Ascorbic Acid and Its Role in Safeguarding Neurons: Updated Evidence by Shirley Wang

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Ascorbic Acid and Its Role in Safeguarding Neurons: Updated Evidence Y. Robert Li1-4*, Hong Zhu1, Yuebin Ke5, Zhenquan Jia4*, Hara P. Misra3, Emanuel J. Diliberto6 Campbell University School of Osteopathic Medicine, Buies Creek, NC 27506, USA

Virginia Tech-Wake Forest University School of Biomedical Engineers and Sciences, Blacksburg, VA 24061, USA

Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA 3

Department of Biology, University of North Carolina, Greensboro, NC 27412, USA

Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China.

Department of Pharmaceutical Sciences, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC 27506, USA 6

* Corresponding author E-mail addresses: yli@campbell.edu (Y.R. Li), z_jia@uncg.edu (Z. Jia) Abstract Ascorbic acid, commonly known as vitamin C, is a watersoluble vitamin synthesized in plants as well as many animal species, but not in humans. Humans obtain ascorbic acid from dietary sources and via vitamin supplementation. Ascorbic acid possesses important biological functions, including serving as a cofactor for many enzymes, acting as an antioxidant, and participating in regulating cell growth, apoptosis, and signaling, which collectively contribute to its essentialness in maintaining and safeguarding the physiological homeostasis and the health of human body. This article summarizes recent evidence for ascorbic acid acting as a booster in neuron physiology and a protector in neuron degeneration. Keywords Ascorbic Acid; Antioxidant; Neuroprotection; Neurodegeneration

Overview Ascorbic acid, also known as ascorbate or vitamin C, is a water-soluble molecule synthesized endogenously in animals except humans, monkeys, guinea pigs, and several other animal species (Bruno et al. , 2006). Humans lost this capability because of a series of inactivating mutations of the gene encoding gulonolactone oxidase (GULO), a key enzyme in ascorbic acid biosynthesis. Humans normally acquire ascorbic acid from dietary sources through an active substrate-saturable transport mechanism. Dietary sources of ascorbic acid are mainly from vegetables and fruits, including Brussels sprouts, broccoli, bell peppers, lettuce, tomatoes, citrus fruits, strawberries,

papayas, and mangoes. Another source is ascorbic acid supplement. Oral ascorbic acid intake produces plasma concentrations that are tightly controlled; once its oral intake exceeds 200 mg daily, it is difficult to further increase plasma concentration. The maximal plasma concentration attainable by oral intake of ascorbic acid has been estimated to be approximately 200 micromolar though the physiological plasma concentrations in healthy humans range from 40 to 100 micromolar. In contrast, intravenous injection of large doses of ascorbic acid produces millimolar concentrations of plasma ascorbic acid (Padayatty et al. , 2004). Under physiological conditions, intracellular levels of ascorbic acid are in the millimolar range. This is due to selective intracellular accumulation via ascorbic acid transport system present in the plasma membrane (Wilson, 2005). The high intracellular concentrations of ascorbic acid in mammalian tissues suggest its essential roles in maintaining physiological homeostasis and proper functions of organs and systems. In this article, we first examine the novel biochemical properties and functions of ascorbic acid, and then discuss recent research evidence supporting its multi-tasking functions in safeguarding neurons and protecting against neurodegenerative disorders, a major contributor to the global burden of disease. Ascorbic Acid as a Multi-tasking Molecule Since its isolation from adrenal glands by Albert Szent-Gyรถrgyi in 1928 (Carpenter, 2012), ascorbic acid

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has gradually gained a reputation of being a multitasking molecule with a wide range of distinct biological activities. These activities can be summarized into the following four categories: (1) as a cofactor for various enzymes; (2) as an antioxidant at physiological doses; (3) as a potential pro-oxidant at pharmacologic doses; and (4) other emerging novel activities.

