Pomegranate peel extract ameliorates autoimmunity in animal models of multiple sclerosis and type 1 diabetes
Introduction
Type 1 diabetes (T1D) and multiple sclerosis are chronic inflammatory diseases that are characterized by autoimmune reactivity against pancreas and central nervous system, respectively. Autoreactive T helper cells (Th) that produce interferon (IFN)-γ (Th1) and those that produce interleukin (IL)-17 (Th17) have been shown crucial for initiation and propagation of autoimmune response in T1D and multiple sclerosis (Petermann and Korn, 2011, Walker and von Herrath, 2016). This autoimmunity ultimately leads to destruction of pancreatic beta cells, insulin hypo-production and hypoglycaemia in T1D and to demyelination and neurodegeneration in multiple sclerosis. Currently, insulin supplementation is the only available therapy for T1D, although there are numerous clinical trials with experimental drugs counteracting autoimmune reactivity and promoting regeneration of pancreatic beta cells (Ludvigsson, 2016). On the contrary, there are numerous disease-modifying drugs for multiple sclerosis that are currently in use (Straus Farber, Harel, & Lublin, 2016). Yet, in spite of this therapeutic plethora, multiple sclerosis, similar to T1D, still remains without the cure. Therefore, investigation of novel potential therapeutics, including plant-based agents is necessary for both diseases.
Pomegranate peel is characterized by the presence of different high molecular weight phenolics such as ellagitannins and proanthocyanidins, as well as flavonoids which were reported to exhibit anti-inflammatory and anti-oxidant effects, among other relevant biological activities (Dikmen et al., 2011, Ismail et al., 2012, Li et al., 2006, Prakash et al., 2013). The whole fruit is rich in phenolic compounds such as punicalagin isomers or ellagic acid derivatives, but biologically active phenolics, predominantly hydrolysable tannins are the most abundantly present in its peel. Punicalagin belongs to a family of ellagitannins and is unique to pomegranate. Its structure includes minor water soluble tannins i.e. punicalin and gallagic acid (Akhtar, Ismail, Fraternale, & Sestili, 2015). Ellagic and gallic acids, punicalagin and punicalin have been shown to act synergistically in achieving anti-inflammatory and anti-oxidant effects (Lee et al., 2010, Seeram and Heber, 2011). Pomegranate fruit is traditionally used in Mediterranean and Asian cuisine, while its peel and peel extract have a potential to be used as food additives and diet supplements (Akhtar et al., 2015).
In this study the effect of PPE on immune cells isolated from different lymphoid tissues of healthy animals or animals with experimental autoimmune encephalomyelitis (EAE) and T1D was examined. Also, impact on the course of EAE and T1D was investigated, followed by search for possible mechanisms of PPE action. It was shown that PPE efficiently restrained activity of immune cells and protected animals from EAE and T1D.
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Plant material and extractions
Pomegranate fruits were collected at natural locality in village Do, Bosnia and Herzegovina during November 2015. Peels were separated from the fruit manually, air-dried at room temperature (4–6 days) and grounded with a laboratory mill. Pomegranate peel which was used for further extraction was characterized by 107.98 ± 2.04 mg GAE/g of total phenolics, 1.77 ± 0.23 mg catechin/g of total flavonoids, 6.52 ± 0.76% of total tannins and it contained 15.21 ± 0.12, 56.01 ± 0.43, 1.62 ± 0.02 and 5.45 ± 0.01 mg/g of
Chemical composition of pomegranate peel extract
The amounts of total phenolics, flavonoids and tannins in PPE were determined spectrophotometrically and results are presented in Table 1. HPLC-DAD technique was applied for characterization and quantification of individual phenolic compounds in pomegranate peel extract. Identification was carried out by comparing UV spectra and retention times with standard compounds and results are summarized in Table 2. We have identified four phenolic compounds: ellagic acid, gallic acid, punicalin and
Discussion
PPE exerts potent immunomodulatory effects that result in prevention or amelioration of EAE and streptozotocin-induced T1D. Although PPE was inefficient in modulating IL-17 production when given to healthy rats, when the cells became activated in vivo (either during EAE or T1D course), PPE effectively blocked IL-17 production in certain lymphoid tissues. Th17 blockade might be the common route of PPE-mediated interference with autoimmunity.
PPE has already been shown to possess anti-oxidant and
Conclusions
Our results demonstrate the ability of polyphenols rich aqueous-ethanol extract of pomegranate peel to interfere with autoimmune response and to prevent and/or reduce clinical expression of autoimmune disorders. Importantly, its effects are shown in T1D and EAE, i.e. autoimmune disorders that affect different target organs and that, although sharing basic mechanisms of autoreactivity, differ in many ways regarding etiopathogenesis. It seems that the inhibitory effects of the extract on Th17
Conflicts of interest
The authors declare that they have no conflicts of interest pertaining to this study.
Acknowledgements
This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (173013, 46013 and 173035).
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