The Role Of Vitamins in Neurodegenerative Disease: An Update Part 3

5.2. Vitamins-Based Animal and Cellular Studies in Alzheimer's Disease

However, in a streptozotocin (STZ)-induced AD mouse model, beta-carotene, a form of VitA, significantly improved measures of cognitive function and oxidative stress and reduced levels of toxic B-amyloid fragments [194]. 

Oxidative stress refers to a series of adverse reactions in organisms where free radicals and reactive oxygen species caused by various reasons exceed the organism's antioxidant capacity. These reactions may have adverse effects on the normal physiological functions of the human body, including the brain's memory.

However, with the continuous advancement of science and technology, people have a deeper understanding of the connection between oxidative stress and memory. Existing research shows that moderate oxidative stress has a certain promoting effect on memory, specifically by promoting the activity of enolase and SOD, thereby enhancing the antioxidant capacity of brain cells, reducing brain cell damage, and maintaining memory. and promotion.

In addition, proper exercise, diet, sleep, and other lifestyle changes can also reduce the negative impact of oxidative stress on memory, further improve the brain's antioxidant capacity, and thereby promote memory improvement.

Therefore, we don't have to worry too much about the impact of oxidative stress on memory. Instead, we should focus on health care and health in our daily lives, to alleviate the impact of oxidative stress on the brain and maintain good memory. I believe that with the right approach, everyone can have a healthy and memorable brain. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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In vitro and in vivo animal studies show that VitA and beta-carotene inhibit the oligomerization and aggregation of Aβ (Figure 3) [146,195,196]. Furthermore, VitC attenuated the advancement of neurodegeneration and improved behavioral deficits in a mouse model of AD [197]. Thus, a combination of VitA, VitC, and VitE therapy may provide a synergistic effect and act as adjuvants in preventing the progression of neurodegeneration in AD [198]. 

In an AD mouse model, neuronal dysfunction was significantly attenuated by intranasal administration of 9-cis retinoic acid (9-cis RA). This might be a novel therapeutic option for the preventive treatment of AD. The astrocyte activation, neuroinflammation, and Aβ aggregation were considerably reduced by 9-cis RA in the AD transgenic mouse model compared to controls (Figure 3). 

As a result, synaptic deficits were restored in the AD model compared to vehicle-treated mice [199]. Retinoids show strong therapeutic efficacy in preventing progressive neurodegeneration by inhibiting the neuroinflammatory processes in AD [200]. Although AD accounts for 60–80% of dementia, there are other types, such as vascular dementia (VD), frontotemporal dementia (FTD), Wernicke-Korsakoff syndrome, etc. [201,202]. 

Interestingly, Wernicke-Korsakoff is a type of dementia caused by a lack of VitB1 (Thiamine), and VitB1 supplementation has been used to treat this type of dementia [203]. Similarly, symptoms of frontotemporal lobe degeneration appear in vascular dementia, and VitB1 supplementation significantly improves these symptoms [204]. VitB12 and folate (VitB9) deficiencies have also been seen in VD and AD patients [205]. 

Severe lack of niacin (VitB3) leads to pellagra, a disease characterized by diarrhea, dermatitis, and dementia, which is treated by niacin supplementation [159,206]. Thus, VitB shows therapeutic activity in AD and other dementias. In another study, pre-treatment with VitC prevented cognitive impairment and improved biochemical measures such as lowering proinflammatory cytokines, modulating anti-apoptotic activity, and contributing to the phosphorylation of p38 mitogen-activated protein kinase (MAPK) activation in the hippocampus of LPS-treated mice [207]. 

In an AlCl3 (100 mg/kg) induced rat model of Alzheimer's disease (AD), ascorbic acid (100 mg/kg daily for 15 days) alleviated the biochemical and behavioral deficits along with neuropathological alteration by its antioxidative activity. Ascorbic acid shows AChE inhibitory and anti-proteolytic activity. Thus, the progression of AD is inhibited by ascorbic acid supplementation [208]. 

Thus, VitC improved cognition by modulating oxidative stress and neuroinflammatory parameters. A study indicated that a low dose of VitC (200 and 400 mg/kg BW) confers protection from colchicine-induced, neuroinflammation-mediated neurodegeneration and cognitive impairments by scavenging free radicals. However, on the other hand, a higher dose of VitC (600 mg/kg BW) was responsible for the generation of oxidative stress, neuroinflammation, and cognitive impairment. Therefore, VitC exhibited dual activity with protection at lower doses and damage at higher [209]. 

