Comparative evaluation of relaxant effects of three prangos species on mouse corpus cavernosum: Chemical characterization and the relaxant mechanisms of action of P. pabularia and (+)-oxypeucedanin
Graphical abstract
Introduction
Erectile dysfunction (ED) is the impairment in initiating and maintaining erection which is necessary for sexual performance (Yafi et al., 2016). ED may develop due to ageing, lifestyle factors, and systemic diseases such as hypertension, diabetes and hyperlipidemia (Ostfeld et al., 2021). Although phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil are used to increase NO bioavailability which is an important tool in the management of ED, some patients still do not respond. Therefore, there is still a great need for more effective therapeutic drugs that can provide long-lasting improvement in ED. Another approach to get success in the treatment of ED may be obtained by targeting other pathways involved in erectile function such as H2S/CSE pathway that contributes to erectile function by relaxing CC (Yetik-Anacak et al., 2015b). Before PDE inhibitors, yohimbine and apomorpine were the most powerful molecules used in the treatment of ED, and had been isolated from plants (Eardley, 1998). Plants have been extensively used to cure sexual dysfunction for centuries. Lepidium meyenii Walp. (Brassicaceae), Tribulus terrestris L. (Zygophyllaceae), Epimedium sp. (Berberidaceae), Panax ginseng C. A. Mey. (Araliaceae), Ferula hermonis Boiss. (Apiaceae) are only some of the popular examples known in different cultures in the world (Bella and Shamloul, 2014). Several plants have also been used traditionally in the treatment of various sexual disorders in Turkey. For example, roots of different species of the genus Ferula L. and Prangos Lindl. called “Caksir or Cagsir” are among the foremost well known aphrodisiacs in Anatolian folk medicine (Baser et al., 2000; Bulut et al., 2014; Guner, 2012; Ozdemir and Alpinar, 2015). The genus Prangos (Apiaceae) is an Iran-Turan element and is represented with 19 species in Turkey (Aytac and Duman, 2016; Behcet et al., 2019; Guner, 2012). Roots of Prangos sp. were detected to be rich in coumarin, furanocoumarin and their derivatives by the previous phytochemical studies. Especially oxypeucedanin, osthole, psoralen, oxypeucedanin hydrate, heraclenin are the main compounds isolated from Prangos sp. (Bruno et al., 2019; Razavi et al., 2008).
Prangos pabularia Lindl. is one of the three Prangos species examined in this study and has the widest distribution area in the world. The plant is found in the North, East and Southeast regions of Anatolia (Davis, 1972). Decoctions prepared from aerial parts of the plant are used as stimulants in East Anatolia (Altundag and Ozturk, 2011). It is known as “kerkule” in the Hakkari-Gecitli region and crushed root of the plant is used externally for wound healing (Kaval et al., 2014). Additionally P. pabularia roots are eaten mixed with honey for aphrodisiac purposes in Anatolia (Bulut et al., 2014). We have also reported the aphrodisiac usage of roots in the Nemrut-Adıyaman region of Turkey in our previous ethnobotanical studies (Baykan-Erel et al., 2013). Phytochemical studies reveal that the roots of P. pabularia mainly contain oxypeucedanin, imperatorin, heraclenin, osthole, which are derivatives of coumarin and furanocoumarin (Numonov et al., 2018). Although the plant has rich metabolites, there are limited number of bioactivity studies concerning the antioxidant, antimicrobial and cytotoxic effects (Kogure et al., 2004; Salehi et al., 2016; Tada et al., 2002).
Prangos uechtritzii Boiss & Hauskn, known as “Deli caksir”, is an endemic species which distributed in Central, Eastern and Southeastern Anatolia (Guner, 2012). Whole plant is used traditionally to treat hemorrhoids in Anatolian folk medicine (Bulut et al., 2014). Antibacterial, antifungal and antioxidant properties of P. uechtritzii have been reported (Ahmed et al., 2011; Oke-Altuntas et al., 2016; Uzel et al., 2006). Prangos heyniae H. Duman & M. F. Watson is the other endemic species found in the Konya region in Turkey (Duman and Watson, 1999). The bioactivity studies with P. heyniae are also limited to antioxidant and mosquitocidal activites (Ahmed et al., 2011; Oke-Altuntas et al., 2015; Ozek et al., 2018). Although the aphrodisiac usages of roots of these two species are especially pointed out by local people in our field studies.
