduced hazard ratio for UPDRS than those receiving no supplement [29]. According to studies, vitamin B12 deficiency can exacerbate apoptosis and cause Parkinsonian phenotypes in rats by impairing the synthesis of S-adenosylmethionine. Mechanistically, vitamin B12 enters the cell via CD320 receptor-mediated transport, reduces oxidative stress, eases movement disorder, and restores mitochondrial function, preventing the degeneration of DA-ergic neurons. [30][31]. Furthermore, vitamin B12 inhibited α-synuclein fibrillation and disassembled pre-existing fibrils, reducing cytotoxicity. These findings show that vitamin B12 is a promising nutritional source that might be investigated as a novel functional food ingredient for the treatment of PD [25].

3. Vitamin C

Vitamin C, also called ascorbic acid, is commonly found in citrus fruits such as oranges, lemons, and grapes and vegetables such as broccoli. It has antioxidant, anti-viral, anti-microbial, and anti-inflammatory properties [32]. Vitamin C plays a crucial role in the antioxidant system, neurotransmission modulation, synaptic potentiation, and myelination in the CNS [33]. Neurological disorders, such as atypical Parkinsonism, have a strong correlation with vitamin C deficiency. Clinical studies have shown that patients with IPD and vascular Parkinsonism are deficient in vitamin C [26][34]. A deficiency of vitamin C is directly associated with the risk of PD. PD patients have reduced levels of vitamin C in their plasma compared to control subjects, suggesting vitamin C is a potent biomarker for PD [35]. In line with this, some other studies have shown that dietary intake of antioxidants, including vitamin C, may reduce the risk of PD and slow the progression of Parkinsonian symptoms in older individuals [13][16][17]. Further, supplementation of vitamin C has also been shown to reduce protein oxidation, suppress H2O2 production, and increase anti-oxidant enzymatic activity in the DJ-1β mutant fly model of PD [36]. Mechanistically, vitamin C becomes internalized in the cell via a transporter called sodium-dependent vitamin C transporter type 2 (SVCT2). Inside the cell, vitamin C induces activation of nuclear factor erythroid 2-related factor 2/kelch-like ECH-associated protein 1(NRF2/Keap1) signaling, resulting in increased levels of antioxidant enzymes, thus aiding in the amelioration of oxidative stress-mediated PD progression [37][38]. Moreover, a study on MPTP-induced mice model of PD highlights that vitamin C also suppresses neuroinflammatory responses related to microglia and astrocytes’ activation and modulates TLR/NF-κB/NLRP3/IL-1β pathway, thus ameliorating PD-associated neuroinflammation [39][40]. Another in vivo study has shown that vitamin C inhibits MPP+-induced oxidative stress, preventing DA-ergic neuronal loss in PD [41]. Vitamin C also inhibits LB formation in PD, inhibiting apoptotic signaling-mediated cell death [42]. These shreds of evidence suggest that vitamin C, an antioxidant and anti-inflammatory agent, could be a potential therapeutic and preventive strategy against DA-ergic neurodegeneration in PD.

