Chemical constituents and anti-inflammatory, antinociceptive, and antioxidant activities of Salvia melissiflora Benth. aerial parts

doi:10.21203/rs.3.rs-3210755/v1

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Chemical constituents and anti-inflammatory, antinociceptive, and antioxidant activities of Salvia melissiflora Benth. aerial parts

https://doi.org/10.21203/rs.3.rs-3210755/v1

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published 16 Nov, 2023

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Chromatographic fractionation of dichloromethane (EDSM) and ethanol (EESM) extracts of Salvia melissiflora Benth. aerial parts led to the identification of five known compounds through analyses of NMR data (1D and 2D), and comparison with literature data: oleanolic acid (1), ursolic acid (2), ent-(5R,9R)-15,16-epoxy-10S-hydroxycerodan-3,13(16),14-triene-17,12S;18,19-diolide (melissiflorine, 3), 7-epi-salvianduline A (4) and rosmarinic acid (5). The anti-inflammatory and antinociceptive activity of EESM and EDSM were evaluated in mice. The oral administration of EESM reduced the second phase of formalin-induced nociception, the lipopolysaccharide (LPS)-induced hyperalgesia and the carrageenan-induced edema in mice. The oral administration of EDSM also reduced LPS-induced hyperalgesia without altering motor performance of the animals. The anti-inflammatory and anti-nociceptive effects are probably related to the presence of compounds 5 and 1, and 2, respectively. The antioxidant activity of the extracts was evaluated using the ORAC method. The EESM extract showed activity (TE relative: 2845.2 µmol TE g^− 1), which can be attributed to the major presence, in this extract, of compound 5, which showed an antioxidant capacity comparable to that of caffeic acid.

Salvia melissiflora

clerodanes

triterpenes

anti-inflammatory activity

antinociceptive activity

antioxidant activity

Salvia (Lamiaceae) is represented in Brazil by 70 species, of which 62 are native (Oliveira et al. 2023). It exhibits a remarkable chemical diversity, characterized by its economically valuable volatile oils, and diterpenes, triterpenes, and phenolic compounds as non-volatile constituents (Jassbi et al. 2016; Ortiz-Mendoza et al. 2022). Salvia species exhibit several therapeutic effects, such as, antimicrobial, antiviral, antioxidant, antidepressant, anti-inflammatory, anticholinesterase, antispasmodic, hypoglycemic, antitumor, and cytotoxic activities (Ortiz-Mendoza et al. 2022; Oliveira et al. 2022).

Salvia melissiflora Benth. (syn: S. paranensis, S. platyfrons) is an aromatic herb or subshrub perennial species that typically reaches a maximum height of 80 cm. It is characterized by its simple leaves arranged in opposite pattern and vibrant red flowers. It is endemic from Brazil, where is distributed in São Paulo, Paraná and Santa Catarina states (Oliveira et al. 2023). There are no vernacular names or uses in traditional medicine for this species.

The essential oil composition of the leaves was previously reported (Kassuya et al. 2009), but there are no other chemical or pharmacological studies on S. melissiflora. To address this research gap, a phytochemical investigation was carried on S. melissiflora aerial parts, and the extracts were evaluated for their potential anti-inflammatory, antinociceptive, and antioxidant activities.

General experimental procedures

Optical rotations were determined using a JASCO PTC-203 polarimeter at room temperature and a wavelength of 589 nm. 1D (¹H, ¹³C) and 2D (gHSQC, gHMBC) NMR spectra were recorded on Brucker spectrometers (Avance 400 and/or Avance 600) observing ¹H at 400 or 600 MHz, and ¹³C at 100 or 150 MHz. CDCl₃ or CD₃OD were used as solvents, and chemical shifts were reported in ppm (δ), with coupling constants (J) in Hz. TMS served as the internal reference.

HPLC separations were conducted on a Waters apparatus equipped with a PDA detector and a semipreparative Nucleosil 100-5 C18 column (250 x 10 mm). Water:acetonitrile (60:40, isocratic) was used as mobile phase, with a flow rate of 2.0 mL min^− 1, at room temperature. The effluent was monitored over the 210–400 nm range. Silica gel 60 (Merck®, 230–400 mesh) was used for column chromatographic separations (CC), while precoated silica gel 60 GF₂₅₄ plates (Macherey-Nagel®) were used for analytical and preparative TLC. Compounds were visualized by exposure under UV_254/366, and spraying with a 5% (v/v) H₂SO₄ in ethanol solution, followed by heating. All solvents and drugs used were of analytical or spectroscopic grade, and the mixtures of solvents were prepared as v/v.

Plant material

Salvia melissiflora Benth. were collected in Quatro Barras, Paraná State, Brazil (S 25° 24' 29.0", W 49° 59' 57.98"), in October 2018. The plant was authenticated by Élide P. Santos who deposited a voucher specimen in the herbarium of Federal University of Paraná (UPCB 85.281). The study of this species was registered on SISGEN under number A19F875.