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C transporter 2 (SVCT2) may participate in transporting ascorbic acid from cytosol into mitochondrial matrix. Together, the above findings may help explain the high concentrations of ascorbic acid in mitochondria and its role in maintaining the redox status of the organelle. Due to its high instability, DHA if not rapidly reduced, undergoes hydrolytic ring opening to 2, 3-diketogulonic acid.

Ascorbic Acid as a Cofactor for Various Enzymes Ascorbic acid serves as a cofactor for at least eight enzymes in mammals, including humans. The most notable ones are proline hydroxylase and lysine hydroxylase, which are involved in collagen synthesis. The other enzymes for which ascorbic acid acts as a cofactor are involved in carnitine synthesis, catecholamine synthesis, peptide amidation, and tyrosine metabolism (Mandl et al. , 2009). Due to its critical role in collagen synthesis, deficiency of ascorbic acid compromises the integrity of blood vessels, leading to scorbutic gums and pinpoint hemorrhage, characteristic manifestations of ascorbic acid deficiency. Ascorbic Acid as an Antioxidant The redox chemical properties of ascorbic acid are responsible for its antioxidant as well as potential prooxidant activities. As shown in Figure 1, ascorbic acid (AscH2) has two ionizable hydroxyl groups. At a physiological pH, ascorbic acid exists predominantly as a monoanion, i.e., ascorbate monoamine (AscH-). AscH- acts as a reducing agent and is converted to ascorbate radical (Asc.-), also known as semidehydroascorbate) after donation of one electron. After losing another electron, Asc.- is converted to dehydroascorbate (DHA). Asc.- can be reduced back to AscH-. DHA can also be reduced by either one electron to Asc.- or by two electrons to AscH-. The twoelectron reduction of DHA to AscH- is catalyzed by DHA reductase using reduced glutathione (GSH) as the cofactor. This two-electron reduction reaction brings together two highly prevalent intracellular antioxidant molecules: ascorbic acid and GSH both present at millimolar concentrations inside the cells. Indeed, ascorbic acid and GSH cooperate closely to maintain redox homeostasis of mammalian cells (Meister, 1994). In addition, mitochondrial electron transport chain, especially the complex III, may also reduce DHA to AscH- (Li et al. , 2002). The in vivo significance of this mitochondria-dependent reduction is, however, unclear. The sodium-dependent vitamin

FIG. 1 REDOX CHEMISTRY OF ASCORBIC ACID AND ITS RELATIONSHIP TO GLUTATHIONE. AS ILLUSTRATED, THE 2ELECTRON REDUCTION OF DHA TO ASCORBIC ACID IS CATALYZED BY DHA REDUCTASE WITH GSH AS THE ELECTRON DONOR. THE OXIDIZED FORM OF GLUTATHIONE (GSSG) IS REDUCED BACK TO GSH BY GSSG REDUCTASE USING NADPH AS AN ELECTRON DONOR

In many vitro systems, ascorbic acid has been found to scavenge various reactive oxygen and nitrogen species (ROS/RNS), and to protect cells from oxidative damage. Ascorbic acid is able to regenerate alphatocopherol and coenzyme Q from alpha-tocopherol radical and coenzyme Q radical, respectively, and thereby playing a role in maintaining the antioxidant activities of alpha-tocopherol and coenzyme Q. It has recently been demonstrated that ascorbic acid is also able to reduce 1-Cys peroxiredoxin (Monteiro et al. , 2007). Peroxiredoxin is critical for the detoxification of hydrogen peroxide and peroxynitrite. As noted above, ascorbic acid and glutathione cooperate to act as an efficient dual-antioxidant system in mammals (Meister, 1994). In addition to the above activities involved in detoxifying ROS/RNS, ascorbic acid is found to inhibit NADPH oxidase subunit p47phox expression induced by inflammatory insults, thereby decreasing the formation of ROS from this important cellular source (Wu et al. , 2007). The inducible expression of inducible nitric oxide synthase (iNOS) in septic mice is also inhibited by ascorbic acid (Wu et al. , 2003). It is unlikely that ascorbic acid directly inhibits the enzyme

