The Role of Vitamin C in Preventing Some Neurodegenerative Diseases: Alzheimer’s, Parkinson’s, and Huntington’s

Abstract

Brain tissue constitutes a small portion of the total body mass. With its high metabolic rate, brain tissue consumes approximately 20% of the total body oxygen. Brain and neural tissue contain higher levels of vitamin C (VC) than other tissues. It is reported that VC is a powerful and natural antioxidant that is not synthesized in any tissue including the brain. VC is abundant in fruits and vegetables. Its most well-known function is by facilitating the hydroxylation of lysine and proline residues in collagen, allowing procollagen to fold intracellularly for export and accumulation as mature collagen. Firstly, it was reported that VC is transported very slowly across the blood brain barrier which distinguishes the central nervous system (CNS) from other systems in VC uptake. Second, the ability to maintain the VC concentration gradient from blood to neuronal cells is produced by cerebrospinal fluid (CSF) and brain cells. VC has neuroprotection and neuromodulation effects. In conclusion; since its distribution and concentration in different organs of the body depend on the requirements of VC the pharmacokinetic properties of ascorbate are closely related to the functions it performs in tissues.

1. Introduction

Brain tissue constitutes a small portion (~2%) of the total body mass [1]. With its high metabolic rate, brain tissue consumes approximately 20% of the total body oxygen [1, 2, 3]. Brain tissue rapidly metabolizes oxygen and accounts for about 25% of the body’s glucose consumption, indicating a fast metabolism. Consequently, this leads to increased production of free radicals [3], making the brain tissue prone to oxidation. Hence, the presence of antioxidants becomes crucial in maintaining the redox balance in the brain tissue [4]. The high metabolic rate of brain tissue and its content of polyunsaturated fatty acids render this organ vulnerable to oxidative damage [2]. Reactive oxygen species (ROS), produced at physiological concentrations in cells, play a role in processes such as neuromodulation, neurotransmission, and synaptic plasticity control. Additionally, brain tissue, being an organ with weak protective antioxidant mechanisms, is vulnerable to oxidative stress. It relies on high levels of antioxidants for maintaining the redox balance. Glutathione is reported to be the most abundant antioxidant in brain tissue, which is converted to vitamin C (ascorbic acid) (VC) subsequently [3]. Neurons rely on the maximal utilization of energy within the brain to maintain the neuronal membrane potential, as well as for neurotransmitter synthesis/release and axoplasmic transport [1]. In combating reactive oxygen species (ROS), neighboring astrocytes and glial cells serve as the primary defense line for neuronal cells. Neurons release ROS-oxidized vitamin C (VC) into the extracellular environment, where it is subsequently captured by adjacent glial cells. Glial cells then recycle VC, converting it back to its reduced form, ascorbate. This recycling mechanism enables the brain to sustain elevated levels of ascorbate. Ascorbate is predominantly localized within nerve cells, while glutathione is predominantly found in glial cells. The progression of aging or the development of neurodegenerative diseases often coincide with heightened oxidative stress levels and redox imbalance due to deficiencies in antioxidants such as VC [3]. The energy demands of different brain regions vary depending on neuronal functions. Age-associated cognitive decline, neurodegeneration, compromised oxygen metabolism, and impaired mitochondrial activities are linked to oxidative stress-mediated molecular pathways that contribute to neurodegeneration and associated behavioral changes [1]. The brain and neural tissues exhibit considerably higher levels of VC in comparison to other tissues [5].

