Role of Antioxidant Vitamins in Neurogenesis

Neurogenesis is vital in the preservation of cognition. Previous studies have reported antioxidant vitamins as a key regulatory factor in neurogenesis. However, current research investigating their role is inconclusive due to the limited number of studies that have been conducted and conflicting results. This review evaluates the scientific evidence behind the potential roles of antioxidant vitamins in neurogenesis. Observations concerned with the mechanistic and functional aspects of how antioxidant vitamins modulate neurogenesis are both assessed. Vitamin A is evidently involved in cell cycle regulation and cell proliferation; vitamin C reportedly promotes neural differentiation and maturation while inhibiting neurite outgrowth; vitamin E is identified to inhibit cell proliferation while improving cell viability. Varying antioxidant vitamin concentrations have been implicated in facilitating cognition in terms of attention, memory, language, and executive function. Moreover, this review suggests a threshold antioxidant vitamin concentration that should be maintained to promote optimal levels of adult neurogenesis.


ABSTRACT
Neurogenesis is vital in the preservation of cognition. Previous studies have reported antioxidant vitamins as a key regulatory factor in neurogenesis. However, current research investigating their role is inconclusive due to the limited number of studies that have been conducted and conflicting results. This review evaluates the scientific evidence behind the potential roles of antioxidant vitamins in neurogenesis. Observations concerned with the mechanistic and functional aspects of how antioxidant vitamins modulate neurogenesis are both assessed. Vitamin A is evidently involved in cell cycle regulation and cell proliferation; vitamin C reportedly promotes neural differentiation and maturation while inhibiting neurite outgrowth; vitamin E is identified to inhibit cell proliferation while improving cell viability. Varying antioxidant vitamin concentrations have been implicated in facilitating cognition in terms of attention, memory, language, and executive function. Moreover, this review suggests a threshold antioxidant vitamin concentration that should be maintained to promote optimal levels of adult neurogenesis. Neurogenesis is the process through which neural progenitor cells generate new neurons 10 . The adult brain preserves the ability to undergo neurogenesis in three regions of the brain: the subgranular zone in the dentate gyrus of the hippocampus, the subventricular zone of the lateral ventricles, and the third ventricles of the hypothalamus 11 . Neural stem cells within the hippocampal subgranular zone develop into intermediate progenitors, which further develop into immature neurons or neuroblasts. Immature neurons move into the inner granule cell layer and differentiate into new granule neurons of the hippocampus 11 . The hippocampus plays a critical role in learning and memory 12 . Current evidence has proposed a significant role for adult-born neurons in pattern separation, learning new conflicting information, and also in memory clearance 13 . Therefore, the preservation of neurogenesis in the adult hippocampus may prove vital in maintaining optimal levels of cognition 13 . Neurogenesis is recognized to be an extremely sensitive process, especially to oxidative stress 14 .
Oxidative stress is caused by increased levels of reactive oxygen species and has been implicated in the decline of neurogenesis and cognition 15 . Superoxide Dismutase (SD) is a primary defense mechanism against superoxide radicals. In SD deficient mouse models, there was a reduction in hippocampal neuron generation after cranial radiation; a form of brain tumor treatment that leads to increased oxidative stress [16][17] . A study done by Ale et al. suggested that oxidative stress promotes accelerated age-dependent decline in adult neurogenesis 18 . Through conditional deletion of the clock gene Bmall (Bmall-/-) in mice, they observed neurodegeneration, accelerate aging, and cognitive deficits through oxidative damage.
Recent literature has described the consumption of antioxidants as a potential method to attenuate cognitive decline caused by deficiencies in adult neurogenesis. Multiple studies have reported the consumption of antioxidants preventing the decline of adult neurogenesis and preserving cognition [19][20] .
Vitamins A, C, and E are essential vitamins necessary for biological functioning. These three vitamins are further recognized for their antioxidant properties 21 .
Given their therapeutic ability to override free radicals, this review aims to evaluate their significance in preserving adult neurogenesis against oxidative stress.
This review critically analyzes the results of 23 studies to develop a holistic understanding of how antioxidant vitamin intake is implicated in neurogenesis. Previous literature assessing both the mechanistic and functional role of antioxidant vitamins will be analyzed to account for any significant correlations. In the context of this study, the term "mechanistic" refers to the specific biochemical process through which antioxidant vitamins regulate adult neurogenesis. The term "functional" refers to explaining antioxidation in neurogenesis through its functional purpose, which will be operationalized by assessing cognitive function in humans as neurogenesis is a proven contributor to cognition 7-8 . Vitamin C Vitamin C, commonly referred to as Ascorbic Acid (AA), is involved in many biosynthetic pathways and functions as an antioxidant 30 . According to Scheffler et al., AA interferes with viability and neurite outgrowth 30 .

