The Role Of Vitamins in Neurodegenerative Disease: An Update Part 2

A clinical trial shows that ascorbic acid (200 mg) is very effective for elderly PD patients. In this clinical trial, the authors have suggested that ascorbic acid improves the absorption of levodopa (100 mg levodopa and 10 mg carbidopa) in a significant manner in PD patients. 

In recent years, there has been growing interest in the relationship between ascorbic acid and memory. Ascorbic acid, also known as vitamin C, is an essential vitamin for the human body. It has a variety of important physiological functions in the body, such as redox, antioxidant, skin maintenance, and vision protection. According to research, ascorbic acid is also closely related to improving memory.

First of all, ascorbic acid is a strong antioxidant that can scavenge free radicals in the body and reduce oxidative damage to cells, thereby protecting the health of the organism. Free radicals are by-products of cell metabolism. When cells collect too many free radicals, they will damage their basic biological functions and lead to aging and disease. Therefore, maintaining adequate ascorbic acid intake can reduce the impact of free radicals on the body, help maintain a healthy state of the body, and thereby improve memory.

Secondly, ascorbic acid can stimulate the activity of receptors in the brain, making the brain's memory and learning abilities more agile. Research shows that consuming enough ascorbic acid in foods or drugs can strengthen the brain's memo function, thereby helping to improve people's memory. Ascorbic acid can also promote hormone secretion and enhance the stability of the nervous system, thus promoting the growth, development and repair of neurons, and enhancing thinking and learning abilities.

In summary, ascorbic acid is indeed closely related to human memory. Therefore, we should pay attention to maintaining adequate intake of ascorbic acid. For example, eating more fruits and vegetables rich in ascorbic acid can help enhance the body's immunity, protect brain health, and improve memory. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola It can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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Therefore, the combinatorial therapy of ascorbic acid with levodopa might get a better result than treatment of one alone [80]. However, there is still controversy in the potential use of VitC for the treatment of PD, and further studies are desired [21]. Researchers have also suggested a link between vitamin D (VitD) and PD, and despite all efforts, it is not clear yet if a deficiency in VitD is responsible for PD or a consequence of PD [81]. 

Cutaneous levels of VitD are directly correlated to sunlight exposure [82,83], and ultraviolet exposure enhances the level of VitD in our body [84,85]. Bone density is directly associated with the concentration of VitD and consequently postural stability [86]; however, the role of VitD in the brain is less understood. Calcitriol (1,25- dihydroxy vitamin D3) is an active metabolite and the most studied form of VitD [87]. 

Compared to age-matched healthy controls, PD patients have a much lower concentration of calcitriol in their blood plasma, which may be related to bone health and fracture risk [88,89]. Interestingly, the receptor of calcitriol is also expressed in the CNS [90]. Thus, VitD mediates its effects in PD through its active form, calcitriol, and associated receptors present in the CNS [86,91]. 

One study shows an inverse association and toxic activity of vitamin D in PD [92]. Another study also indicates the toxicity of VitD as responsible for reversible symptoms of Parkinsonism [93]. Regrettably, a recent meta-analysis found few studies focusing on vitamin D supplementation in PD treatments. This study shows an inverse relationship between VitD level and risk and severity of PD in 2866 PD patients [94]. There is a limited response of VitD supplementation (≥400 IU/day) in early PD patients, and this warrants further study to justify its therapeutic potential [95]. 

Therefore, more cohort studies of early and late PD patients are needed to illuminate the connection between VitD and PD further. Vitamin E (VitE) is a well-known antioxidant found in vegetables, and it has multiple therapeutic uses [96]. From the mid-1990s, the role of VitE has been demonstrated in several neurological diseases including PD [97]. Similar to other vitamins, VitE exhibits a strong connection with PD [97]. 

Results from a recent study demonstrated that the effect of VitE was age- and sex-independent and showed an inverse relation between VitE intake and PD occurrence [97]. Consequently, diets rich in VitE may minimize the risk associated with PD [98,99]. The progression of PD might be controlled by high-dose alpha-tocopherol and ascorbate as shown by a pilot study. 