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activity of either NADPH oxidase or iNOS. The reduced expression of the above enzymes or enzyme subunits by ascorbic acid most likely results from its modulation of cellular redox signaling that is involved in the inducible expression of the ROS/RNSgenerating enzymes. Interestingly, ascorbic acid induces heme oxygenase-1 (HO-1), an enzyme with potent antioxidative and anti-inflammatory activity (Huang et al. , 2012). While the mechanism involved in the induction of HO-1 remains to be determined, it is likely that ascorbic acid provokes a pro-oxidant state in cells that subsequently activates HO-1 gene expression. Indeed, HO-1 is known as an oxidative stress-responsive gene. Ascorbic Acid as a Potential Pro-oxidant Under certain conditions, such as in the presence of redox active metal ions, ascorbic acid may behave as a potent pro-oxidant, giving rise to ROS, damaging DNA, and causing protein glycation. Indeed, increased oxidative DNA damage occurs in individuals consuming large amount ascorbic acid (Levine et al., 1998). Ascorbic acid induces decomposition of lipid hydroperoxide to genotoxins even in the absence of redox active metal ions (Lee et al. , 2001). In a humanized mouse model, ascorbic acid is found to mediate chemical aging of lens crystallins via the Maillard reaction (Fan et al., 2006). In experimental animals, administration of pharmacological doses of ascorbic acid causes formation of ascorbic acid radical and ROS in extracellular fluid and decreases growth of aggressive tumor xenografts (Chen et al. , 2008). Pharmacological doses of ascorbic acid have been employed as a potential therapeutic modality for cancer patients, especially those with advanced cancers (Cameron and Pauling, 1976, 1978, Mikirova et al. , 2013). The prooxidant activity of ascorbic acid makes it an effective agent for killing drug-resistant Mycobacterium tuberculosis (Vilcheze et al. , 2013). Hence, the prooxidant activities of ascorbic acid may exert either detrimental or beneficial effects dependent on the physiological and pathophysiological conditions. Other Emerging Novel Activities of Ascorbic Acid Ascorbic acid reduces ferric ion to ferrous ion and thus facilitates iron absorption in the duodenum. Recent studies suggest a role for ascorbic acid in nucleic acid and histone demethylation, as well as proteoglycan deglycanation. Due to its role in hydroxylation reactions, ascorbic acid participates in downregulating hypoxia-inducible transcription factor-1alpha (HIF-

1alpha). In this regard, proline hydroxylation targets HIF-1alpha for ubiquitin-mediated degradation (Knowles et al. , 2003). Moreover, ascorbic acid was shown to regulate angiogenesis (Mikirova et al. , 2008, Yeom et al. , 2009). Ascorbic acid may also play a role in stem cell biology. It enhances the reprogramming efficiency of mouse and human fibroblasts transduced with three (Oct4/Klf4/Sox2) or four (Oct4/Klf4/Sox2/cMyc) factors. It also alleviates cell senescence by p53 repression and may accelerate reprogramming by synergizing with epigenetic regulators (Esteban et al. , 2010, Shi et al. , 2010). More recent studies identified a novel function of ascorbic acid in promoting Tet-mediated generation of 5-hmC, suggesting that the availability of ascorbic acid may have a profound effect on many cellular functions dictated by DNA demethylation and that ascorbic acid may act as a critical mediator of the interface between the genome and environment (Blaschke et al. , 2013, Minor et al. , 2013). These novel mechanisms may also contribute to the biological functions of ascorbic acid in health and disease, including neuron physiology and degeneration. Experimental Approaches for Studying the Functions of Ascorbic Acid in Neurobiology A number of approaches have been employed to study the biological activities of ascorbic acid in experimental animals. These include direct administration of ascorbic acid either orally or parenterally. As noted earlier, intravenous injection of large doses of ascorbic acid produces millimolar plasma concentrations, causing pharmacological effects, such as antitumor activity. Due to limited oral bioavailability of ascorbic acid, lipophilic ascorbic acid derivatives (e.g., ascorbyl stearate) with increased bioavailability have been developed as a potential protector in animal models of human diseases. As aforementioned, humans are unable to synthesize ascorbic acid endogenously due to inactivating mutations of the gene encoding gulonolactone oxidase (GULO). Targeted disruption of GULO gene in mice leads to creation of mutant mice of ascorbic acid deficiency (Maeda et al. , 2000). This ascorbic acid deficient GULO-knockout mouse model has been extensively used to understand the biological functions of ascorbic acid under experimental conditions. Studies using GULO-null mice over the past several years have provided important insight into the molecular functions of ascorbic acid in

