Effects of the Methyl Donors Supplementation on Hippocampal Oxidative Stress, Depression and Anxiety in Chronically High Fructose-treated Rats

Highlights

• This study examined the effects of Methyl Donors in depression induced by fructose.

• Methyl donors normalized the depression and oxidative stress in the hippocampus.

• Methyl donors reversed the damage observed in the hippocampal neurons.

• Methyl donors normalized lipid profile and adipose tissue weight in fructose rats.

• Methyl donors may be of potential therapeutic value in the treatment of depression.

Abstract

Evidence suggests that oxidative stress plays an important role in the development of anxiety and depression. The aim of the present study was to investigate whether methyl donors supplementation could exert beneficial effects on hippocampal oxidative stress, anxiety and depression in chronically high fructose-treated rats, a new animal model of anxiety and mood disorders. Rats were divided into two groups and treated for 10 weeks as follows: Group 1 represents the control group and Group 2 was treated with 23% fructose. After 10 weeks, the fructose-fed animals were divided into two groups and treated for 8 weeks as follows: Group 2 continued to receive fructose while Group 3 was treated with methyl donors and fructose. High fructose-fed rats showed increases in glucose, triglycerides, total cholesterol as well as in the final body weight and the adipose tissue weight. High fructose induced anxiety- and depression-like behaviors. High fructose caused an increase of the nitrite content and the Malondialdehyde (MDA) levels in the hippocampus tissue in association with an induction of damage in the dorsal hippocampus neurons. The 8-weeks dietary supplementation with methyl donors normalized the depression-like behavior, oxidative stress in the hippocampus, reversed the damage observed in the hippocampal neurons. These findings demonstrate that high fructose induced depression in association with the induction of a hippocampal oxidative stress. The anti-depressive action of methyl donors appears to be associated to their anti-oxidative properties since they normalized the nitrite content and the MDA levels at the hippocampus in the high fructose-fed female rats.

Introduction

During the last centuries, the consumption of fructose has increased drastically mainly through the consumption of sucrose or high-fructose corn syrup which are incorporated in the industrial foods and beverages (Campos and Tappy, 2016). The fructose constitutes approximately 8% of the total energy intake in the United States (Park and Yetley, 1993). The consumption of fructose has increased by approximately 32% over the last three decades in the United States (Marriott et al., 2009). It is noteworthy that the highly consumption of fructose is currently not limited only to developed countries since the increased of the middle income in southern countries is associated with nutritional transition toward high fat or carbohydrates diets. It is well known that high fructose intake is associated with detrimental effects on human health.

Studies have shown that high fructose intake increased hepatic de novo lipogenesis, VLDL triglycerides secretion and fat concentrations in liver (Stanhope, 2016). High fructose-fed rats are commonly used as an animal model for studying the diet-induced metabolic disturbances (Tran et al., 2009). Indeed, investigations have reported that fructose intake exacerbates the deleterious effects of short-term high-fat feeding on hepatic steatosis and lipid metabolism (Crescenzo et al., 2014, Crescenzo et al., 2015).

Chronic high-fructose intake was shown to induce reduction in the neurogenesis of hippocampus tissue which is known to be required for learning and memory (Van der Borght et al., 2011). In addition, studies undertaken on animals have shown that high-fructose supplemented diet was associated with hypothalamic astrogliosis and neuroinflammation (Li et al., 2014), accumulation of advanced glycation end products, widespread reactive gliosis, and altered mitochondrial activity in the hippocampus (Mastrocola et al., 2016). High-fat diets were also found to induce alteration in hippocampus morphology (Freeman et al., 2011, Koga et al., 2014, Monti et al., 2014, Hoeijmakers et al., 2015). Investigators have suggested that the metabolic alterations induced by high fructose intake may cause the development of mood disorders (Gancheva et al., 2017). Previous studies have reported that oxidative stress is potentially implicated in the development of anxiety disorders and depression (Solanki et al., 2017). Indeed, Lindqvist et al. (2017) have shown an increase in oxidative stress and inflammation markers as reflected by a rise in 8-OH 2-deoxyguanosine and IL6 respectively in subjects suffering from major depressive disorder. Accumulating evidence supports the idea that dietary components can influence the activity of genes and potentially affect the health of the organisms (Jaenisch and Bird, 2003, Jirtle and Skinner, 2007, Feil and Fraga, 2012). One crucial epigenetic mechanism that seems to underlie the interaction between diet and human genome is chemical change of the DNA. The well studied of these modifications is methylation of cytosine residues. Epigenetic processes have now been largely implicated in human development and diseases, including mental disorders (Ptak and Petronis, 2010, Klengel et al., 2014). In fact, studies have suggested that the development and function of the central nervous system is dependent on the methylation of cytosines (Couvert et al., 2001, Hendrich et al., 2001, Shahbazian et al., 2002).

Methyl donors supplementation have been found to exert beneficial effects on the hepatic triglyceride accumulation induced by an obesogenic diet (Cordero et al., 2013). Moreover, investigations have demonstrated that methyl donors supplementation increases DNA methylation in the brain resulting in therefore antidepressant effects in animals (Paternain et al., 2016). S-adenosyl-l-methionine (SAM), a methyl donor was found to be safe and effective in the treatment of depression (Mischoulon and Fava, 2002). In addition, several studies have suggested that low levels of methylation, folate, and S-adenosyl-l-methionine (SAM) correlate with depression and other neurological diseases (Botez et al., 1979, Bottiglieri et al., 2000, Stuffrein-Roberts et al., 2008). Studies have reported that the raised DNA methylation via an increase in dietary methyl donor content improved the anxiety-like behavior in rats bred with low response to novelty (McCoy et al., 2017). The aim of the present study was thus to examine whether the treatment with methyl donors could exert beneficial effects on plasma glucose, visceral obesity, lipid profile, hippocampal oxidative stress, anxiety and depression behaviors in chronically fructose-fed rats.