2. Vitamin C

Physiologically, VC is a six-carbon compound similar to glucose, containing two acid-ionizable groups, and it loses hydrogen ions depending on the pH of the environment, forming ascorbate monoanion or dianion by losing hydrogen ions attached to the 2nd and 3rd carbons [4]. VC is reported to be a water-soluble vitamin that is naturally hydrophilic [1]. It is a powerful natural antioxidant that is not synthesized in any tissue, including the brain [5, 6, 7, 8]. VC is described as a neutral molecule and is suggested to be a white crystalline solid [4]. Vitamin C (VC) is an essential nutrient with various health-promoting properties. Unlike most mammals, humans lack the ability to synthesize VC endogenously and rely on dietary intake for meeting their physiological requirements [9]. VC is abundant in fruits and vegetables, and its consumption is vital for humans to obtain this essential vitamin [5]. VC plays a crucial role in the synthesis of catecholamines, carnitine, cholesterol, amino acids, and certain peptide hormones. Additionally, it acts as a cofactor in numerous important enzymatic reactions [6, 7, 10]. One of the well-known functions of VC is its involvement in the hydroxylation of lysine and proline residues during collagen synthesis. This process is essential for the proper intracellular folding, export, and accumulation of procollagen, ultimately leading to the formation of mature collagen [2, 6, 7]. VC is reported to be an indispensable electron donor in various biological reactions, including collagen hydroxylation, carnitine biosynthesis, and tyrosine metabolism, making it a fundamental nutrient for humans (Figure 1) [12].

Figure 1.

Chemical structure of vitamin C [11].

VC functions as an electron donor during the generation of ascorbate free radical (AFR). Within the cell, AFR is subsequently reduced back to VC through the activity of NADH- and NADPH-dependent reductases. However, if AFR accumulates or becomes concentrated in areas where NADH and NADPH-dependent reductases are not accessible, it can react with VC and dehydroascorbic acid (DHA) to form a different molecule. Furthermore, AFR can undergo a process called dismutation. DHA, on the other hand, can be enzymatically reduced to VC through various cellular mechanisms, including reduction by reduced glutathione (GSH) or enzymatic reduction by thiol transferases or NADPH-dependent reductases. This enzymatic recycling system allows for the regeneration of VC from its oxidized form within the cell. Notably, due to its hydrophilic nature and negative charge at physiological pH, VC can traverse various cell types, including neurons [6]. Vitamin C plays a crucial role in the biochemical functions of redox processes, making it a vital substrate for several key enzymes in the organism’s functioning. One of its significant functions is its ability to be oxidized to ascorbyl radical and further to dehydroascorbic acid (DHA), thereby acting as an antioxidant [4]. Deficiency of vitamin C leads to scurvy, a condition characterized by swollen and bleeding gums, as well as the reopening of previously healed wounds. The enediol structure of vitamin C enables it to function as a potent reducing agent in aqueous solutions, readily undergoing reversible oxidation to DHA. It can also undergo irreversible degradation into diketogulonic acid. In addition to its role as an antioxidant, vitamin C is essential for detoxification reactions and combating bacterial infections [2]. Most animals synthesize VC in their livers, providing a regular supply to the body through circulation. However, humans, primates, and several other species, including guinea pigs, have lost this ability due to functional loss mutations in the gene encoding gulonolactone oxidase, the terminal enzyme in the biosynthetic pathway of VC [13]. The physiological intake and storage of VC can be measured by both plasma and leukocyte levels [14]. It is believed that VC protects cellular DNA, proteins, and lipids from oxidative damage by undergoing self-oxidation, neutralizing reactive oxygen species (ROS). In fact, VC can donate two electrons to ROS, rendering them ineffective. Additionally, VC has various beneficial functions such as immune stimulation and anti-inflammatory effects [7]. Diet and food have been reported to play a protective role in cognition. Various diets, B vitamins, VC, vitamin E, omega-3 fatty acids, polyphenols, flavonoids, and caffeine, among other dietary components, further enhance cognition in association with biliş [15]. It has been reported that foods and functional foods have neuroprotective roles against neurodegeneration. In particular, certain vitamins, minerals, and phytochemicals play a crucial role in exhibiting antioxidant properties by directly scavenging reactive oxygen species (ROS), acting as cofactors to antioxidant enzymes, and regulating genes that control intracellular antioxidant systems [5]. Numerous compounds, including GSH, VC, vitamin E, coenzyme Q10, and others, possessing antioxidant properties, are currently under investigation for their potential to mitigate the impact of ROS-related neurodegenerative processes. Typically, neurodegenerative diseases are characterized by elevated levels of oxidative stress and reduced levels of antioxidant defense markers in the brain and peripheral tissues [16]. The neuroprotective effects of VC have been documented to be effective in various neurodegenerative diseases (Table 1) [5].

1	Immune functions
2	Catecholamine + neuro-transmitter synthesis
3	Synthesis of collagen
4	Synthesis of cortisol
5	Endothelial vasodilation + barrier function
6	Iron and folic acid metabolism

Table 1.