Extraction and isolation of the compounds

Dried and powdered aerial parts (174.3 g) were subjected to sequential extraction, at room temperature, using n-hexane (Hex, mixture of isomers), CH₂Cl₂, and EtOH (500 mL, three times each solvent). After solvent removal were obtained the extracts in Hex (1.67 g), CH₂Cl₂ (EDSM, 1.72 g) and EtOH (EESH, 3.90 g). Aliquots of EDSM and EESM were reserved for biological assays.

The remaining EDSM (1.70 g) was fractionated by CC, eluted with several solvents in polarity order (Hex, Hex:CH₂Cl₂ 1:1, CH₂Cl₂, CH₂Cl₂:acetone 9:1, 8:2 and 1:1, and finally MeOH), resulting in thirteen pooled fractions (A_1 − 13) after TLC analysis. Fraction A₇ (256.0 mg) was subjected to an additional CC using a mixture of Hex:EtOAc:MeOH (5:4:1), followed by pure EtOAc, yielding seven subfractions (A_7.1−7). Subfraction A_7.4 (55.2 mg) was purified by preparative TLC in toluene:EtOAc (3:2), yielding 3 (1.5 mg), 1 + 2 (2.5 mg), and a mixture (19.3 mg) that was purified by HPLC to give 4 (2.3 mg, retention time 17.15 min).

The remaining EtOH extract (3.70 g) was dissolved in H₂O:EtOH (9:1) and subjected to extraction with EtOAc and n-butanol. The n-butanol fraction (MSB, 298.7 mg) was submitted to CC, eluted with mixtures of CH₂Cl₂:MeOH (9:1, 8:2), followed by MeOH, yielding five subfractions (B_1 − 5). Subfraction B₅ (98.7 mg) yielded 5 (23.3 mg) after PTLC in CH₂Cl₂:MeOH (8:2).

Animals

The experiments were conducted using male Swiss mice (25–45 g), housed under a 12 h/12 h light/dark cycle, with controlled humidity (60–80%), and temperature (22 ± 1 ºC). Food and water were freely available to the animals. The animals were acclimatized to the experiment room at least 2 h before testing and were used only once throughout the experiments. The studies were carried out in accordance with the current Brazilian and International guidelines for the care of laboratory animals and were approved by the Institution’s Ethics Committee for Animal Use (# 937). The number of animals was the minimum necessary to show consistent effects and all efforts were made to minimize the number of animals used and their suffering. All the drugs used were of analytical grade.

Formalin-induced nociception

Formalin-induced nociception was evaluated as described before (Lomba et al. 2017). The mice were orally treated with the EESM (10, 30 or 100 mg kg^− 1) 1 h before injection of 20 µL of 2.5% formalin (0.92% formaldehyde), made up in saline, in the right hind paw. Control animals received the same volume of vehicle (Tween 20 1%, p.o.) or indomethacin (IND, 5 mg kg^− 1, p.o.). The time that the animals spent licking the injected paw (nociceptive behavior) was recorded in blocks of 5 min for 40 min. Phase I was considered as the time spending executing the nociceptive behavior in the first 5 min and phase II the time spending executing the nociceptive behavior from 15–40 min.

Mechanical hyperalgesia

Mechanical hyperalgesia was assessed using an electronic Von Frey apparatus (Insight, Brazil) as described previously (Lomba et al. 2021) with an adaptation for mice. First, the mice were placed in individual clear Plexiglas boxes (9.5 x 6.5 x 9.5 cm) on an elevated wire mesh platform for adaptation. The mesh floor allowed the tip of the apparatus to stimulate the midplantar region of the right hind paw using a disposable polypropylene tip (0.5 mm diameter). This tip was connected to a force transducer and digital display that allowed determination of the mass (in g) applied. Increasing force was applied to the paw, until the occurrence of paw withdrawal response. The mechanical threshold was calculated as the average value of three similar withdrawal responses, with a maximum of five stimulations with an interval of 15 s between them. After the determination of the basal withdrawal threshold, the animals were treated with EESM (10, 18 and 30 mg kg^− 1), EDSM (7.5 mg kg^− 1), the vehicle (Tween 20 1%), or the positive control IND (5 mg kg^− 1) by oral route. After 1 h animals received 20 µL injection of E.coli lipopolysaccharide (LPS, 0111:B4, 100 ng/paw, Sigma-Aldrich, USA) into the right hind paw. The occurrence of mechanical hyperalgesia was determined as the difference between the average mechanical threshold observed prior to any treatment (baseline) and 1, 3 and 5 h after the injection of LPS.

Carrageenan-induced edema

Edema was measured as described before (Lomba et al. 2017). Paw thickness (in µm) was measured using a digital micrometer (Metal Great Tools Co., MT-045B, China) before any treatment. The mice were then treated with EESM (100 mg kg^− 1) or vehicle (Tween 20, 1%) or the positive control dexamethasone (DEX, 5 mg kg^− 1, Sigma-Aldrich, USA) orally. One hour after oral treatment, the animals received carrageenan (300 µg) suspended in 20 µL of sterile 0.9% saline into the right hind paw. Contralateral paw received only saline and was used as control.