VitD3 improved cognitive function by inhibiting neuroinflammatory and oxidative stress responses and improved cholinergic function in the mouse model of STZ-induced AD [210]. VitD improved the age-related cognitive decline in a rat model by modulating the activity of proinflammatory cytokines. VitD also decreased the amyloid burden responsible for cognitive impairment [211]. 

A recent study demonstrated that maxacalcitol, an analog of the active form of VitD, improved cognitive function and inhibited neuroinflammation induced by LPS in a rat model of AD, through Keap1/Nrf2 and MAPK-38p/ERK signaling pathways [212]. Thus, VitD and its analogs effectively prevent AD pathology in animal models and AD patients [177,183]. The deficiency of Vit-D promotes AD-like pathology by reducing the antioxidative potential. Enhanced production of amyloid-beta, the elevated phosphorylation status of tau, enhanced inflammatory loads, and reflected VitD deficiency in mice. 

A reduced concentration of the active form of VitD might improve AD and dementia risk in a significant way [213]. In the D-Galactose-induced memory impairment mice model, neuroprotective activity is shown by VitD via SIRT1/Nrf-2/NF-kB signaling pathways [214]. 

Therefore, the VitD level should be checked and managed by the patients during AD treatment [215]. Extended administration of VitE provided better results as it counteracted effectively with Aβ plaques and NFT. Further, a type of VitE, α-tocopherol, prevented progressive neurodegeneration in animal models of AD [190]. In addition, α-tocopherol showed synergistic effects with antioxidative and anti-inflammatory compounds that are beneficial in treating AD [190,216].

In a retrospective study, a multivitamin exhibits its therapeutic potential to improve cognitive impairment. In this multivitamin retrospective study, higher folate concentration improved cognitive performance, as shown by its MMSE score. Folate deficiency is directly linked with hyperhomocysteinemia and is associated with worse cognitive performance. Further study will be needed to define the optimal vitamin status among affected individuals [191]. Another multivitamin-based study suggests a neuroprotective role of vitamin B6, B12, folate, and choline in hypoxia. This multivitamin treatment significantly alleviated hypoxia-induced memory deficits. Reduced tau hyperphosphorylation and decreased levels of homocysteine are detected by vitamin B6, B12, folate, and choline treatment. Memory functions were improved by this multivitamin approach [217]. 

Therefore, instead of a single vitamin-based approach, the multivitamin strategy might offer better therapeutic options for AD and MCI. Vitamin K2 prevents the Aβ induced neurotoxicity by the phosphatidylinositol 3-kinase (PI3K) associated signaling pathway [218]. In conclusion, vitamins have been studied for the treatment of AD and other types of dementia, and many of these studies have indicated vitamins' beneficial role with evidence of VitA inhibiting the formation of Aβ plaques, and VitB, VitC, VitD, and VitE intervening with the progression of neurocognitive decline. 

As such, the role of many vitamins in adjuvant therapy treatments for AD has been underestimated [146]. Therefore, future clinical studies that employ vitamins in AD therapeutics might illuminate important details of how vitamins help alleviate AD symptoms.

6. Vitamins in Huntington's Disease

Huntington's disease (HD) is also an example of a progressive, neurodegenerative disease of the CNS. Similar to PD and AD, motor abnormalities, dementia, and psychiatric problems are the main characteristics of HD [219,220]. HD is caused by a dominantly inherited genetic mutation that elongates a section of the huntingtin gene by the repetition of trinucleotide (CAG) segments (more than 36 repeats), leading to toxic intracellular polyglutamine aggregates and neuronal degradation [221,222] (Figure 4). Alterations in vitamins are involved in the pathogenesis of HD [223]. 

Oxidative stress is one of the major causative factors responsible for progressive neurodegeneration. Antioxidative therapy targeting the reactive oxygen species shows the potential impact of reducing the stress burden in associated neuronal cells [224]. Similar to AD and PD, vitamins also offer strong antioxidative activity and prevent progressive neurodegeneration in HD [225]. RA is the most studied form of VitA, and its receptors are present in the CNS [226]. RA effectively regulates adult brain physiology through its receptors [227–229]. 