4. Vitamin D

Vitamin D is a steroid hormone that is essential for the functioning of body’s organs, including the brain [43]. Vitamin D can be obtained through food or produced in the skin by sunlight exposure. Almost most of the population across the globe receives their vitamin D demands from solar radiation. When it comes to vitamin D and geographical location, various elements such as ozone, latitude, clouds, month of the year, and season all have an impact on UV radiations at a particular geographical site. Deficiencies and insufficiencies in vitamin D and calcium have been found in several Asian nations, including India, China, Korea, and Japan, indicating the necessity of vitamin D for bone mass preservation and development. Due to geographical variations and the extent of exposure to UV radiation, there are variations in vitamin D synthesis in the population [44][45]. Insufficiency of vitamin D is frequent among the elderly worldwide and is the most common health issue associated with neurodegenerative disorders such as AD and PD [46]. Numerous studies have shown that PD patients had low serum vitamin D levels, suggesting that a deficiency of vitamin D is associated with an increased risk of developing PD [46][47].
Vitamin D deficiency has been attributed to poor memory, impaired verbal fluency, increased postural instability, and motor severity [48]. It has been demonstrated that PD patients, regardless of gender, have vitamin D deficiencies and, as a result, lower bone mineral density. Since vitamin D plays a crucial role in the metabolism of bones, its deficiency may cause an increased risk of falls and fractures. Consequently, there is an increased chance of fatal disability in PD patients [47].
The biological effect of vitamin D is regulated by vitamin D receptor (VDR). VDR is expressed in various brain regions, such as the cortex, caudate putamen, amygdala, hypothalamus, and DA-ergic neurons of SNpc. According to various reports, the VDR gene deletion results in motor dysfunction [49][50]. Furthermore, in the Asian population, the gene polymorphism rs1544410 has been related to PD susceptibility. A meta-analysis study has observed that deficiency and insufficiency of (25(OH)D), the biologically inactive form of vitamin D, and decreased exposure to sunlight are significantly associated with an enhanced risk of PD [51]. Along with the motor symptoms, vitamin D is also significantly associated with some non-motor symptoms in PD patients [47]. In elderly adults with MCI, vitamin D deprivation results in decreased hippocampus subfield volume and connectivity deficits. Consequently, it may result in the exacerbation of cognitive dysfunction [52]. Additionally, it has been demonstrated that Folk, an active VDR polymorphism, is also associated with loss of cognitive function in PD [53]. An independent association has also been demonstrated between vitamin D3 deficiency and olfactory dysfunction in PD patients [54].
Dietary supplementation with vitamin D3, the biologically active form, has demonstrated remarkable therapeutic value in PD. Vitamin D3 has been shown to improve behavioral impairments, reduce oxidative stress, and mitigate the loss of DA-ergic neurons and DA depletion in various animal models of PD [43][55][56]. In terms of molecular mechanism, it causes an increase in the expression of dopamine transporter and enzyme tyrosine hydroxylase. It suppresses ROS generation mediated by NADPH oxidase (NOX), MAO-B and inducible nitric oxide synthase (iNOS). Furthermore, vitamin D treatment reduces pro-inflammatory responses while activating anti-inflammatory responses, resulting in PD neuroprotection. Mechanistically, vitamin D3 decreases neuroinflammatory TNF-α, TLR-4, iNOS, CD11b, MAO-B, IL-I β, p47phox, and M1 microglia (pro-inflammatory) activation while promoting M2 microglia activation for an anti-inflammatory response. Moreover, vitamin D3 supplementation restores levels of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) in the animal models of PD, thereby contributing to the survival of neurons [43]. GDNF binds to GDNF family receptor alpha 1 and then interacts with proto-oncogene tyrosine-protein kinase receptor Ret, forming a complex. This complex induces activation of intracellular signaling that confers neuronal survival [46]. GDNF, a powerful anti-oxidant, also stimulates the production of glutathione (GSH), SOD, and CAT in the striatum and aids in the regeneration of DA-ergic neurons [43]. Taken together, vitamin D holds immense antioxidant, anti-inflammatory, and neuroprotective potential in PD pathogenesis, which needs to be explored in more detail.