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safeguarding neurons neurodegeneration.

and

attenuating

FIGURE 2 TISSUE LEVELS OF ASCORBIC ACID. HUMAN RED BLOOD CELLS (RBCS) EXPRESS A HIGH NUMBER OF GLUT1, BUT HAVE NO SVCT TRANSPORTERS (64), AND THE INTRACELLULAR CONCENTRATION OF ASCORBIC ACID IN THESE CELLS IS SIMILAR TO THAT IN PLASMA. ASCORBIC ACID CONCENTRATION IF CEREBROSPINAL FLUID IS ~5-10 TIMES HIGHER THAN THAT IN PLASMA. LARGER ARROWS INDICATE THE MAIN DIRECTION OF ASCORBIC ACID TRANSPORTATION. AS SHOWN, ASCORBIC ACID ACCUMULATES IN ORGANS AND TISSUES AND THE HIGH TISSUE CONCENTRATIONS ARE DUE TO HIGH INTRACELLULAR LEVELS OF ASCORBIC ACID, USUALLY IN THE MILLIMOLAR RANGE. NOTE: THE FIGURE IS BASED ON THE INFORMATION PROVIDED IN THE LITERATURE (28, 29)

Ascorbic Acid Acts as a Neuron Safeguard Neuronal Uptake of Ascorbic Acid The highest tissue concentrations of ascorbic acid are found in brain and in neuroendocrine tissues especially adrenal gland, which may range from 1 mM to 3 mM (Figure 2). These concentrations are 15-50 times higher than those in plasma (Harrison and May, 2009, Michels et al. , 2013), pointing to the existence of active transporters. Early seminal work by E. J. Diliberto and coworker show that adrenomedullary cells accumulate ascorbic acid through a saturable and energy-dependent process and that the newly takenup ascorbic acid is also secreted from these cells through exocytosis from the catecholamine-containing chromaffin vesicle compartment as well as from the cytosol compartment by a specific transporter mechanism (Daniels et al. , 1982, 1983, Diliberto et al. , 1983, Knoth et al. , 1987). It is now well-established that ascorbic acid enters and accumulates in neurons

