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Ursolic and Oleanolic Acids: Plant Metabolites with Neuroprotective Potential

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Ursolic and Oleanolic Acids: Plant Metabolites with Neuroprotective Potential International Journal of Molecular Sciences Review Ursolic and Oleanolic Acids: Plant Metabolites with Neuroprotective Potential Evelina Gudoityte 1,2, Odeta Arandarcikaite 1, Ingrida Mazeikiene 3 , Vidmantas Bendokas 3,* and Julius Liobikas 1,4,* 1 Laboratory of Biochemistry, Neuroscience Institute, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; [email protected] (E.G.); [email protected] (O.A.) 2 Celignis Limited, Unit 11 Holland Road, Plassey Technology Park Castletroy, County Limerick, Ireland 3 Lithuanian Research Centre for Agriculture and Forestry, Institute of Horticulture, Akademija, LT-58344 Kedainiai Distr., Lithuania; [email protected] 4 Department of Biochemistry, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania * Correspondence: [email protected] (V.B.); [email protected] (J.L.) Abstract: Ursolic and oleanolic acids are secondary plant metabolites that are known to be involved in the plant defence system against water loss and pathogens. Nowadays these triterpenoids are also regarded as potential pharmaceutical compounds and there is mounting experimental data that either purified compounds or triterpenoid-enriched plant extracts exert various beneficial effects, including anti-oxidative, anti-inflammatory and anticancer, on model systems of both human or animal origin. Some of those effects have been linked to the ability of ursolic and oleanolic acids to modulate intracellular antioxidant systems and also inflammation and cell death-related pathways. Therefore, our aim was to review current studies on the distribution of ursolic and oleanolic acids in plants, bioavailability and pharmacokinetic properties of these triterpenoids and their derivatives, Citation: Gudoityte, E.; and to discuss their neuroprotective effects in vitro and in vivo. Arandarcikaite, O.; Mazeikiene, I.; Bendokas, V.; Liobikas, J. Ursolic and Keywords: ursolic acid; oleanolic acid; neuroprotection; ischaemia; neurodegeneration; Alzheimer’s Oleanolic Acids: Plant Metabolites disease; Parkinson’s disease; neuro-inflammation; cancer; glioblastoma with Neuroprotective Potential. Int. J. Mol. Sci. 2021, 22, 4599. https:// doi.org/10.3390/ijms22094599 Academic Editor: Luigi Brunetti 1. Introduction The brain is an essential part of the human body, therefore neurological disorders such Received: 30 March 2021 as neurodegenerative diseases (e.g., Alzheimer’s or Parkinson’s disease), stroke/ischaemia Accepted: 26 April 2021 and brain cancer usually have a significant effect on vital functions. Noteworthy, oxidative Published: 27 April 2021 stress has been recognized as a hallmark of the pathogenesis of these disorders. Moreover, the elevated levels of reactive oxygen (ROS) and nitrogen (RNS) species are implicated Publisher’s Note: MDPI stays neutral in the progression of pathological neuro-inflammation [1]. Therefore, the stimulation of with regard to jurisdictional claims in cellular antioxidant systems and quenching of ROS and RNS generation, modulation of published maps and institutional affil- cell death and anti-inflammatory pathways have proven to be promising neuro-therapeutic iations. approaches [2–4]. Over the last decades the attention to triterpene-enriched plant extracts and especially to purified triterpenoids as bioactive phytochemicals has been considerably increased [5–8]. Pentacyclic triterpenoids are secondary plant metabolites that arise from cyclization of Copyright: © 2021 by the authors. squalene and are widespread in stem bark and leaves of a variety of plants, and are present Licensee MDPI, Basel, Switzerland. in substantial amounts in apple peels [9–12]. Among various triterpenoids, naturally This article is an open access article occurring and synthetic ursane and oleanane triterpenes have been immensely studied due distributed under the terms and to their wide ranging and promising anti-inflammatory and anticancer activities [13–16]. conditions of the Creative Commons Therefore, in this review we will outline the major natural sources and summarize the Attribution (CC BY) license (https:// current studies on the chemistry, bioavailability and pharmacokinetic properties of ursolic creativecommons.org/licenses/by/ and oleanolic acids and some of their derivatives. We will also discuss the most recent 4.0/). Int. J. Mol. Sci. 2021, 22, 4599. https://doi.org/10.3390/ijms22094599 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 16 Int. J. Mol. Sci. 2021, 22, 4599 2 of 15 sources and summarize the current studies on the chemistry, bioavailability and pharma- findingscokinetic relatedproperties to theirof ursolic modulatory and oleanolic