Original articleEffects of lipoic acid and n-3 long-chain polyunsaturated fatty acid on the liver ovariectomized rat model of menopause
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.
Section snippets
Animals
All animal studies followed the rules from the U.K. Animals (Scientific Procedures) Act, 1986 and associated guidelines, the European Union (EU) Directive for animal experiments 2010/63/EU, the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publications No. 8023, revised in 1978), and were approved by the Ethics Committee of the institution.
This study employed 25 three-month-old Wistar female rats (Rattus norvegicus). Rats were housed with
Hormone levels and metabolic activity
In this study, oestrogen levels decreased significantly in the OVX group and in all ovariectomized-treated groups (Fig. 1a). This result confirms that the animals were subjected to an effective menopausal model. When analysing the data individually, it is evident that all the ovariectomized animals had oestrogen levels lower than the SHAM group.
Ovariectomy and omega-3 fatty acid treatment did not change the activity of fumarase, a biomarker of metabolic activity, while the LA-treated group had
Discussion
Despite the decline of oestrogen levels being responsible for most of menopause’s symptoms and despite the well-known antioxidant properties of oestrogens [11], hormonal replacement therapy with oestrogens is not considered entirely safe. Oestrogen replacement needs to take into account the possible collateral effects, such as an increase in the risk of developing cardiovascular disease and breast cancer [39]. Current controversy about hormonal replacement therapy reinforces the necessity of
Conclusions
LA and n-3 LCPUFA supplementation showed a beneficial effect on oxidative damage markers, and all evaluated antioxidant supplements were able to alter the activity of antioxidant enzymes. In summary, the present results indicate that supplementation using LA and n-3 LCPUFA DHA and EPA were beneficial to the livers of OVX rats. Save for appropriate precautions, the results suggest dietary supplementation with LA and n-3 LCPUFA fish oil is promising for menopausal women.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
None.
Acknowledgements
We thank Z. Almeida for technical assistance, Dr. I. Vaz for generously providing equipment.
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