Due to the increasing interest in Prangos species used as aphrodisiacs among the public, the research is needed to scientifically support and validate the traditional uses of these plants. It's shown that the coumarin and furanocoumarin derivatives have relaxation effects on various smooth muscles by previous studies and Prangos species draw attention as sources of these metabolites (Kozioł and Skalicka-Woźniak, 2016; Sadraei et al., 2012, 2013). However, there isn't any study in the literature regarding the effects of P. pabularia, P. heyniae and P. uechtritzii on erectile function or any pharmacological activity related to ethno-traditional uses of these plants.
In the light of this information, the design of our study includes three stages. In the first step, the relaxant effects of the root extracts of P. pabularia, P. uechtritzii and P. heyniae on MCC were investigated to verify the traditional claim of the aphrodisiac activity. Then, based on the extract having the strongest response, the roles of NO and H2S in the possible relaxant effect were studied to clarify the mechanism of action of the extract in the management of erectile function. In the third step, phytochemical constituents present in the most active extract were evaluated and (+)-oxypeucedanin, its major compound, was selected for further analysis. (+)-Oxypeucedanin was examined for the pharmacological activity studies and its possible mechanism of action was evaluated.
Section snippets
Chemicals
(R)-(−)-Phenylephrine hydrochloride, acetylcholine chloride, Nω-Nitro-L-arginine methyl ester hydrochloride, aminooxy acetic acid hemihydrochloride, sodium sulfide nonahydrate were purchased from Sigma-Aldrich. All other chemicals were obtained from Sigma-Aldrich, as well.
Plant materials
The roots of P. pabularia were collected from Nemrut mountain/Adiyaman region, 1950 m. altitude on July 5, 2016. The roots of P. uechtritzii were collected from Taskent /Konya province, 1350 m altitude on June 3, 2016. The
Relaxant effect of P. pabularia, P. heyniae and P. uechtritzii extracts
Chloroform, n-hexane, and methanol extracts of P. pabularia (Fig. 1A), P. heyniae (Fig. 1B) and P. uechtritzii (Fig. 1C) caused concentration dependent relaxations in pre-contracted MCC compared to vehicle. The strongest relaxing effect was obtained with chloroform extracts in all three plants (P < 0.001, One and Two-Way ANOVA, Bonferroni post-hoc test) (Fig. 1). The maximum relaxing effect and potency of chloroform extract of P. pabularia (Pp-CE, Emax = 79.34 ± 2.93, pD2 = 5.01 ± 0.04) was
Discussion
ED is the inability to achieve or maintain an erection related with age, health status and emotional factors. ED is a sensitive indicator of systemic endothelial dysfunction and an early marker of cardiovascular diseases (Yetik-Anacak et al., 2015b). The diagnosis of ED has importance as a potential to protect from cardiovascular diseases (Yafi et al., 2016). Plant species traditionally used as aphrodisiacs in Anatolia have been attracting an increasing interest by the scientists. Especially
Conclusions
In our study, in addition to 7 known furanocoumarins including (+)-oxypeucedanin as the major compound, (−)-prantschimgin was reported for the first time from P. pabularia root chloroform extract. This is the first study to show that P. pabularia relaxes MCC and H2S plays an important role in its relaxant effect and that (+)-oxypeucedanin a major compound of P. pabularia is responsible for H2S-mediated effect by stimulating the formation of H2S. Our results demonstrate that n-hexane,
Author's contributions
Gulnur Sevin: Writing original draft, visualization, investigation, methodology.
Elif Alan: Investigation, formal analysis, validation, writing original draft.
Serdar Demir: Formal analysis, methodology, resources.
Gokay Albayrak: Investigation.
Tugce Demiroz: Investigation.
Gunay Yetik Anacak: Supervision, visualization, methodology, writing - review & editing.
Sura Baykan: Conceptualization, methodology, writing - review & editing., funding acquisition, supervision, project administration.
Declaration of interest statement
The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest, or non-financial interest in the subject matter or materials discussed in this manuscript.
Acknowledgements
This work was supported by The Scientific and Technological Research Council of Turkey (TUBITAK, Grant number: 117-S-116).
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