Citronellol, a Monoterpene Alcohol with Promising Pharmacological Activities - a Systematic Review T
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Food and Chemical Toxicology 123 (2019) 459–469 Contents lists available at ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox Citronellol, a monoterpene alcohol with promising pharmacological activities - A systematic review T Priscila L. Santosa, João Pedro S.C.F. Matosa, Laurent Picotb, Jackson R.G.S. Almeidac, ∗ ∗∗ Jullyana S.S. Quintansa, , Lucindo J. Quintans-Júniora, a Laboratory of Neuroscience and Pharmacological Assays (LANEF), Department of Physiology (DFS), Federal University of Sergipe (UFS), São Cristóvão, SE, Brazil b Faculty of Science and Technology, University of La Rochelle, La Rochelle, France c Federal University of San Francisco Valley, 56304-205, Petrolina, PE, Brazil ARTICLE INFO ABSTRACT Keywords: Many diseases, such as inflammatory and central nervous system disorders, currently have a limited number of Biological products effective side-effect free treatments. Citronellol (CT) is a monoterpene alcohol present in the essential oil of Plants several plants used in cooking and traditional medicine, such as those of the genus Cymbopogon and Citrus, with Medicinal pharmacological activities already described in the literature. The aim of this review was to summarize the Monoterpenes pharmacological activities already attributed to CT that could be used in treatments for humans. The databases Pharmacology PubMed, MedLine, Scopus, Lilacs and Scielo were searched using the terms “Citronellol” and “Drug effect”.32 Drug effects fi Review articles were identi ed and used in the study. Twenty-one articles demonstrated CT activities, including anti- biotic and antifungal effects in vitro, and 11 properties including analgesic and anticonvulsant effects in vivo, besides presenting low toxicity. In view of the need to discover new drugs and the activities reported for CT, it can be stated that CT is a promising molecule to target in future pharmacological studies. 1. Introduction botulinum)(Scott and Collins, 1973). These natural products need to be more fully investigated as many have not had their mechanisms of It has become evident that existing therapies for the treatment of action defined, while many others have not been studied at all (Gu various diseases, including central nervous system disorders and dis- et al., 2013). eases of inflammatory etiology such as rheumatic diseases, are not al- Medicinal plants have been used since the beginning of the ways effective (D'Angelo et al., 2018; Dubash et al., 2018; Gribkoff and humanity and popular knowledge, including in food, in the form of tea, Kaczmarek, 2017; Wegener and Rujescu, 2013) There is, therefore, a soups and curries, such as Cymbopogon citratus in tropical countries growing need for treatments that are not only more effective but also (Petrovska, 2012; Shah et al., 2011). Medicinal plants has been used as have fewer side effects. In addition, there are a growing number of a clue to the investigation of new active principles (Petrovska, 2012). antibiotic resistant microorganisms that can cause infection and even The effects of several medicinal plants has been described in the lit- lead to death (González et al., 2018). One option is to search for new erature, including the anti-inflammatory and antifungal effects of therapeutic alternatives among the various classes of drugs already in Cymbopogon citratus (Boukhatem et al., 2014), the cardiovascular ef- existence. fects of Cymbopogon winterianus (Menezes et al., 2010a,b), the anti- For thousands of years, natural products have been used in the oxidant activity of Lippia alba (Chies et al., 2013) and the analgesic treatment of many diseases. They are the source of various medications effect of Ocimum basilicum (Nascimento et al., 2015). available today, such as morphine (derived from the plant Papaver The essential oils of medicinal plants are rich in secondary meta- somniferum)(Goerig and Schulte am Esch, 1991), aspirin (derived from bolites whose main function is plant defense. Terpenes are composed of the acetylsalicylic acid, extracted from the plant Salix alba)(Vane, isoprene units and constitute a considerable part of the secondary 1971), ziconotide (cone snail toxin isolated from Conus ssp)(McGivern, metabolites found in plants, and have several pharmacological effects 2007) and botulinum toxin (produced by the bacterium Clostridium already described in the literature, such as the antihyperalgesic activity ∗ Corresponding author. Laboratory of Neuroscience and Pharmacological Assays (LANEF). Department of Physiology, Federal University of Sergipe-UFS, Av. Marechal Rondom, s/n, São Cristóvão, Sergipe, 49100-000, Brazil. ∗∗ Corresponding author. E-mail addresses: [email protected], [email