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via two different transporting systems: (1) the reduced form of ascorbic acid is transported into neurons via sodium-dependent vitamin C transporter 2 (SVCT2), which was noted earlier, also transports ascorbic acid from cytosol into mitochondria; and (2) the oxidized form of ascorbic acid, DHA enters neurons as well as glial cells via the ubiquitous glucose transporters of the GLUT family. Once inside the cells, DHA is reduced to ascorbic acid via DHA reductase using GSH as the electron donor (Figure 1). Notably, ascorbic acid level in astrocytes is 10 times lower than that in neurons (Burzle et al. , 2013). GSH deficiency may also affect ascorbic acid levels in both neurons and glial cells. Studies in knockout mice show an essential role for SVCT2 in neuronal ascorbic acid homeostasis (Sotiriou et al. , 2002). SVCT2-null mice die of brain hemorrhage and lung failure shortly after birth, and the ascorbic acid level in the brains of the newborns is barely detectable (Sotiriou, Gispert, 2002). Ascorbic Acid in Neuronal Catecholamine Biosynthesis Ascorbic acid plays an active role in the synthesis of catecholamine neurotransmeters, including dopamine and norepinephrine. It enhances catecholamine biosynthesis via three mechanisms: (1) the pioneering work by E. J. Diliberto and coworkers has established that ascorbic acid helps maintain the activity of dopamine β-hydroxylase by recycling its essential cofactor, ascorbate (Diliberto and Allen, 1981, Diliberto et al. , 1991, Menniti et al. , 1986). Two Ascorbate molecules undergo one-electron reductions to the ascorbate free radical that is generated upon hydroxylation of dopamine by dopamine β-hydroxylase. Ascorbic acid is much more efficient in this recycling than cellular GSH or L-cysteine; (2) ascorbic acid directly contributes electrons to dopamine βhydroxylase in neurosecretory vesicles to allow it to hydroxylate dopamine to form norepinephrine (Diliberto and Allen, 1981, Diliberto, Daniels, 1991, Menniti, Knoth, 1986). The levels of neurosecretory vesicle ascorbate appear to be maintained by mitochondrial semidehrdroascorbate reductase, cytocolic ascorbate and electron transport across the vesicle membrane by cytochrome b561 [37]. Without ascorbic acid, the activity of dopamine β-hydroxylase is low, possibly maintained by an electron from dopamine itself; and (3) ascorbic acid may stimulate catecholamine synthesis via enhancing the transcription of tyrosine hydroxylase (May et al. , 2013). A recent study shows that the embryonic brain

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cortex neurotransmitter synthesis and tyrosine hydroxylase expression are dependent on intracellular ascorbic acid (Meredith and May, 2013), highlighting an essential role for this molecule in neural development. There is also evidence that ascorbic acid might play a role in promoting neuron stem cell differentiation and may thus have important implications in stem cell transplantation for treating neurodegenerative disorders (Nualart et al. , 2012). Ascorbic Acid in Neuronal Development and Behavior The critical role for ascorbic acid in neurotransmission and neuromodulation may make it an essential molecule for normal development of neurobehavior. Studies using ascorbic acid-deficient Gulo-/- mice with a chronic low ascorbic acid status show ascorbic acid deficiency during postnatal development affects adult behavior. These adults are less active in moving in their environment though they exhibit no cognitive, anxiety or sensorimotor-gating problems. Despite being less active, Gulo-/- mice show exaggerated hyperactivity to the dopaminergic agonist methamphetamine. The subnormal movement, combined with hypersensitivity to a dopamine agonist, points to that developmental ascorbic acid deficiency may cause long-term striatal dysfunction (Chen et al. , 2012). Maternal ascorbic acid deficiency during pregnancy also persistently impairs hippocampal neurogenesis in offspring of guinea pigs (TvedenNyborg et al. , 2012). A role for ROS, especially those derived from NADPH oxidase in developing depression has been increasingly recognized (Seo et al. , 2012). Since ascorbic acid suppresses NADPH oxidase subunit expression and possesses antioxidant activity, its antidepression effects have been examined. Ascorbic acid treatment, similar to fluoxetine, reverses depressionlike behavior and brain oxidative damage induced by chronic unpredictable stress in mice (Moretti et al. , 2013, Moretti et al. , 2012). On the other hand, ascorbic acid deficiency results in decreases in dopamine and serotonin metabolites in both the cortex and striatum, contributing to a depression-like behavior in mice (Ward et al. , 2013). Such a behavior change can be reversed by supplementation with ascorbic acid (Ward, Lamb, 2013). Interestingly, infusion of ascorbic acid into the medial preoptic area facilitates appetitive sexual behavior in female rats (Mehdinia et al. , 2013). Ascorbic Acid in Neurodegeneration Ascorbic acid not only plays a crucial role in the