However, the mechanism of action is not clearly understood. One of the main locations of RA receptors is in the striatum, a brain region critical for planning and the execution of movement, cognition, reward, and motivation [230,231]. One isoform of the RA receptor, known as retinoic acid receptor β (RARβ), is widely studied in PD, AD, and HD [232]. The characterization of RARβ transcriptional targets through genome-wide analysis identified possible mechanisms of action for RARβ activity [230]. RARβ controls the striatal pathways through transcription, energy metabolism, and neurotransmission through G-protein, cAMP, and calcium signaling [230]. In HD transgenic mouse models, striatal signaling genes induced by retinoids are downregulated [233]. 

In addition, the RARβ receptor is sequestered inside huntingtin protein aggregates in the R6/2 mouse striatum [230]. These studies indicate that RA signaling is compromised in HD and contributes to HD pathology. Therefore, drugs that target this signaling pathway may offer a potential treatment for HD. Similar to AD and PD, more studies will be needed to reach any definite conclusion regarding the mechanism of action behind RA and its receptor in HD therapy [230].

The direct association of thiamine (VitB1) with HD is far from clear, but results have demonstrated that a deficiency in thiamine causes oxidative stress and neuroinflammation, which could contribute to the progression of HD [234–236]. Researchers investigated the role of supplemented thiamine in HD pathogenesis by assessing the viability of human B lymphocytes with and without the abnormal huntingtin gene [237]. 

Results indicated that energy metabolism is a vital step in HD pathogenesis, and thiamine deficiency caused a reduction in cellular energy metabolism by altering the expression of various genes. In the HD human B lymphocyte model, the genes affected were glyceraldehyde-3-phosphate dehydrogenase (GAPDH), isocitrate dehydrogenase gene (IDH1), and the solute carrier family 19, member 3 (SLC19A3) gene. GAPDH, IDH1, and SLC19A3 are involved in the synthetic process of ATP and other high-energy-containing molecules [237]. Thus, thiamine controls the expression of genes involved in energy metabolism and could provide effective therapy for HD. Recent results demonstrated that nicotinamide (VitB3) improved motor functioning and prevented the progression of 3-nitro propionic acid (NPA)-induced HD-associated neurodegeneration by balancing the redox state in a rat model. 

In addition, nicotinamide also improved histopathological parameters by decreasing the expression of lactate dehydrogenase, a marker of tissue degradation [238]. Thus, nicotinamide exhibits potent neuroprotective activity in a chemical-induced rat model of HD.

VitC, the most prescribed vitamin by clinicians, is involved in many body functions, including postural stability and bone health. Postural stability is the most common motor abnormality observed during neurodegenerative diseases, and bone density is significantly related to serum VitC concentration [239–242]. Therefore, VitC activity in HD has been widely explored. HD transgenic mouse models display dysregulation of ascorbate (VitC) within the cortical and striatal pathways [243]. These pathways regulate the activity of ascorbate with the help of the neurotransmitter glutamate in HD pathogenesis. Glutamate transporters on astrocytes are responsible for the removal of extracellular glutamate [244]. 

Both ascorbate release and glutamate uptake were impaired in a transgenic model of HD [245]. External ascorbate was responsible for increased glutamate uptake and, consequently, the inhibition of HD progression [245]. In addition, results indicated that for the uptake of glutamate, the release of ascorbate is needed, and in the absence of ascorbate, glutamate receptor activity is compromised by overactivation [245]. Overactive glutamate receptors were responsible for dysregulation of the corticostriatal pathway and contributed to HD pathogenesis in the R6/2 mouse HD model [246]. 

Furthermore, ascorbate deficiency contributed to behavioral deficits in HD by influencing the striatal pathway in the R6/2 mice model, and intake of ascorbate alleviated behavioral abnormalities [245,246]. Further studies are needed to clarify the interactions between ascorbate and glutamate within the different signaling pathways and their influence on motor function. Calcitriol (VitD) also plays an important role in muscle strength and bone density. As such, VitD deficiency is directly related to motor abnormalities [247,248]. A study of institutionalized HD patients found a high prevalence of VitD deficiency or insufficiency, and a positive association between calcifediol 25 (OH)D levels, an indicator of Vit D status, and ambulatory abilities was observed [221]. 

In a transgenic mouse HD model, supplementation of calcitriol significantly improved clinical symptoms and augmented the life span [249]. Thus, serum calcitriol is positively related to the treatment of HD. In a localized and limited clinical trial, α-tocopherol, a major constituent of VitE, slowed the progression of motor abnormalities associated with HD [250]. Kasparová et al. studied the synergistic effects of CoQ10 and VitE in the NPA-induced rat model of HD. NPA-induced rat models exhibit reduced energy homeostasis. They found that creatine kinase (CK), an energy biomarker in brain diseases, was increased in their HD model. On the other hand, CoQ10, ATP, and the activity of the electron transport chain were reduced. 