Further clinical trials at a broader level will be needed to confirm the protective efficacy of alpha-tocopherol and ascorbate [100]. As shown by a clinical trial, high dose vitamin E (2000 IU vitamin E orally per day) treatment enhanced its concentration in the cerebrospinal fluid (CSF) of an early untreated PD patient. High CSF and a high brain concentration of alpha-tocopherol show a protective effect on the PD patients [101]. One study also shows that there is not any relation between serum VitE and risk of PD [102]. 

Another study recommended daily multivitamin supplementation that should contain at least 30 IU of alpha-tocopherol instead of 400 IU of alpha-tocopherol in the affected individuals. This combination showed an improved therapeutic response in PD patients [103]. A multivitamin approach by using vitamin E, vitamin C, and carotenoids is not beneficial in reducing PD risk. Instead, dietary vitamin supplementation rich in VitE shows enhanced therapeutic potential to reduce the PD risk. A very high dose might lead to losses in the therapeutic activity of Vitamin E [104]. 

Therefore, care should be taken, and a broader level of clinical study is needed to prove the therapeutic potential of VitE. A case report on an old PD patient shows the enhanced therapeutic activity of multivitaminmultimineral supplementation with Ginkgo biloba [105]. A large population-based study is necessary to confirm the same.

4.2. Vitamin Based Animal Studies in Parkinson's Disease

The cellular retinol-binding protein found on the blood-brain barrier (BBB) allows the brain easy access to VitA and its derivatives [106]. In the CNS, the prominent target of RA action is the nigrostriatal dopaminergic system [107,108]. RA-receptor heterodimers bind to the RA-response element within the promoter region and drive the transcription of the dopamine 2 receptor gene. 

As such, RA receptor knockout mice exhibited reduced expression of the D2 dopamine receptors [60]. Thus, the RA receptor effectively regulates the homeostatic regulation of the nigrostriatal dopaminergic system as supported by multiple pieces of evidence [108–111]. Therefore, further investigation into the incorporation of VitA in prospective PD therapies may prove fruitful. A recent study suggested that there is no effect of oral supplementation of retinol in the 6-hydroxydopamine intoxicated Wistar rat model [112]. 

RA receptor based therapeutic approaches might be beneficial in preventing the progression of PD and suggest the mechanism of action behind it [113]. Lycopene is an important carotenoid that also exhibits its effectiveness in the MPTP-induced Parkinsonian mouse model. The lycopene treatment reversed physiological anomalies, oxidative stress, neurochemical abnormalities, and apoptosis. Lycopene shows anti-apoptotic and antioxidative properties in this PD mouse model [114]. Lycopene also protects the cognitive decline in the rotenone-induced PD model [115]. 

Vitamin C (VitC), which humans cannot synthesize due to the absence of the enzyme L-gulonolactone oxidase, has many health benefits including essential antioxidant activities [116]. For example, treatments with VitC mitigated the PD-like phenotype of dopaminergic neuron degeneration and locomotor deficits in a UCH-L1 gene knockdown Drosophila PD model (Figure 2) [117]. 

Recently, a study explored the dose-dependent effects of VitC using this knockdown fly model. The authors suggested that for PD treatment, VitC dose-response activity should not be ignored as high concentrations of VitC had adverse effects on behavior and locomotion [118]. Ascorbic acid (100 mg/kg) administration just before the 20 min of MPTP intoxication showed a protective effect by its antioxidative activity in the BALB/c PD model (Figure 2) [119]. In an animal model of PD, VitD inhibits neuroinflammation by regulating microglial activity and protects the death of dopaminergic neurons (Figure 2) [120]. 

In a hemiparkin-sonian rat model, VitD protects the death of dopaminergic neurons by inhibiting oxidative stress and neuroinflammation [121]. The PD-like symptoms and associated pathology regarding mitochondrial abnormalities and synaptic impairment in a PD knockdown model were significantly improved by VitE supplementation [97]. Chronic intake of VitE (500 mg/kg-diet) lowers the death of dopaminergic neurons in the substantia nigra of the zitter mutant rat model of PD [122]. 

