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The Metabolite Urolithin-A Ameliorates Oxidative Stress in Neuro-2A Cells, Becoming a Potential Neuroprotective Agent

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The Metabolite Urolithin-A Ameliorates Oxidative Stress in Neuro-2A Cells, Becoming a Potential Neuroprotective Agent antioxidants Article The Metabolite Urolithin-A Ameliorates Oxidative Stress in Neuro-2a Cells, Becoming a Potential Neuroprotective Agent Guillermo Cásedas 1, Francisco Les 1,2 , Carmen Choya-Foces 3, Martín Hugo 3 and Víctor López 1,2,* 1 Facultad de Ciencias de la Salud, Universidad San Jorge, 50830 Villanueva de Gállego (Zaragoza), Spain; [email protected] (G.C.); fl[email protected] (F.L.) 2 Instituto Agroalimentario de Aragón-IA2 (CITA-Universidad de Zaragoza), 50059 Zaragoza, Spain 3 Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP), E-28009 Madrid, Spain; [email protected] (C.C.-F.); [email protected] (M.H.) * Correspondence: [email protected] Received: 7 February 2020; Accepted: 17 February 2020; Published: 21 February 2020 Abstract: Urolithin A is a metabolite generated from ellagic acid and ellagitannins by the intestinal microbiota after consumption of fruits such as pomegranates or strawberries. The objective of this study was to determine the cytoprotective capacity of this polyphenol in Neuro-2a cells subjected to oxidative stress, as well as its direct radical scavenging activity and properties as an inhibitor of oxidases. Cells treated with this compound and H2O2 showed a greater response to oxidative stress than cells only treated with H2O2, as mitochondrial activity (MTT assay), redox state (ROS formation, lipid peroxidation), and the activity of antioxidant enzymes (CAT: catalase, SOD: superoxide dismutase, GR: glutathione reductase, GPx: glutathione peroxidase) were significantly ameliorated; additionally, urolithin A enhanced the expression of cytoprotective peroxiredoxins 1 and 3. Urolithin A also acted as a direct radical scavenger, showing values of 13.2 µM Trolox Equivalents for Oxygen Radical Absorbance Capacity (ORAC) and 5.01 µM and 152.66 µM IC50 values for superoxide and 2,2-diphenyss1-picrylhydrazyl (DPPH) radicals, respectively. Finally, inhibition of oxidizing enzymes, such as monoamine oxidase A and tyrosinase, was also detected in a dose-dependent manner. The cytoprotective effects of urolithin A could be attributed to the improvement of the cellular antioxidant battery, but also to its role as a direct radical scavenger and enzyme inhibitor of oxidases. Keywords: urolithin A; pomegranate; ellagic acid; dietary polyphenols; neuroprotection; peroxiredoxins 1. Introduction Urolithins are natural polyphenolic compounds obtained from ellagic acids and ellagitannins by the gut microbiota. Ellagic acid is a phenolic antioxidant compound present in numerous fruits, such as pomegranates, strawberries, or nuts. Ellagitannins are a class of polymeric ellagic acid derivatives also present in pomegranates (punicalagins and punicalins) and other sources, such as oak or chestnut wood (castalagin, castalin, roburin A, grandinin) or Melaleuca quinquenervia leaves (castalin and grandinin) [1–3]. The beneficial properties of these plants and foods seem to be in relation with these polyphenolic metabolites; however, the metabolism of polyphenols from food seems to be insufficient to achieve adequate levels of urolithins in the body. In addition, it has been proven that apparently beneficial foods such as pomegranates have had a lot of interindividual variability due to the different urolithin Antioxidants 2020, 9, 177; doi:10.3390/antiox9020177 www.mdpi.com/journal/antioxidants Antioxidants 2019, 8, x FOR PEER REVIEW 2 of 16 Antioxidants 2020, 9, 177 2 of 16 metabotypes present in the population [4]. In fact, only 1 in 3 people have the right microbiota to metabotypesperform this metabolism present in thewith population maximum [ 4efficiency]. In fact, [5]. only 1 in 3 people have the right microbiota to performTherefore, this metabolism it is very with important maximum to eevaluatefficiency [th5].e activity of isolated urolithins as potential therapeuticTherefore, agents. it is very In addition, important the toevaluate use if urolit the activityhin A ofin isolated humans urolithins and the as safety potential profile therapeutic of this agents.compound In addition, have been the widely use if urolithinevaluated, A inwith humans no adverse and the effects safety on profile health of observed this compound [6]. have been widelyAlthough evaluated, urolithins with no adverseare a group effects onof healthmetabolites, observed urolithin [6]. A (UA), also known as 3,8- dihydroxyurolithin,Although urolithins is one of are the amost group representa of metabolites,tive compounds. urolithin There A are (UA), numerous also studies known that as 3,8-dihydroxyurolithin,demonstrate an important is one role of of the this most compound