EFFECT OF VITAMINS C AND E ON MEMORY IN ADULT MICE

EFFECT OF VITAMINS C AND E ON MEMORY IN ADULT MICE

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Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement and is destroyed by heat or reduced by prolonged storage (Weinstein et al., 2001). Humans, unlike most animals, are unable to synthesize vitamin C endogenously, so it is an essential dietary component (Naidu, 2003; Li, 2007). Sex steroids are hormones produced mainly by the reproductive glands, either the ovaries or testes, which share a similar basic structure of three hexane rings and a pentane ring (Gasbarri, 2010). The primary role of the gonadal steroid hormones in mammals is to regulate reproduction and related behaviours; however, both androgens and estrogens are also integrally involved in mediating higher brain function and processes, including cognition, neural development and neural plasticity (Dohanich, 2002). The hippocampal system plays an important role in memory function. Neurohormones like androgens and oestrogens are present in the hippocampus and have important roles in learning and memory (Talebi et al., 2010).

Oestrogens act on the central nervous system (CNS) both through genomic mechanisms, modulating synthesis, release and metabolism of neurotransmitters, neuropeptides and neurosteroids, and through non-genomic mechanisms, influencing electrical excitability, synaptic function and morphological features. Therefore, oestrogen’s neuroactive effects are multifaceted and encompass a system that ranges from the chemical to the biochemical to the genomic mechanisms, protecting against a wide range of neurotoxic insults (Genazzani et al., 2007).

Vitamin C, also known as ascorbic acid AA is required for the biosynthesis of collagen, L-carnitine, and certain neurotransmitters; vitamin C is also involved in protein metabolism (Carr and Frei, 1999). Collagen is an essential component of connective tissue, which plays a vital role in wound healing. Vitamin C is also an important physiological antioxidant (Carr and Frei, 1999) and has been shown to regenerate other antioxidants within the body, including alpha-tocopherol (vitamin E) (Jacob, 2002). In addition to its biosynthetic and antioxidant functions, vitamin C plays an important role in immune function (Jacob, 2002) and improves the absorption of non-haeme iron, the form of iron present in plant-based foods. Insufficient vitamin C intake causes scurvy, which is characterized by fatigue or lassitude, widespread connective tissue weakness, and capillary fragility (Weinstein et al., 2001; Wang, 2007).

Vitamin E is a generic name for tocopherols and tocotrienols. It is a family of α, β, γ and δ tocopherols and corresponding tocotrienols. Tocopherol contains saturated phytol side chains and tocotrienol have 3 double bonds in the side chain (Blatt et al., 2001; Dietrich et al., 2006). The alpha-tocopherol form of vitamin E is an important lipid-soluble antioxidant. In the brain and other tissues, alpha-tocopherol has a key role in preventing oxidant-induced lipid destruction and is, therefore, vital in maintaining the integrity of cell membranes (Blatt et al., 2001; Dietrich et al., 2006). Accordingly, vitamin E deficiency causes lipid peroxidation in brain tissues. Severe vitamin E deficiency results mainly in neurological symptoms, including impaired balance and coordination (ataxia), injury to the sensory nerves (peripheral neuropathy), muscle weakness (myopathy), and

damage to the retina of the eye (pigmented retinopathy) (Traber et al., 2006). The

 

developing nervous system appears to be especially vulnerable to vitamin E deficiency. For instance, children who have severe vitamin E deficiency from birth and are not treated with vitamin E rapidly develop neurological symptoms. In contrast, individuals who develop malabsorption of vitamin E in adulthood may not develop neurological symptoms for ten to 20 years (Drake, 2011).

Gender differences in cognitive function tests have been widely reported: men tend to excel in fields of spatial cognition, whereas women show greater abilities in verbal fluency (Halpern, 1992). Many factors influence the development of these abilities, such as environment, education, cultural background and inherited factors, but sex hormones also play a role in development and maintenance of cognitive functions. Variation and overlapping scores between genders show the limited extent of this impact; to a much higher degree, an individual's cognitive abilities are derived from experience, education and inheritance (Zitzmann, 2001).

Oxidative stress is an imbalance between oxidants and antioxidants in favour of the oxidants, potentially leading to damage (Sies, 1991). It occurs when the oxidative stress- related molecules, generated in the extracellular environment or within the cells exceed the intracellular antioxidant defences (Vrba and Modriansky, 2002). Oxidative stress involves a number of chemical reactions, leading to the production of free radicals (FRs) and other reactive molecules that are able to induce cellular injury (Kennedy et al., 2005). It results in loss of normal balance between free radical species production and the antioxidant system (Himmelfab and Hakim, 2003) or interruption of the equilibrium between pro- and antioxidant systems (Lazarova et al., 2004).

 

Free radicals are chemical species that have an unpaired delocalized electron in an outer orbital (Campanella et al., 2007), hence they are molecules with an “open” or half bond (McCord, 1985), and are capable of independent existence no matter how brief (Halliwell and Gutteridge, 1999). This unstable configuration causes these chemical species to be very aggressive and to have a short life span (Halliwell, 1987). The unpaired electron confers on these molecules a strong propensity to react with target molecules, by withdrawing one electron from target molecules to complete their own orbital (Halliwell and Gutteridge, 1999; Younes, 1999), and thereby stabilizing themselves. Thus, FR causes the molecule whose electron had been withdrawn to become unstable and even become a FR itself (Halliwell and Gutteridge, 1999). The resulting FR can in turn react with another molecule until the chain reaction is terminated; either by random collision of two or three FRs to form a molecule with stable bond or by one of the cellular defence mechanisms (McCord, 1985; Goldfarb, 1999). In view of their high reactivity and instability, FRs can react with several chemical compounds such as proteins, lipids, nucleic acids and carbohydrates, present in cellular compartments and other classes of molecules like extracellular matrix glycosaminoglycans (hyaluronic acid) and damaging them (Halliwell and Gutteridge, 1985; Schimdley, 1990; Campanella et al., 2007).