However, many researchers have shown contrasting findings regarding the dietary intake of VitE for treatment of PD [123]. Tocotrienols (T3s) are well-known members of the VitE family that also offer neuroprotective potential through their antioxidative activity [124]. Biochemical and behavioral evidence have suggested that the PD progression induced by intrastriatal injection 6-OHDA was ameliorated by VitE treatment in the PD rat model [125]. Similarly, behavioral, neurochemical, and biochemical studies proved that VitE benefits the rotenone-induced rat model [126]. 

Histochemical and biochemical evidence also suggested that the repeated intramuscular administration of vitamin E (24 I.U./kg, i.m) offers the significant neuroprotective property in an early rat PD model induced by unilateral intrastriatal 6-hydroxydopamine (12.5 microg/5 microl) [127]. Alpha-tocopherol also exhibited a similar neuroprotective activity in the unilateral 6-OHDA model and might be used as an effective PD drug [128]. 

Results from a study demonstrated that a combination of a higher dose of Coenzyme Q10 (CoQ10) (600 mg/kg/day) with levodopa (10 mg/kg/day) significantly protected subjects from neurodegeneration in a rotenone-induced rat model of Parkinsonism as compared to a low dose combination of CoQ10 (200 mg/kg/day) with levodopa (10 mg/kg/day). The higher dose of CoQ10 with levodopa improved abnormalities in the electron transport chain and exhibited anti-apoptotic activity. Striatal dopamine levels were considerably restored by this treatment paradigm [129].

4.3. Vitamins in Cell-Based Parkinson's Disease

A pluripotent stem-cell-based study shows that RA-γ is the most effective among α and β RA receptors in forming striatopallidal-like neurons in PD by affecting the dopamine 2 receptor gene [130]. Niacin (VitB3) shows potent anti-inflammatory activity through its receptor GPR109A by inhibiting the nuclear translocation of NF-κB in a lipopolysaccharide (LPS)-induced RAW264.7 cell model of PD. This nuclear inhibition of NF-κB prevented the upregulation of proinflammatory cytokines and the associated neurodegeneration in this PD model [131]. 

NADH is the active coenzyme of VitB3. NADH causes enhanced release of dopamine from the striatal slices at a 350 microM concentration in vitro. There is no effect of NADH (10 or 100 mg/kg) in vivo. For the synthesis and regeneration of tetrahydrobiopterin, NADH is needed. In addition, tetrahydrobiopterin is needed to synthesize Tyrosine hydroxylase, a rate-limiting enzyme in the synthesis of dopamine. 

A study will be required to validate the in vitro findings in an in vivo model [132]. In a cellular model of PD, the survival rate and energy activity were improved significantly by Nicotinamide mononucleotide (NMN). In the human neuroblastoma cell line SK-N-SH, ascorbic acid (200 microM) led to enhanced expression (three-fold) of tyrosine hydroxylase (TH) after 5 days of treatment. 

Consequently, dopamine synthesis was increased as a result of enhanced expression of TH. Therefore, ascorbic acid might be utilized in early PD as a potential anti-Parkinsonian agent [133]. In the cellular model, ascorbic acid also exhibits its therapeutic potential against levodopa-induced neurotoxicity [134]. MN ameliorated the process of apoptosis in this cellular model [135]. 

Further, studies have demonstrated that 1,25-dihydroxyvitamin D3 exhibited strong anti-inflammatory and neuroprotective effects, and reduced the neurotoxin-induced microglial activation and expression of proinflammatory cytokines in experimental models of inflammation-mediated neurodegenerative disease (Figure 2) [136,137]. In a cellular PD model, T3s exhibited cytoprotective activity through the estrogen receptor-activated β-PI3K/Akt pathway [124].

In conclusion, numerous cell-, animal-, and human-based studies have found that vitamins have beneficial effects in the prevention and/or treatment of PD due to their antioxidant properties and other biological functions such as regulating gene expression. However, some studies disagree [21]. Specifically, some studies also show that there is no impact regarding the therapeutic potential of vitamins. In addition, the dose is the very crucial factor that decides the efficacy of the action of vitamins in the PD. Therefore, more clinical studies are necessary to clarify the potential use of vitamin supplementation in PD therapeutics.