ANALYSIS OF ANTIOXIDANT VITAMIN ROLE IN NEUROGENESIS
Their study involved PC12 cells as the model for neural plasticity, where neurite outgrowth is dependent on ERK1/2 phosphorylation via the Nerve Growth Factor receptor. The-AA induced PC12 model showed increased levels of phosphorylation of ERK1/2; however, it remains unclear whether AA-induced formation of advanced glycation end products is responsible for the inhibition of neurite outgrowth 31 . Furthermore, PC12 cells have been widely used as a neuron cell model. These cells have served as strong models to assess neurite outgrowth, but they do have their limitations such as their tumor origin, non-development of synaptic endings even after 14-day differentiation, and high morphological variability [32][33] . Future studies should test the validity of these results by using primary neuronal cell cultures and in vivo models. The negative effect of AA on neurite outgrowth is contrasted by the observations of Nam et al., where AA is reported to improve neuronal differentiation and maturation 34 . This study used mice that were co-treated with D-galactose (D-gal) (a long-term treatment known to induce oxidative stress and reduce hippocampal neurogenesis) and AA. In comparison to the control mice, the D-galinduced hippocampus experienced a weight reduction, whereas the D-gal-AA-induced hippocampus weight remained stable. Nam et al. described this observation by stating that the AA co-treatment with D-gal reduced the D-gal induced reduction of Ki67-immunoreactive proliferating cells, DCX-immunoreactive neuroblasts and immature neurons, and BrdU-incorporated NeuNimmunoreactive mature neurons 34 . Overall, these results from these studies investigating the role of vitamin C in adult neurogenesis indicate that vitamin C has a multifaceted role in terms of cell growth. When neurons begin to differentiate and mature, vitamin C supports their growth by maintaining oxidative stress 34 .
However, vitamin C may become an inhibitory factor for neurite outgrowth as indicated by Scheffler et al. 32 .
Like vitamin A, these findings suggest there may be a certain threshold concentration of vitamin C that must be maintained to balance the multiple effects it can have on adult neurogenesis.
To further understand the role of vitamin C in adult neurogenesis, it is important to note the functional aspect of AA in the human brain. Across two cross-sectional studies from 2016 to 2019, human participants who were supplemented with vitamin C exhibited higher cognitive abilities [35][36] . Their results demonstrated a positive association between vitamin C supplementation and immediate memory, delayed recall, visuospatial skills, language, attention, and working memory. Pearson et al. found similar results when evaluating plasma vitamin C concentrations 37 . They observed lower levels of mild cognitive impairment in individuals with higher plasma vitamin C concentrations; a 1 μmol/L increase in plasma vitamin C was associated with 3% reduced odds of mild cognitive impairment.

LIMITATIONS
This review is limited by many of the studies using mice as model organisms for adult neurogenesis. Although mice serve as effective model organisms, they are not a direct representation of humans and oftentimes elicit very different responses to experimental interventions. Secondly, it is important to recognize that a disruption

Review Articles
Role of Antioxidant Vitamins in Neurogenesis in neurogenesis due to varied vitamin levels may not be the only reason for changes in cognition. The brain is an intricate organ in terms of how various processes are related. A decline in cognition in vitamin-deficient patients may not directly be due to the vitamin deficiency or excess affecting neurogenesis. Studies evaluating patient cognition were incorporated into this review to develop a possible relationship between varied vitamin levels and cognition. Given neurogenesis is involved with various aspects of cognition, the relationship between vitamin levels and cognition is used to provide some direction that addresses the contrast in mechanistic studies of antioxidant roles in neurogenesis.
Vitamins A, C, and E exhibited multifaceted roles in regulating various aspects of adult neurogenesis. Due to their multiple roles and functions in adult neurogenesis, there appears to be a certain threshold level at which these vitamins need to be maintained. An excess or deficiency in either of these vitamins can lead to complications in neurogenesis. However, it is inconclusive whether antioxidant vitamin levels need to be maintained at consistent, adequate amounts for optimal neurogenesis, or if these vitamin levels can fluctuate around a threshold.

CONCLUSION
In this review, various studies implicating the involvement of antioxidant vitamins in neurogenesis were evaluated. Vitamin A reportedly facilitates cell cycle regulation and cell proliferation. Moreover, vitamin A deficiencies have been associated with cognitive decline, particularly in executive function and memory. Vitamin C evidently promotes neural differentiation and maturation while inhibiting neurite outgrowth. Supplementation of vitamin C is correlated with improved immediate memory, delayed recall, visuospatial skills, language, attention, and working memory. Vitamin E is noted to inhibit cell proliferation while maintaining cell viability. However, studies have identified that vitamin E supplementation reduces the rate of cognitive decline in terms of attention, perceptual/motor speed, memory, and language in humans. Furthermore, this review suggests that there is a threshold level for antioxidant vitamin concentration. Deficiencies or excess in antioxidant vitamin levels can carry negative consequences that will lead to cognitive impairments. Many current studies have evaluated the effect of these vitamins on neurogenesis by measuring the weight of cells produced or using markers to evaluate cell quantity. Future studies should focus on identifying the direct biochemical mechanism by which these vitamins regulate neurogenesis. Moreover, further studies need to assess how different levels of each vitamin affect neurogenesis through their respective mechanism. When evaluating the results of different vitamin levels, it is important to note whether a consistent moderate amount of vitamin concentration is needed to promote optimal neurogenesis, or if a fluctuation in vitamin concentration within a specific threshold is tolerable. Overall, antioxidant vitamins are important regulators in adult neurogenesis and have the potential to be therapeutically managed to preserve the cognitive decline experienced by the aging human brain.