protected] (J.S.S. Quintans), [email protected] (L.J. Quintans-Júnior). https://doi.org/10.1016/j.fct.2018.11.030 Received 28 May 2018; Received in revised form 6 September 2018; Accepted 12 November 2018 Available online 16 November 2018 0278-6915/ © 2018 Elsevier Ltd. All rights reserved. P.L. Santos et al. Food and Chemical Toxicology 123 (2019) 459–469 List of acronyms and abbreviations IC50 The half maximal inhibitory concentration IgE Immunoglobulin E (−) S or sinister or left IR Inhibition rate (+) R or rectus or right IκBα Inhibitor of nuclear factor kappa B, alpha (±) R,S or racemic mixture LPS Lipopolysaccharide ACh Acetylcholine MAP Mean arterial pressure AGE Advanced glycation end products MBC Minimal bactericidal concentration BV Bilateral vagotomy MFC Minimal fungicidal concentration CFU Colony-forming units MIC Minimal inhibitory concentration CG Carrageenan MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro- CT Citronellol mide DA Dopamine Nd Not described EFS Electrical field stimulation NF-κB Nuclear factor kappa B EVA Poly(ethylene-co-vinyl acetate) copolymer NO Nitric oxide FICI Fractional inhibitory concentration indices p.o. oral administration GC Gas chromatography PGE2 Prostaglandin E2 Hb Hemoglobin SOD Superoxide dismutase HbA1C Glycated hemoglobin STZ Streptozotocin HR Heart rate TNF-α: Tumor necrosis factor-α i.c: Intracardiac TRPA1 Transient receptor potential ankyrin-1 i.p. intraperitoneal TRPV1 Transient receptor potential cation channel subfamily V i.v. intravenous member 1 of citronellal (Santos et al., 2016), the anti-inflammatory effects of 3. Results carvacrol (Lima et al., 2013) and the antioxidant properties of linalool (Seol et al., 2016). Menthol, an alcoholic monoterpene, has been stu- The studies in this review examine various activities of citronellol. died for many years and a number of formulations in which it is present In the initial keyword search 444 articles were identified, distributed as are available on the market. (Eccles, 1994). In addition to the promising follows in the databases: 129 from PubMed, 198 from Scopus, 117 from activities already described for terpenes, the possibility of synthesis of MedLine, 0 from Lilacs and 0 from Scielo. After reading the titles and these compounds may result in reduced costs and time to discover new abstracts and assessing the inclusion and exclusion criteria, 77 articles drugs (Jansen and Shenvi, 2014). were selected: 31 from PubMed, 19 from Scopus and 27 from MedLine. Citronellol (Fig. 1) is a monoterpene alcohol monoterpene found in Of these, 45 articles were indexed in two or more databases, resulting in the essential oil of plants of the genus Cymbopogon and has several 32 articles that were used in the study. Fig. 2 is a flowchart showing the pharmacological activities already described in the literature, such as study selection process. Twenty-one articles addressed in vitro activities anticonvulsant, antihyperalgesic and orofacial antinociceptive proper- of CT, and eleven, in vivo activities. The methodologies used in the ties (Brito et al., 2015a,b, 2013a; Sousa et al., 2006). Therefore, in view articles included in the study are summarized in Tables 1 and 2. of the need to identify new sources of drugs that are more effective and Several activities have been described for CT, such as antibacterial, have less side effects, and given the fact that citronellol is a terpene antifungal and repellent properties in in vitro studies, and cardiovas- whose class has already been found to have a number of beneficial cular, antidiabetic and antinociceptive effects in in vivo studies. A pharmacological effects, this study aimed to review the pharmacolo- summary of the results obtained by the studies included in the review is gical effects already described for citronellol that present possibilities given in Table 3. for treatments in humans. This review article presents papers that described pharmacological activities of CT relevant to use in humans. In vitro studies investigated possible antibacterial (Echeverrigaray et al., 2008; Kotan et al., 2007; 2. Methods Mulyaningsih et al., 2011; Ngan et al., 2012; Nostro et al., 2013), an- tifungal (Kim and Park, 2012; Mahmoud, 1994; Pereira et al., 2015; This systematic review used a literature search to find all relevant Shin, 2003; Shin and Lim, 2004; Viollon and Chaumont, 1994; Zore articles published up to June 2017. The search was performed through specialized databases (PubMed, MedLine, Scopus, Lilacs and Scielo - Scientific Electronic Library Online) using a combination of the key- words ‘citronellol’ and ‘drug effects’, either as Medical Subject Headings terms (MeSH terms) or as free-text words. Clinical and/or preclinical studies demonstrating some pharmacological activity of citronellol and written in English, Portuguese or Spanish