proper function of neurotransmission, but also acts as an important protective molecule against oxidative neurodegeneration. Ascorbic acid deficiency in GULOknockout mice results in increased oxidative stress in brain tissue as well as sensorimotor deficits (Harrison et al. , 2008). Neurological disorders, such as ischemic stroke, Alzheimer’s disease, Parkinson’s disease, and Huntington’s diseases usually involve oxidative stress. Ascorbic acid as an important antioxidant in the brain has thus been implicated in the protection against these diseases in animal models (Harrison and May, 2009). Indeed, an early study showed that when monkeys were given 1g/day of ascorbic acid perenterally for six days before middle cerebral artery occlusion, brain infarct size was decreased by ~50% in the ascorbic acid-treated group compared with the control group not treated with ascorbic acid (Ranjan et al. , 1993). Administration of ascorbic acid also results in amelioration of experimental parkinsonism (Desole et al. , 1993, Khan et al. , 2012), beta-amyloid peptideinduced oxidative damage in rat brain (Murakami et al. , 2011, Rosales-Corral et al. , 2003), as well as Huntington’s behavioral phenotype in mice (Rebec et al. , 2003). The neuroprotection by ascorbic acid is believed to result from its antioxidant function and inhibition of cell death, including apoptosis and autophagy (Dong et al. , 2013), as well as glutamate excitotoxicity (Ballaz et al. , 2013). The emerging novel biological activities of ascorbic acid, as described earlier may also be involved in its neuroprotection, and their discrete contribution warrants further investigation. Although ascorbic acid shows consistent efficacy in preventing and treating neurodegenerative disorders in animal models, the benefits of ascorbic acid supplementation in counteracting neurodegeration in humans are equivocal (Heo et al. , 2013). The ineffectiveness of ascorbic acid treatment may be due to multiple reasons, including the route of administration. In this regard, the maximal plasma concentration of ascorbic acid attainable by oral administration is about 200 micromolar, which might not be high enough to exert protection against ongoing neurodegereation. Another factor may be related to the status of ascorbic acid as well as other antioxidants in the patients. Antioxidant vitamin therapy, including ascorbic acid treatment seems to be more effective in individuals with relative deficiency of the vitamins and augmented oxidative stress status (Lopes da Silva et al. , 2013, Sadat et al. , 2013). Ascorbic acid also safeguards peripheral nervous system via promoting myelination by forming a

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collagen- and laminin-containing extracellular matrix. SVCT2 transports ascorbic acid into the peripheral neurons, and heterozygous deficiency of SVCT2 (SVCT2+/-) results in hypomyelination and decreased nerve conduction velocities and sensorimotor performance (Gess et al., 2011). Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease, the most common hereditary peripheral neuropathy involving primarily abnormal myelination of the peripheral nerves (Passage et al. , 2004). However, ascorbic acid fails to show an efficacy in treating Charcot-Marie-Tooth disease in randomized clinical trials (Gess et al. , 2013). It remains unclear why ascorbic acid is effective for treating Charcot-Marie-Tooth disease in animal models but not in humans. Possible reasons may include the different time window of treatment and dosages used as well as the unknown status of ascorbic acid in the patients. All these may affect the response of the patients to ascorbic acid therapy. Conclusion and Perspectives Ascorbic acid as an essential micronutrient functions to safeguard neurons and protect against neuron degeneration in animal models. However, clinical trials using ascorbic acid in the intervention of neurodegenerative disorders have yielded equivocal results. While the exact reasons for the inconsistency remain elusive, the antioxidant and oxidative stress status of the individual patients might be a key factor. Future studies should focus on developing reliable biomarkers to assess the status of antioxidants and oxidative stress in selected patient subpopulations, and test the efficacy of vitamin C supplementation in patient groups with overt oxidative stress and/or antioxidant deficiency in well-designed clinical trials. There is also a need to further characterize the pharmacokinetics and pharmacodynamics of vitamin C not only in normal individuals, but also in selected patient groups with neurodegenerative disorders. Such studies will provide important insight into the pharmacological basis of vitamin C-based modalities in both preventive and therapeutic intervention of human neurodegenerative diseases. REFERENCES

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