Effects of lipoic acid and n-3 long-chain polyunsaturated fatty acid on the liver ovariectomized rat model of menopause

Abstract

Background

Bilateral ovariectomy is an experimental model used to analyse the effects of menopause and develop strategies to mitigate the deleterious effects of this condition. Supplementation of the diet with antioxidants has been used to reduce potential oxidative stress caused by menopause. The purpose of the study was to analyse the effects of α-lipoic acid (LA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), dietary supplementation on oxidative stress in the livers of ovariectomized rats.

Methods

In this study, we evaluated the effect of dietary supplementation with LA, DHA and EPA for a period of 16 weeks on oestrogen levels and oxidative stress biomarkers in the livers of ovariectomized 25 three-month-old rats.

Results

Serum oestrogen levels were lower after ovariectomy but were not altered by dietary treatments. LA was capable of acting in the liver, recovering the activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase, and reducing protein oxidative damage. Moreover, LA supplementation reduced nitrite and nitrate levels. DHA and EPA recovered the antioxidant activity of cytosolic and mitochondrial superoxide dismutase, decreasing protein oxidation. Protection against lipid oxidation differed between treatments. The DHA-treated group showed increased levels of the lipid peroxidation biomarker malondialdehyde compared to the ovariectomized group. However, malondialdehyde levels were not altered by EPA treatment.

Conclusions

The results suggest that the antioxidant response varies among evaluated supplementations and all supplements were able to alter enzymatic and non-enzymatic antioxidants in the livers of ovariectomized rats. DHA presented the most evident antioxidant effect, decreasing protein and lipid damage.

Introduction

The menopausal model produced by ovariectomy is used to analyse the deleterious effects of this condition and propose possible strategies to minimize the increased risk factors at this stage of women's lives [1], [2], [3]. Menopause is associated with inflammation and oxidative stress since the decrease in oestrogen levels leads to an increase in proinflammatory cytokines [4], [5], [6] and lack the antioxidant properties of oestrogen.

Oestrogen regulates transcription of enzymatic antioxidants [7], [8], [9], and additionally, molecules of this class of hormones act directly as non-enzymatic antioxidants against reactive oxygen species (ROS) [10], [11]. Dietary supplementation with antioxidants could help organisms cope with the loss of oestrogen. Moreover, antioxidant supplementation may minimize the symptoms of ageing-related conditions associated with oxidative stress and inflammation, such as menopause [12], type 2 diabetes, obesity, metabolic syndrome and neurodegenerative diseases [13], [14], [15].

Lipoic acid (LA) is a bioactive molecule synthesized in the mitochondria and is considered a powerful antioxidant by acting in two oxidation states. In the oxidized state, it is referred to asα- lipoic acid and as dihydrolipoic acid in its reduced form. LA is a key regulator of energy metabolism in the mitochondria [16]. Another important feature of LA is its anti-inflammatory properties, being a promising molecule to minimize the consequences of the proinflammatory state associated with menopause [4], [5], [6].

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) associated with the resolution of inflammation via production of protectins, especially in the case of DHA, and resolvins that help the tissues return to homeostasis [17], [18], [19]. Therefore, dietary supplementation with fish-derived n-3 LCPUFA may help organisms cope with oxidative stress and inflammatory conditions.

The liver is the central distribution organ of nutrients and antioxidant molecules, such as vitamins C and E, for the body [20], [21], [22]. Importantly, antioxidant activity changes in the liver after ovariectomy [23], [24], which can compromise the physiological functions of this organ. In this context, the liver can be damaged due to the increased recruitment of proinflammatory cells [25]. Previous reports showed polyunsaturated fatty acids are capable of reducing the synthesis of inflammatory cytokines increased by the low oestrogen levels in women [26], [27], [28].

Thus, the aim of this work was to evaluate the effect of dietary supplementation with LA, DHA and EPA on oxidative stress in the livers of ovariectomized rats.