5. Vitamin E

Vitamin E consists of a family of major lipid-soluble antioxidants that protect the cell membrane from polyunsaturated fatty acid-generated free radicals. It contains many lipophilic molecules (α-, β-, γ-, δ-tocotrienols, and α-, β-, γ-, δ-tocopherol). Vitamin E has an antioxidant effect and free radical scavenging properties and can prevent neuronal damage [57]. Patients with IPD and vascular Parkinsonism have shown deficiency in vitamin E, suggesting its potential link with neurodegenerative diseases, such as PD [26][34]. An in vivo study on a 6-OHDA-induced rat model of PD has shown that mice with vitamin E deficiency, when kept on a vitamin E-free diet for 52 weeks, showed a reduction in TH-positive cells, suggesting that vitamin E deficiency may cause DA-ergic neurodegeneration. However, supplementation of vitamin E provides neuroprotection by stabilizing cell membranes against the detrimental effects of lipid peroxidation (LPO) and scavenging free radicals produced by the metabolism of 6-OHDA in PD [58]. Dietary intake of vitamin E-rich food is also associated with a reduced risk of PD in in-vivo studies. Treatment with tocopherol derivative at a dosage of 20 mg/kg was reported to improve motor coordination and locomotor activity, boost neurotransmitter and antioxidant levels, and reduce α-synuclein expression and inflammatory cytokines in a haloperidol-induced mice model of PD [59]. Similarly, vitamin E supplementation also ameliorated motor deficits, improved biochemical oxidative stress biomarkers such as GSH and SOD levels, and significantly reduced LPO in the rotenone-induced rat model of PD [60]. Mechanistically, vitamin E becomes internalized inside the cell via LDL receptor-related protein (LRP) present on the neuronal surface. By controlling NRF2 and NF-κB signaling inside the cell, vitamin E lowers the burden of oxidative stress in the presence of PD [61]. Vitamin E also activates the estrogen receptor β/phosphatidyl inositol 3-phosphate kinase/Akt (ERβ/PI3K/Akt) signaling and inhibits the GSK-3β signaling to reduce neuroinflammation and hence suppress DA-ergic neurodegeneration [57][62]. Moreover, treatment with vitamin E also decreases the number of activated astrocytes in rat memory model of PD [61].
A recent meta-analysis study attempted to determine the effect of vitamin E on the risk of development of PD. It was reported that high vitamin E intake was associated with a lower risk of PD compared to the low vitamin E intake group [62]. Contrary to this finding, another study has shown that treatment with high vitamin E in combination with vitamin C delayed the progression of PD by 2.5 years in comparison to the placebo group [63]. A randomized, double-blind, placebo-controlled clinical trial involving 60 PD patients was conducted to evaluate the effect of co-supplementation of vitamin E (400 IU/day) and omega-3 fatty acid (1000 mg/day) on metabolic status and clinical symptoms of PD patients for 12 weeks. It was observed that co-supplementation of vitamin E and omega-3 fatty acid significantly improved UPDRS, increased total antioxidant capacity, GSH, and decreased high-sensitive C-reactive protein (hs-CRP) in comparison to the placebo group [64]. Thus, these findings suggest that vitamin E intake, alone or in combination with other antioxidative compounds, is neuroprotective against PD-induced neurodegeneration.

6. Vitamin K

Vitamin K is a group of fat-soluble vitamins existing in two forms, viz., vitamin K1 and K2. Vitamin K is a cofactor in synthesizing sphingolipids, the vital parts of the neuronal membranes. Epidemiological studies determining the relationship between vitamin K and PD are scarce. A case-controlled study involving 93 PD patients and 95 control subjects revealed that deficiency of vitamin K2 is associated with PD progression. Thus, vitamin K2 could be a potential biomarker for diagnosing PD [65]. Vitamin K2 is a potential treatment for mitochondrial abnormalities, particularly in PD patients lacking PINK1 or parkin. Vitamin K2 is essential and sufficient for transporting electrons in drosophila mitochondria, leading to the repair of mitochondrial abnormalities using a PINK1 mutant model. Like ubiquinone, vitamin K2 has been shown to transport electrons, enabling drosophila mitochondria to produce adenosine triphosphate (ATP) efficiently. Vitamin K2 was even helpful in addressing systemic locomotion abnormalities in adult PINK1 and parkin mutant flies [66]. In light of this, vitamin K2 has been recommended as a potential therapy option for mitochondrial dysfunction, particularly in PD patients with a PINK1 or parkin deficit. It has also been shown that vitamin K reduced α-synuclein fibrillization at sub-stoichiometric dosages [67]. A study by Yu et al. revealed that menaquinone-4 (MK-4), a vitamin K2 homolog, suppresses microglial activation in rotenone-treated BV2 cells by restoring mitochondrial membrane potential, reducing ROS production, and inhibiting NF-κB activation. MK-4 also prevented microglial-induced neuronal cell death, thus demonstrating the inflammation regulatory role of vitamin K2 in PD pathogenesis [68].

This entry is adapted from the peer-reviewed paper 10.3390/brainsci13020272

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