Interestingly, supplementation of CoQ10 and VitE reversed these abnormalities [251]. In summary, for the treatment of HD, vitamins offer adjuvant therapeutic options. Both VitC and VitD prevent the progression of postural instability for HD patients. CoQ10, VitE, nicotinamide (VitB3), and VitB1 all show significant neuroprotective activity to minimize the load for HD patients. In addition, VitA and several intracellular mediators such as calcium and cyclic adenosine monophosphate are involved in the vitamin-mediated protection of HD. Large-scale clinical studies may help uncover the detailed mechanisms of action behind the neuroprotective effects of vitamins in HD pathogenesis.

7. Vitamins in Multiple Sclerosis

Multiple sclerosis (MS) is characterized by progressive neuroinflammation and subsequent neurodegeneration [252]. In the CNS, the body's immune system attacks the myelin sheaths that coat and protect nerve fibers [253,254]. Movement abnormalities, vision problems, fatigue, and pain are common symptoms associated with MS. The etiology of MS is not clearly defined [255]. However, it is thought that both environmental and genetic factors are equally responsible for MS [256]. While there is no cure for MS, the usefulness of vitamins in MS therapeutics has been explored due to their antioxidant activities. VitD has protective activity in MS that usually depends on the patient's developmental stage. As such, VitD supplementation was more efficacious at ameliorating MS-like neuroinflammation in a juvenile/adolescent rat model of MS compared to adult-aged animals [257]. Observational studies and clinical trials have shown that a reduced level of VitD in the blood is a risk factor for developing MS [258–260]. Supplementation with VitD shows potent anti-inflammatory activity by increasing the oxidation of white matter. However, overdosing on VitD can lead to hypercalcemia, a toxic build-up of calcium in the blood [259,261–264]. In MS patients, supplementation with VitD enhanced blood perfusion, which supports tissue oxygenation and, therefore, reduces neuroinflammation and neurodegeneration [265]. 

Several studies suggested that the level of apolipoprotein E and two isoforms of VitD binding protein (DBP) in the cerebrospinal fluid could be utilized as potential biomarkers for the diagnosis of MS [266,267]. In contrast, another study found no association between DBP, MS, and VitD in blood samples from MS patients [268]. Therefore, larger controlled clinical trials are needed to evaluate the efficacy of VitD supplementation in MS therapies. There is significant evidence from in vitro and in vivo studies of the beneficial effects of VitA/retinoic acid in treating MS [269,270]. 

VitA exhibited anti-inflammatory and antioxidant activity in the brain, and VitA serum levels were reduced in MS patients [269,271–273]. VitA improved the function of astrocytes, led to remyelination, and suppressed immune function in MS patients [218,269,274–277]. In contrast, results from one study demonstrated no correlation between serum VitA concentration and the progression of MS [278]. To date, few studies have investigated the potential therapeutic effects of the antioxidative ability of VitC or VitE in treating MS [279]. However, several studies have shown that as compared to a healthy individual, MS patients exhibit reduced levels of VitC [280–282]. Direct intrahippocampal injections of VitC in a rat model of MS improved memory dysfunction in passive avoidance learning [283]. Studies investigating VitE showed the improved function of oligodendrocytes and inhibition of factors related to the necrosis process in MS [284]. 

Due to the limited amount of information currently available for VitC and VitE in MS [285]. The role of VitB in MS is very controversial. Some studies have found that VitB levels are reduced in MS patients, while others show no relation between VitB levels and MS [286]. However, VitB may still be useful in MS therapies. Vitamins B9 and B12 regulate the immune function in MS by effectively improving the uptake of homocysteine, which is responsible for the synthesis of myelin sheaths [287–291]. In addition, the roles of VitB1, VitB3, and VitB6 in MS have been explored. VitB3 showed a remyelination ability and may be effective in the treatment of MS [292]. High-dose thiamine (VitB1) therapy improved the fatigue commonly associated with MS [293]. 

More clinical trials are needed to validate the role of VitB in MS therapies. Because many observational studies have related VitD levels to MS risk, and because of the anti-inflammatory activities of VitD, there has been much focus on the utilization of VitD for the prevention and/or intervention of MS (for a comprehensive review, see Sintzel 2018) [260]. In addition, other vitamins such as VitA and VitE, due to their anti-inflammatory and antioxidative effects, may be helpful for adjuvants in MS treatments [269,270,294,295]. The role of VitB in MS is still controversial. Future clinical trials are necessary to determine the role of each vitamin in the potential treatment of MS.