effects acids in neurodegeneration, and some of their derivatives. brain ischaemia We willand canceralso discuss in experimental the most recent models findings in vitro related and to in their vivo. modulatory effects in neurodegener- ation,We brain retrieved ischaemia the literatureand cancer from in experimental PubMed, Science models Direct, in vitro MDPI, and in Webvivo. of Science and GoogleWe Scholar. retrieved Search the literature terms from comprised PubMed, “ursolic/oleanolic Science Direct, MDPI, acid”, Web “triterpene”, of Science and “triter- penoid”,Google Scholar. “pentacyclic”, Search terms “extract”, comprised “plant”, “ursolic/oleanolic “neuroprotection“, acid”, “cancer”, “triterpene”, “cell”, “triterpe- “glioma”, “glioblastoma”,noid”, “pentacyclic”, “brain”, “extract”, “ischaemia”, “plant”, “human”, “neuroprotection“, “rat”, “mouse”, “cancer”, “model”, “cell”, “bioavailability”, “glioma”, “pharmacokinetics”,“glioblastoma”, “brain”, “metabolite” “ischaemia”, and “human”, “distribution”. “rat”, “mouse”, The most “model”, recent studies “bioavailabil- in English withity”, full“pharmacokinetics”, text available and “metabolite” indexed in Clarivateand “distribution”. Analytics The Web most of Science recent were studies included. in WeEnglish also with used full the text reference available lists and of indexed identified in articlesClarivate to Analytics find additional Web of papers.Science were The last searchincluded. was We performed also used on the the reference 22 February lists of 2021. identified articles to find additional papers. The last search was performed on the 22 February 2021. 2. Chemistry, Occurrence and Isolation of Ursolic and Oleanolic Acids 2.1.2. Chemistry, Chemical Structure Occurrence of Ursolic and Isola andtion Oleanolic of Ursolic Acids and Oleanolic Acids 2.1. ChemicalTriterpenes Structure constitute of Ursolic a significant and Oleanolic portion Acids of all phytochemicals, and more than 20,000 triterpenoidsTriterpenes have constitute been identified a significant so far. portion Their biosynthesisof all phytochemicals, is based on and squalene more than cycliza- tion,20,000 which triterpenoids involves have a chair-chair-chair-boat been identified so far. transition Their biosynthesis state, and is results based on in compounds,squalene comprisedcyclization, ofwhich six isoprene involves units. a chair-chair-chair-boat Such structures are transition precursors state, to and steroids results in bothin com- plants andpounds, animals comprised [17,18]. of six isoprene units. Such structures are precursors to steroids in both plantsUrsolic and animals acid (UA) [17,18]. (3β -hydroxyurs-12-en-28-oic acid) and oleanolic acid (OA) (3β- hydroxyolean-12-en-28-oicUrsolic acid (UA) (3β-hydroxyurs-12-en-28-oic acid) are pentacyclic acid) triterpenoids and oleanolic which acid have (OA) therapeutic (3β-hy- potentialdroxyolean-12-en-28-oic [19]. They are biosynthesized acid) are pentacyclic in the triterpenoids mevalonate which pathway have from therapeutic the primary poten- sterol metabolismtial [19]. They precursor are biosynthesized 2,3-oxidosqualene in the mevalonate which is pathway transformed from the into primary dammarenyl sterol me- cation tabolism precursor 2,3-oxidosqualene which is transformed into dammarenyl cation by by oxidosqualene cyclases. Subsequently, dammarenyl undergoes ring expansion and oxidosqualene cyclases. Subsequently, dammarenyl undergoes ring expansion and cy- cyclization to form α-amyrin and β-amyrin skeletons with the characteristic ring system clization to form α-amyrin and β-amyrin skeletons with the characteristic ring system and and methyl groups. The α-amyrin constitutes a UA skeleton, whereas its C30 isomer, methyl groups. The α-amyrin constitutes a UA skeleton, whereas its C30 isomer, β- β-amyrin, forms OA [20]. Thus, UA and OA are structural isomers differing in the position amyrin, forms OA [20]. Thus, UA and OA are structural isomers differing in the position of one methyl group (see Figure1) and having comparable physicochemical properties and of one methyl group (see Figure 1) and having comparable physicochemical properties pharmacologic activity [21,22]. UA and OA are ubiquitous in plants and may constitute and pharmacologic activity [21,22]. UA and OA are ubiquitous in plants and may consti- severaltute several percent percent of the of dry theweight dry weight [17,18 [17,18].]. They They occur occur as free as acidsfree acids or serve or serve as aglycones as agly- for triterpenecones for triterpene saponins saponins [18]. [18]. FigureFigure 1.1. Chemical structures structures of of ursolic ursolic acid acid (UA) (UA) and and oleanolic oleanolic acid acid (OA) (OA) (drawn (drawn according according to to [23]). The[23]). structural The structural differences differences
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