representative in metabolic compounds. syndrome, There improving are numerous cardiovascular studies that demonstratefunction, decreasing an important the formation role of this of triglycerides, compound in inhibiting metabolic enzymes syndrome, such improving as lipase or cardiovascular glucosidase, function,or relieving decreasing insulin resistance the formation [7–9]. of It triglycerides,has also been inhibitingobserved that enzymes UA may such have as lipase an important or glucosidase, role in orthe relieving prevention insulin of certain resistance cancers, [7–9]. such It has as also colorectal been observed or prostate that cancers UA may [10,11]. have an UA important also has role an inimportant the prevention role at the of certainmitochondrial cancers, level, such being as colorectal able to activate or prostate mitophagy cancers and [10,11 prolonging]. UA also lifespan has an importantin Caenorhabditis role at theelegans mitochondrial worms, as level, well beingas beneficial able to activatemitochondrial mitophagy effects and in prolonging the skeletal lifespan muscle in Caenorhabditis[12,13]. elegans worms, as well as beneficial mitochondrial effects in the skeletal muscle [12,13]. The set of all these beneficialbeneficial properties for healthhealth may be due to the antioxidant capacity of polyphenols. However, However, there are few studies that link the antioxidant properties of this metabolitemetabolite with aa potential potential therapeutic therapeutic activity activity in neurodegenerativein neurodegenerative diseases, diseases, where where the redox the status redox is status essential. is Therefore,essential. Therefore, the objective the objective of this study of this was study to was evaluate to evaluate whether whether urolithin urolithin A has A antioxidant has antioxidant and neuroprotectiveand neuroprotective effects effects using using Neuro-2a Neuro-2a cells andcells other and inother vitro inmodels vitro models involving involving the use the of centraluse of nervouscentral nervous system system (CNS) enzymes (CNS) enzymes or free radicals.or free radicals. 2. Materials and Methods 2.1. Reagents and Chemicals Urolithin AA (3,8-dihydroxyurolithin) (3,8-dihydroxyurolithin) (Figure (Figure1) was 1) purchased was purchased from Toronto from ResearchToronto Chemicals Research (TRC,Chemicals Toronto, (TRC, ON,Toronto, Canada). ON, Canada). Neuro-2a Neuro-2a (N2a) (N2a) cell cell line line was was provided provided from from the the American Type Culture Collection Collection (ATCC, (ATCC, Manassas, Manassas, VA, VA, USA), USA), while while Monoamine Monoamine oxidase oxidase A (MAO-A), A (MAO-A), 5,5′- 5,5dithiobis-(2-nitrobenzoic0-dithiobis-(2-nitrobenzoic acid) acid) (DTNB), (DTNB), Tris, Tris, galantamine, galantamine, levodopa levodopa (L (l-DOPA),-DOPA), tyramine, horseradish peroxidase, 2,20′-azobis(2-methyl-propionamidine)-di-hydrochloride (AAPH), hydrogen peroxide (30%(30% ww/w/w),), 2,4,6-Tris(2-pyridyl)-1,3,5-triazine2,4,6-Tris(2-pyridyl)-1,3,5-triazine (TPTZ),(TPTZ), 220,7′,70′-dichloro-dihy-drofluorescein-dichloro-dihy-drofluorescein diacetate (DCFH-DA), (DCFH-DA), 3-(4,5-Dimethyl-2-thiazolyl)-2,5- 3-(4,5-Dimethyl-2-thiazolyl)-2,5- diphenyltetrazolium diphenyltetrazolium bromide bromide (MTT), (MTT), 6- 6-hydroxy-2,5,7,8-tetra-methylchromane-2-carboxylichydroxy-2,5,7,8-tetra-methylchromane-2-carboxylic acid acid (Trolox), (Trolox), bovine bovine serum serum albumin albumin (BSA), vanillic acid, 4-aminoantipyrine, penicillin, stre streptomycin,ptomycin, tyrosinase, thiobarbituric acid acid (TBA), trichloroacetic acidacid (TCA), (TCA), bicinchoninic bicinchoninic acid acid (BCA), (BCA), and and pyrogallol pyrogallol were obtainedwere obtained from Sigma-Aldrich from Sigma- (Madrid,Aldrich (Madrid, Spain). Clorgyline Spain). Clorgyline and α-kojic and were α-kojic from Cymitwere qufromímica Cymit (Barcelona, química Spain). (Barcelona, Na2CO Spain).3, HCl, NaCl,Na2CO dimethyl3, HCl, NaCl, sulfoxide dimethyl (DMSO), sulfoxide MeOH, (DMSO), and potassium MeOH, and phosphate potassium were phosphate supplied were from supplied Panreac (Barcelona,from Panreac Spain). (Barcelona, Dulbecco’s Spain). modified Dulbecco’s Eagle’s modi mediumfied Eagle’s (DMEM), medium phosphate-bu (DMEM), phosphate-bufferedffered saline (PBS), andsaline fetal (PBS), bovine and serumfetal bovine (FBS) wereserum acquired (FBS) were from acquired Gibco (Invitrogen, from Gibco Paisley, (Invitrogen, UK). Paisley, UK). Figure 1. Structure of Urolithin A. Synonyms: 3,8-Dihydroxyurolithin; 3,8-Hydroxydibenzo-α-pyrone; 2Figure0,7-Dihydroxy-3,4-benzocoumarin; 1. Structure of Urolithin A.δ-Lactone Synonyms: 20,4,4 3,8-0-Trihydroxy-2-biphenylcarboxylicDihydroxyurolithin; 3,8-Hydroxydibenzo- acid. α- pyrone; 2′,7-Dihydroxy-3,4-benzocoumarin; δ-Lactone 2′,4,4′-Trihydroxy-2-biphenylcarboxylic acid. Antioxidants 2020, 9, 177 3 of 16
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