Physiological functions of vitamin C [17].

2.1 Brain tissue and vitamin C

VC is found in millimolar concentrations in neurons [2, 4, 6], hence it serves as a “micronutrient” in the central nervous system (CNS) [4, 6, 10]. VC is most abundant in the hippocampus, cerebral cortex, and amygdala [8]. Neurons are vulnerable to VC deficiency because they have higher rates of oxidative metabolism compared to glia. The antioxidant effect of VC enhances its impact on reducing ROS-mediated neurodegenerative disorders [6]. VC plays a significant role as a scavenger of ROS in brain tissue [8]. In terms of VC uptake in the CNS, it has been reported that VC is transported very slowly across the blood-brain barrier. Additionally, the ability to maintain a concentration gradient of VC from blood to neuronal cells is produced by the cerebrospinal fluid (CSF) and brain cells [4, 6]. VC distributes throughout the body and reaches the highest concentrations in brain tissue [2, 12]. VC exhibits neuroprotection and neuromodulation effects [2, 3]. It has been reported that VC plays an important role in modulating neurotransmitter synthesis and release in brain tissue. The functions of VC in brain tissue include its involvement in the conversion of dopamine to noradrenaline, where dopamine serves as a cofactor for beta-hydroxylase. It also regulates the release of catecholamines and acetylcholine from synaptic vesicles. VC has been reported to possess antioxidant properties in limiting ischemia-reperfusion damage and protecting against glutamate excitotoxicity in brain tissue [4, 14]. It particularly plays a crucial role in the synthesis of catecholamines, including norepinephrine and dopamine. Additionally, it is involved in the synthesis of elastin and collagen, components of blood vessels that supply the basal lamina and neural tissue [4]. Vitamin C (VC) has multiple functions in brain tissue. It has both antioxidant and non-antioxidant functions. Its antioxidant function directly acts to remove nitrogen-based radical species or oxygen generated during normal metabolism. It has been suggested to effectively clear superoxide in neurons in vivo [6]. VC with antioxidant properties plays a role in the structure of the nervous system, memory, and the learning process. It has been reported that p38, a member of the MAP kinase family, plays an important role in the early stages of VC- and laminin-induced myelination. Therefore, the main effect of VC on myelination is likely to be due to the preservation of the structural integrity of the basal lamina [4]. VC, due to its involvement in the synthesis and modulation of biogenic amines, has been recognized as a potential adjuvant for anxiolytic, antiepileptic, antipsychotic, and antidepressant drugs. Its redox capacity is believed to delay the onset of neurodegeneration in brain tissue by mitigating oxidative stress associated with aging. However, high doses of VC consumption have been reported to reverse or reduce neurodegeneration. Endogenous deficiency of VC in the brain leads to oxidative stress and neurodegeneration. The interaction between VC and oxidative protein folding in the brain, as well as its impact on the initiation and progression of neurodegeneration, remains unclear. The neuroprotective function of VC stems from its ability to attenuate neurotoxicity [2, 3]. VC safeguards neurons against oxidative stress, promotes their differentiation and maturation, and regulates the synthesis or release of neuroregulatory factors such as serotonin, catecholamines, and glutamate [10, 12, 18]. In a study on VC deficiency, a decrease of up to 1% in plasma and liver, and up to 30% in brain cells compared to the control group was observed [18]. Various nutrients, including VC, have been implicated in cognitive function. VC also stimulates the production of brain-derived neurotrophic factor, facilitates nerve development, reduces lipid peroxidation through collagen production, and decreases proinflammatory cytokines by binding to nuclear factor kappa β. Plasma VC is transported to the cerebrospinal fluid (CSF) predominantly through the choroid plexus via an active transport mechanism, resulting in CSF concentrations 2.5–4 times higher than in plasma. From there, it diffuses to the extracellular fluid, maintaining consistent VC levels in the CSF and providing a source for neuronal uptake. Despite significant fluctuations in plasma ascorbate levels, CSF concentrations remain relatively stable [8]. VC is recognized as highly important for the homeostasis and proper functioning of the central nervous system (CNS). Its pivotal role in the synthesis of catecholamines suggests that VC is a critical factor influencing the optimal performance of the CNS [3].