8. Vitamins in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal form of motor neuron disease (MND) characterized by progressive degeneration of motor neurons in the brain and spinal cord. The loss of motor neurons leads to the deterioration of whole-body muscle mass [296–298]. Similar to MS, very few studies have been performed regarding the role of vitamins in ALS. However, as in MS, there is a strong correlation between ALS and VitD supplementation. The active form of VitD is reduced in ALS patients and animal models of ALS [81,299]. 

VitD was shown to be protective in motor neurons in vitro, and plasma levels of VitD were directly correlated to the severity of the disease in ALS patients [300]. Genetic studies have shown that VitD is linked to ALS pathology through the regulation of various immune components such as toll-like receptors, major histocompatibility complex (MHC) class II molecules, poly (ADP-ribose) polymerase 1 (PARP1), and heme oxygenase-1 (HO-1) [81]. In addition, VitD influences ALS pathology through cell-signaling mechanisms, including Wnt/β-catenin, mitogen-activated protein kinase (MAPK), glutamate, prostaglandins, reactive oxygen species (ROS), matrix metalloproteinases, and nitric oxidase synthase [81]. In transgenic mouse models of ALS, VitD supplementation reduced symptoms of muscle weakness and improved motor functional capacity but did not prevent the final disease outcome [201–303]. 

In contrast, a recent study of ALS patients found no reduction in VitD levels, and no benefit from VitD supplementation for improving the prognosis of this disease [304]. Therefore, future studies are needed to determine the role of VitD in ALS pathophysiology. The impact of VitE supplementation has been monitored in a clinical study. Results suggested that individuals who did not take the regular dose of VitE exhibited early death as compared to those who regularly took VitE supplementation. This study also concluded that VitE significantly improved motor functioning in ALS patients [305]. 

In a study focusing on transcriptional profiles, VitE prevented the death of NSC-34 motor neurons in ALS through the downregulation of the c-Jun N-terminal kinase (JNK) and p38 MAPK pathway (cell death), and upregulation of the extracellular signal-regulated kinase (ERK) pathways (cell survival) [306]. In summary, ALS is responsible for progressive muscular degeneration. Vit D and Vit E may have beneficial activities in ALS by protecting motor neurons and improving motor symptoms. However, more studies are needed to understand the roles of these vitamins fully and to uncover the potential use of other vitamins in the treatment of ALS.

9. Vitamins in Prion Disease

Prion disease (PRD), also known as transmissible spongiform encephalopathies, is a rare progressive neurodegenerative disorder caused by abnormal prion protein accumulation, which leads to subsequent brain damage [307]. Structural differences occur between two forms of prion protein [308]. PrPC is the normal prion protein, while the misfolded PrPSc (scrapie) is the pathogenic form [309]. The difference between the two versions of the prion protein is in the secondary structure [310,311]. Secondary structure α-helix motifs within the normal protein are converted to β-sheet secondary structures, which leads to protein misfolding and toxicity. The molecular mechanisms for this conversion are unclear [312]. 

Vitamins prevent the transformation of the normal form of the prion protein towards the pathogenic form [313]. Various micronutrients, including copper (Cu) and iron (Fe), are also involved in the vitamin-meditated maintenance of the normal form of the prion protein [314]. In addition, it is thought that oxidative stress and inflammation lead to the formation of the pathogenic form of the prion protein. Therefore, compounds or vitamins with antioxidative and anti-inflammatory characteristics should be beneficial in decreasing the risk of PRD [313]. Cobalamin (Cbl, Vitamin B12) deficiency plays a major role in the disturbance of the connection between the CNS and the peripheral nervous system (PNS) [315,316]. 

Cbl deficiency mainly affects glial cells, myelin sheaths, and the interstitium of the nervous system [317,318]. In the rat CNS, Cbl deficiency causes a reduction in the epidermal growth factor (EGF) and an enhancement of the activity of tumor necrosis factor-α (TNF-α), which leads to myelin damage and glial activation in both the CNS and PNS [319]. Interestingly, Cbl inhibits the nuclear localization of the NF-κB pathway, which is responsible for the upregulation of cytokines such as TNF-α and affects the conversion of the normal form of PrPC to the diseased form [320]. 