5. Vitamins in Alzheimer's Disease

Worldwide, Alzheimer's disease (AD) is ranked first in occurrence among all neurodegenerative diseases [105]. In the aging population, AD is the most common cause of dementia [138]. Clinical symptoms of AD begin with cognitive impairments, which further progress into dementia [139]. AD neuropathology includes the progressive degeneration of neurons, the formation of amyloid (Aβ) plaques, and neurofibrillary tangles (NFT) of the hyperphosphorylated tau protein [140,141]. 

As such, post-mortem analysis of AD patient brains reveals a reduction in the size of the cerebral cortex and abnormal deposits inside and around neurons [138]. Similar to other neurodegenerative diseases, one of the leading causes responsible for progressive neurodegeneration in AD is oxidative stress [142]. Accumulating evidence has shown that the antioxidative activity of vitamins may be beneficial in the treatment of AD. As such, vitamins have been used as adjuvants in AD therapy [6,143].

5.1. Vitamins Based Clinical Studies in Alzheimer's Disease

In AD treatment, nicotinamide can be used as an adjuvant therapy because it is a potent inhibitor of Poly (ADP-ribose) polymerase 1 [144]. Multiple pieces of evidence have suggested that compared to healthy individuals with intact neurocognitive function, AD patients show reduced levels of VitA, VitB, and VitC in blood serum [145]. Meta-analytic studies have found reduced serum levels of VitA, VitB [6,9,21], VitC, VitD, VitE, and VitK in AD patients [146,147]. Moreover, reduced levels of VitA, VitC, and VitE were observed in dementia patients as compared to healthy controls [148,149]. 

Interestingly, a cross-sectional and prospective study reported that a combination of VitC and VitE supplements reduced the prevalence and incidence of AD; however, they made no report of VitA, and found no association of VitB intake with AD [150]. Cognitive function in US women was significantly improved by long-term treatment with retinoids [151]. Clinical trials on RA and associated derivatives might confirm its therapeutic efficacy and role as a biomarker in AD patients. Gut microbiota also might affect retinoid signaling in AD. 

Dynamic gut microbiota may directly link with retinoic acid to mediate therapeutic responses in AD [152]. In the early AD stage, there is no correlation between Retinol binding protein 4 and AD. Therefore, RBP4 is not used as a clinical biomarker in early AD [153]. Failures of RA signaling and associated RA deficiency are linked with age-related cognitive decline in AD. Thus, RA therapeutic activity is directly linked with AD and associated symptoms [154]. Several types of B vitamins (VitB9, VitB12, VitB6, and VitB2) are involved in the metabolism of homocysteine [155]. 

Elevated levels of total plasma homocysteine lead to cognitive impairments, which may ultimately lead to dementia [66,156,157]. Several studies have demonstrated that VitB supplementation lowers total homocysteine in the treatment for cognitive decline [158–160]. In an unbiased analysis, Douaud et al. showed that AD pathology, characterized by atrophy of cerebral gray matter, was reduced by VitB supplementation, reducing the total homocysteine in serum plasma [156]. In contrast, a meta-analysis on randomized control trials suggests that no improvements in cognitive impairment have been observed in therapies that reduce total homocysteine with VitB supplementation [161–163]. 

As such, results from a 26-week randomized, double-blind, placebo- controlled study of Taiwanese AD patients given a multivitamin supplement containing vitamins B6, B12, and B9 in addition to acetylcholinesterase inhibitor treatment demonstrated a decrease in the concentration of serum homocysteine but no beneficial effects on cognition or the daily living activity of the AD patients [164]. Another clinical study showed that a high dose of B vitamins (VitB9, VitB12, VitB6), while effectively lowering homocysteine levels, did not affect cognition in individuals with mild to moderate AD [165]. 

However, in older MCI patients, vitamin B prevented cognitive decline as demonstrated by a randomized placebo-controlled trial [166]. On the other hand, there is no effect of a 2-year treatment of vitamin B on the elevated level of homocysteine and cognitive performance as shown by secondary data from a RCT [167]. Higher vitamin B12 and folate exhibited potent therapeutic activity and improved cognitive performance in a cross-sectional study on AD [168]. 

The screening of presymptomatic AD cannot be diagnosed by measuring the serum folic and vitamin B12 levels as shown by a Turkish threecenter based study [169]. Thus, the role of vitamin B and folic acid for MCI and AD is very speculative and needs a complete investigation. Therefore, a complete evaluation of the therapeutic efficacy of vitamin B and folate in MCI and AD on a broader population might solve the puzzle mentioned above. 