Biological systems have evolved endogenous defence mechanisms to protect against FR- induce cell damage (Singh et al., 2004). These are called antioxidants. Antioxidants were originally defined as any substance that when present in low concentration, compared with that of oxidizable substrate, significantly prevent the pro-oxidant-initiated oxidation of that substrate (Halliwell and Gutteridge, 1985; Black, 2004). However, because of the

imperfection in the definition in relation to the concentration of antioxidants (Halliwell

 

and Gutteridge, 2007), Halliwell and Gutteridge (2007) redefined antioxidants as any substance that delays, prevents or removes oxidative damage to a target molecule. Higher organisms have developed a remarkably efficient antioxidants defense system over the course of evolution. The antioxidants neutralize FR by donating an electron to stabilize the FR (Chihuailaf et al., 2002), the antioxidant molecules “internalize” the loss of an electron through resonance between carbon bonds. The antioxidant systems can prevent oxidative damage by (Sen. 1995):

1. 1. 1. Scavenging of reactive oxygen species (ROS) and other reactive derivatives;

 

1. 1. 1. Decreasing the conversion of less reactive ROS to more reactive ROS

 

1. 1. 1. Facilitating repair of damage caused by ROS; and

 

1. 1. 1. Providing a favourable environment for the activity of other antioxidants

 

The antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) (Drewa et al., 1998; Schneider and De Oliveira, 2004), glutathione reductase and transferases, thiol disulfide oxidoreductases and peroxiredoxins (Halliwell and Gutteridge, 1990; Stocker and Keaney, 2004) are primary enzymes involved in the direct elimination of toxic oxygen species. Other enzymes, including glucose-6-phosphate dehydrogenase and cytosolic glutathione sulphur-transferase (GST), are secondary enzymes, which help in the detoxification of ROS by decreasing peroxide levels or maintaining a steady supply of metabolic intermediates like glutathione or NADPH necessary for optimum function of the antioxidant enzymes (Singh et al., 2003). The antioxidant enzymes are primarily intracellular and, thus, extracellular FRs either produced extracellularly, or from the environment  must be inactivated by circulating

antioxidants such as vitamins and ceruloplasmins (Machlin and Bendich, 1987). Their

 

effectiveness varies with the stage of development and other physiological aspect of the organism (Halliwell and Gutteridge, 1999; Livingstone et al., 2001). The antioxidants require micronutrients such as selenium, zinc, iron, copper, and manganese as co-factors for optimum catalytic activity and effective defence mechanisms (Halliwell and Gutteridge, 1992; Halliwell, 2001).

Statement of Research Problem

 

The need to preserve cognitive functioning is present at every stage in life, whether at childhood when the focus is cognitive development or at adulthood when the need is protection or alleviation of short-term or long-term cognitive decline. This has led to promotion of the use of prescription drugs, herbal supplements, among others, in order to promote or preserve cognitive performance levels (Schmitt, 2010). Starting from adulthood, there is an age-related decline in the level of gonadal hormones, which has been correlated with impairment in some cognitive tasks (Leonard, 2011). Hence, the need for a substance that can promote cognitive development as well as protect against cognitive decline (Schmitt, 2010). Micronutrient supplementation has been shown to be associated with less cognitive decline (Morris, et al., 2002). It is reported that treatment with ascorbic acid significantly improved cognitive function in rats (Shahidi et al., 2008) and it ccould enhance learning and memory processes (Cho, et al., 2003). While a lot of work has been done on the effects of antioxidant supplementation in improving cognitive functions in aged rodents and humans (Durga, et al., 2007; Saleem, et al., 2012) there is paucity of information on effects of vitamins C and E supplementation on serum testosterone and estrogen levels as well as on learning and memory in adult mice of both sexes. Thus, the question this study seeks to answer is whether vitamins C and E affect the level of the testosterone and estrogen which in turn affect learning and memory, and whether endogenous levels of these hormones can be correlated to the optimum cognitive capacity observed in adulthood.

​​​​​​​Justification

The maintenance of brain health underpinning intact cognition is a key factor to maintaining a positive, engaged, and productive lifestyle (Stough et al., 2012). There is an age-related decline in the level of gonadal hormones, which has been correlated with impairment in some cognitive tasks such as learning and memory (Leonard, 2011).

It is reported that treatment with ascorbic acid significantly improved cognitive function in aged rats (Shahidi, et al., 2008), and it can enhance learning and memory processes (Cho, et al., 2003). Vitamin E intake, from foods or supplements, was also shown to be associated with less cognitive decline with age (Morris et al., 2002). The combined effects of multiple antioxidant nutrients might be more influential on cognition than a single antioxidant as reported by Devore et al. (2010).

​​​​​​​General Aim

The general aim of this study was to investigate the effect of vitamins C and E on learning and memory in healthy adult mice.

​​​​​​​Specific objectives

The specific objectives of this work were as follows:

1. To assess the effect of administration of vitamins C and E on learning and memory using the elevated plus maze for memory (EPM), object recognition test (ORT) and object location test (OLT) in mice.
2. To determine the effect of vitamins C and E on lipid peroxidation; malondialdehyde (MDA), and enzymatic activities; superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) in mice.
3. To relate the effect of endogenous testosterone and estrogen with animals performance in the EPM, ORT and OLT models for memory.​​​​​​​

Hypothesis

Ho: Vitamins C and E have no effect on learning and memory in adult mice.

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