3. Alzheimer’s disease

It is expected that the number of Alzheimer’s disease (AD) cases will rise to 152 million by the year 2050. It is estimated that over 50 million people worldwide are affected by AD [19, 20]. According to projections, approximately one in ten individuals over the age of 65 will be diagnosed with Alzheimer’s disease in the coming years [1, 21]. AD is one of the most common types of dementia worldwide, accounting for two-thirds of all dementia cases [21]. Lifestyle and genetic factors play a role in the development of AD, with oxidative stress playing an important role in the pathogenesis of the disease [6]. AD is characterized by cognitive impairment, typically starting with memory loss and progressing to a state where individuals become dependent on caregivers [15, 20]. It is described as a degenerative brain disease characterized by memory decline, language impairment, and cognitive deficits [1, 19]. VC has been reported to have a neuroprotective effect due to its ability to scavenge free radicals, reduce β-amyloid activity, and participate in the chelation of iron, zinc, and copper [21]. Despite adequate nutrient intake, Alzheimer’s patients have low levels of VC, making VC supplementation a therapeutic approach for AD. VC has been reported to be a potent acetylcholinesterase inhibitor [6]. Mitochondrial dysfunction, high oxidative stress, and amyloid plaque formation play significant roles in the pathogenesis of AD. Long-term VC intake has been reported to significantly reduce amyloid plaque formation [3]. VC supplementation as an adjuvant therapy has gained significant interest in individuals with AD and Parkinson’s disease (PH) [10]. Alzheimer’s patients have reported low plasma levels of VC, which are associated with increased oxidative stress [1]. A study has reported that a VC-rich diet increases amyloid precursor protein levels [22].

4. Parkinson’s disease

Parkinson’s disease (PD) is recognized as the second most prevalent neurodegenerative disorder following Alzheimer’s disease (AD) [23, 24]. PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the basal ganglia, leading to a depletion of dopamine levels and subsequent neurodegeneration. Dopamine also plays a crucial role in other brain regions, such as the striatum, which is involved in the regulation of the frontal brain’s motor system [5]. Clinical manifestations observed in individuals with Parkinson’s include tremors, bradykinesia, rigidity, genitourinary disorders, autonomic dysfunction, and speech difficulties. Additionally, symptoms like depression, psychiatric disorders, hallucinations, and insomnia are commonly observed. PD is influenced by various factors, including lifestyle, environmental factors, age, and pre-existing conditions [5, 24]. Oxidative damage is recognized as a key contributor to the pathogenesis of PD, and VC has demonstrated protective effects against disease progression [6]. The use of VC supplementation as an adjuvant therapy has garnered significant attention in individuals with neurodegenerative diseases, including AD and PD [10].

5. Huntington’s disease

Huntington’s disease (HD) is reported to be an autosomal dominant neurodegenerative disorder caused by the expansion of CAG trinucleotide repeats in the amino-terminal region of the huntingtin protein [25, 26, 27]. It is characterized by involuntary choreiform movements, behavioral and psychiatric disorders. It has been reported to primarily affect the nervous system for unknown reasons [25, 27]. HD leads to neuronal loss in the striatum, causing severe motor and cognitive impairments. HD exhibits a deficiency in ascorbate release in the striatum during behavioral activity periods [6]. In the striatum, the main target of HD-related neuropathology, extracellular VC levels are significantly reduced in HD mouse models [28].

6. Conclusion

In conclusion, the distribution and concentration of VC in different organs are closely related to its requirements, and its pharmacokinetic properties are linked to the functions it performs in tissues. VC is an active compound that affects various intracellular processes, including epigenetic regulation of gene expression, intracellular signaling, and modulation of redox status. Due to its antioxidant effect, VC has gained significant interest. Considering its involvement in numerous biochemical and biological processes, it is crucial to compensate for its deficiency in patients. Determining the optimal timing, dosage, duration, and target population among critically ill patients is essential for maximizing the benefits of VC administration. VC should be a focal point in future research as an adjunct therapy for patient treatments.

Acknowledgments

This work is not endorsed by any organization.

Conflict of interest

All authors declare that there is no potential conflict of interest.