Another vitamin relevant to PRD is VitD2, which effectively crossed the BBB and suppressed PrPc oligomerization, a required step before PrPSc formation [321]. Metal homeostasis plays an important role in the maintenance of CNS [322]. Metals participate as cofactors in the vitamin-mediated therapeutic processes. Thus, the efficiency of vitamins is reduced in the absence of ample amounts of metal ions. Metals also participate in various enzyme-mediated activities in the CNS. Abnormalities in metal homeostasis might be responsible for the formation of ROS, which could contribute to the progression of neurodegenerative disease. PRD is also regulated by metal ion concentrations [323].

Harmful metals from animal proteins might induce the risk of PRD. The Mediterranean diet may have a protective role in preventing PRD [324]. The foundation of the Mediterranean diet is vegetables, fruits, herbs, various nuts, beans, and whole grains, which are rich in polyphenols that can cross the BBB and act on multiple targets to inhibit the formation of the toxic form of prion proteins [313]. Polyphenols are responsible for regulating harmful metal ions and inhibiting the aggregated form of the prion protein [323]. Thus, the Mediterranean diet controls the activity of harmful metals and proves its efficacy in preventing PRD progression [323].

10. Vitamins in Age-Related Macular Degeneration

Not only influential in PD, AD, and HD, vitamins also exert their therapeutic response against age-related macular degeneration (AMD). Oral supplementation and modifications in diet show significant protection against AMD [325]. The Age-Related Eye Disease Study 2 (AREDS2) research group suggested that lutein/zeaxanthin plays a very vital role in the protection against AMD [326]. In AMD, the cone cell abnormalities caused by oxidative stress were significantly improved by VitD supplementation [327]. A clinical study on the Korean population exhibits that the degeneration of AMD progresses due to a lower level of VitD [328]. In the pathogenesis of AMD, the Vit D metabolism plays a very novel role as suggested by a system-biology-based analysis. Therefore, we can say that vitamins are also very effective against AMD. More studies will be needed to confirm the applicability and suitability of vitamins in AMD.

11. Conclusions and Future Prospective

Oxidative stress and neuroinflammation are the two major factors involved in the progression of neurodegenerative diseases. As such, compounds having antioxidative and anti-inflammatory properties should provide significant neuroprotection. In recent years, accumulating evidence has suggested a beneficial role for vitamins in protecting CNS diseases, as both WSV and FSV can protect neurons from death [329,330]. PD, AD, HD, MS, ALS, and PRD are the major neurodegenerative diseases found in humans. Animal models for these diseases have been utilized to prove the therapeutic efficacy of vitamins. 

However, the utilization of vitamins in therapies has been delayed due to studies that suggest no correlation between vitamin levels and neurodegenerative diseases. Despite this, several clinical trials support a potential role for vitamins in future therapies for neurodegenerative diseases. Hormesis is an important factor and should be taken into consideration while designing the dose of vitamins. Hormesis differentiates between the beneficial and toxic activity of vitamins at a particular dose. Multivitamin supplementation shows therapeutic solid potential for neurodegenerative diseases as compared to a single vitamin-based option. Multiple signaling pathways are involved in the multivitamin approach that can boost the antioxidative response manifold. 

Here, we discussed both beneficial and controversial studies involving the role of vitamins in neurodegenerative diseases. Future studies involving different drug-dose paradigms, diverse animal models, and various geographical locations are necessary to determine precisely the potential roles of vitamins in therapies to treat neurodegenerative diseases. Moreover, human clinical trials are desirable to prove the efficacy and the protective role of vitamins in neurodegenerative diseases.

Author Contributions: S.N.R. and P.S. wrote the manuscript. Editing of the manuscript was conducted by H.W.M.S., E.V., G.A., and M.P.S. All authors have read and agreed to the published version of the manuscript.

Funding: Not applicable.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: All of the authors have approved the contents of this paper and have agreed to submission policies.

Data Availability Statement: Each of the authors confirms that this manuscript has not been previously published and is not currently under consideration by any other journal. Additionally, all of the authors have approved the contents of this paper and have agreed to submission policies.

Acknowledgments: The authors also acknowledge the University grant Commission D.S. Kothari Postdoctoral Fellowship to Sachchida Nand Rai (Reference #: F.4-2/2006 (BSR)/BL/19-20/0032) and The Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, Saudi Arabia has funded this project under grant no. (FP-81-42). The authors also would like to acknowledge Biorender (https://app.biorender.com/biorender-templates (accessed on 20 April 2020)) for providing an efficient platform to create all the figures.

Conflicts of Interest: The authors declare no conflict of interest.

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