Significant cognitive impairment with progressive dementia is associated with thiamine deficiency. These symptoms have been improved by the supplementation of thiamine in affected individuals [170]. In elderly patients, reversible dementia is associated with a deficiency in cobalamin [171].

Vitamin B12 inhibits the tau fibrillization and formation of the neurofibrillary tangle. Thus, VitB12 prevents the tau aggregation and ultimately neurofibrillary tangle formation that might progress the severity of AD (Figure 3) [172]. A Havana, Cuba based study also suggests a relationship between the level of homocysteine and vitamins among older AD patients. In this study, a total of 424 peoples above or equal to the age of 65 were included in which 131 were MCI, 43 AD, and, in 250 individuals, no sign of cognitive impairment was detected. 

As compared to healthy participants, the level of vitamin A, C, and B2 was reduced significantly among AD patients. In addition, in the same AD patients and MCI patients, the homocysteine level was elevated significantly compared to healthy individuals. The level of vitamin B12, folic acid, and thiamine was unrelated in all groups. The authors concluded that in MCI and AD, various vitamin deficiencies are directly related to impairment in the metabolism of homocysteine [173]. 

Although this is a very small-scale study, a larger population-based study is needed to find any valid correlation between different B vitamins and hyperhomocysteinemia among AD and MCI patients. In patients with folate deficiency, cognitive impairment was ameliorated by folate supplementation for a short period [174]. Inflammation is one of the major factors that lead to progressive neurodegeneration in AD. 

A clinical trial suggested that folic acid shows anti-inflammatory solid activity and prevents neurodegeneration in AD. ChiCTR-TRC13003246 is the registration number of this clinical trial conducted in China [175]. A greater understanding of the relevance of VitB and homocysteine metabolism to cognitive function is wanted. The risk of AD also increases due to a low serum level of VitD [176,177]. 

Calcium levels and the parathyroid hormone, along with specific cytokines, regulate the concentration of the active form of VitD, calcitriol. The inactive form of VitD crosses the BBB, and, inside glial and neuronal cells, it is converted into the active form by the enzyme CYP27B1 [178,179]. Microglial cells are also responsible for converting provitamin D into the active form of VitD [180]. Calcitriol controls the synthesis of the nerve growth factor (NGF) and ultimately governs the process of neuronal cell differentiation and maturation. In addition, calcitriol regulates the synthesis of the glial cell-line-derived neurotrophic factor (GDNF) [181,182]. Both the NGF and GDNF regulate learning and memory through the septohippocampal pathway. With advancing age, the level of the NGF decreases [183]. 

NGF levels are also reduced in AD patients [184]. Amyloid precursor protein (APP) concentration is effectively modulated by the NGF [184]. NGF signaling interruption leads to an up-regulation of APP levels and an increased production of Abeta intracellular aggregates [185]. Of great interest Cognitive function is affected by the B12 levels as suggested by an elderly Korean population-based study [187]. VitE plays an important role in improving cognitive function along with memory deficits [188]. VitE can be combined with other antioxidants to promote the efficacy of the treatment strategies effectively [189]. Despite several pieces of evidence regarding the antioxidant activity of VitE, the role of VitE is controversial [190]. 

In contrast, clinical trials regarding the activity of VitE in AD showed conflicting findings [190]. One such trial, reporting the impact of VitE in conjunction with donepezil supplementation for mild cognitively impaired (MCI) patients (early stage of AD), found no added benefit for VitE supplementation [191]. This double-blinded study treated MCI patients with 2000 IU of VitE daily and 10 mg of donepezil daily or a placebo for three years. There was no effect of VitE for MCI; however, donepezil lowered the rate of progression of MCI towards AD for the first 12 months and longer for apolipoprotein E4 carriers [192]. 

Slower functional decline was observed as a result of 2000 IU/d of alpha-tocopherol in AD patients compared to controls in a collaborative randomized trial-based study [193]. In conclusion, as it is unclear whether prolonged and synergistic treatments with VitE are beneficial for the management of AD, broader population studies are needed [189].

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