Motor performance

Mice were previously selected based on their ability to remain on a rotarod apparatus (Ugo Basile, Italy) that rotated at 22 rotations per minute for at least 60 s (one of three trials). Animals were treated with vehicle or EDSM (7.5 mg kg^-1) by oral route. Positive control group received diazepam (5 mg kg^-1, subcutaneously). Three hours after EDSM treatment or 30 min after diazepam treatment, the animals were subjected to the rotarod test as previously described (Lomba et al. 2017).

Antioxidant assay

The antioxidant capacity of the samples was determined using the Oxygen Radical Absorbance Capacity (ORAC) assay, employing fluorescein as the fluorescent probe and AAPH (2,2'-azobis(2-amidinopropane) dihydrochloride) as a free radical source. The experiments were carried on 96-well plates (Prior et al. 2003). Various dilutions of the samples (5 to 500 µg mL^− 1) were prepared in a phosphate buffer/DMSO solution (99:1). Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) was used as a standard, at concentrations of 12.5–200 µmol L^− 1. The measurements were performed using a fluorescent filter (excitation λ: 485 nm and emission λ: 528 nm) in a microplate reader, monitoring the reaction at 37°C every 2 min for a period of 70 min. Results were expressed as µmol of Trolox equivalent (TE) per gram of dried extract (µmol TE g^− 1). Caffeic acid, chlorogenic acid, quercetin, isoquercetin, and rosmarinic acid were utilized as positive controls, while the solvent was the negative control. All experiments were conducted in triplicate.

Statistical Analysis

Data are expressed as mean ± the standard deviation or mean ± standard error of the mean. The data were analyzed using one-way or two-way repeated measures analysis of variance (ANOVA) followed by Bonferroni’s test. The data obtained were analyzed using the GraphPad Prism software version 9.0. P values less than 0.05 (p < 0.05) were considered significant.

Phytochemical study

The dichloromethane extract from aerial parts of S. melissiflora furnished four known compounds (1–4), while the ethanol extract yielded 5 as main constituent (Fig. 1). These compounds were identified by analyses of their NMR data and comparison with literature.

Compounds 1 and 2 were isolated in mixture. Their NMR data revealed typical signals of triterpenes. The basic skeleton was determined by analyzing the chemical shifts of the carbons of the double bond, which indicate the presence of triterpenes belonging to the oleanane (δ_C 143.8, C-13 and 122.2, C-12) and ursane types (δ_C 138.3, C-13 and 125.7, C-12) (Olea and Roque, 1990). Analyses of HSQC and HMBC spectra led to identification of oleanolic acid (1) and ursolic acid (2) (Dais et al. 2017).

Compound 3 exhibited characteristic signals of a clerodane diterpenoid in its NMR data. Signals for a monosubstituted furan ring (δ_H 7.45, H-16; 7.39, H-15; 6.40, H-14), a γ-lactone (δ_Η 4.37 and 4.30, H-19; δ_C 170.5, C-18; 71.6, C-19), a δ-lactone (δ_Η 5.65, H-12; δ_C 174.8, C-17; 71.7, C-12), a methyl group (δ_Η 1.28, H-20), a trisubstituted double bond (δ_Η 6.90, H-3; δ_C 136.3, C-3; 132.0, C-4), and an oxygenated quaternary carbon (δ_C 73.8, C-10) were observed. Careful analyses of HSQC and HMBC correlations confirmed that 3 is a pentacyclic cis-clerodane known as ent-(5R,9R)-15,16-epoxy-10S-hydroxycerodan-3,13(16),14-triene-17,12S;18,19-diolide (Almanza et al. 1997), for the which we suggested the common name melissiflorine.

The NMR data of compound 4 were similar to those of 3, indicating a clerodane diterpenoid. However, the ¹H and ¹³C NMR spectra of 4 exhibited additional signals that could be attributed to an α,β-unsaturated ketone (δ_C 197.5, C-10) and an acetyl group (δ_H 2.02; δ_C 169.5). Additionally, the methyl group at C-20 (δ_H 2.09) appeared to be more deshielded in comparison with the same methyl group in 3. These findings suggested the presence of a double bond between C-8 and C-9 and a cleavage of the bond between C-9 and C-10, resulting in a tetracyclic rearranged seco-clerodane. HSQC and HMBC correlations confirmed the structure of 4, a compound known as 7-epi-salvianduline A (Ortega et al. 1991).

The ¹H NMR spectrum of 5 showed signals characteristic of two trisubstituted aromatic rings (δ_H 7.02–6.25), and an olefinic bond (δ_H 7.50 and 6.25, J = 15.9 Hz, H-8, H-7; δ_C 169.3, C-9), suggesting a caffeoyl-derivative. The remaining data supported the identification of rosmarinic acid (Kuhnt et al. 1994).

Antinociceptive and anti-inflammatory activity studies

Formalin-induced nociception is characterized by two phases: an initial phase (phase I), which is believed to be neurogenic, and a second phase (phase II), which starts approximately 15 min after the injection of formalin and lasts till the end of the experiment and is considered to be an inflammatory phase. The treatment of the mice with 10, 30 or 100 mg kg^− 1 EESM did not change the first phase of formalin-induced nociception but significantly reduced the second phase (Fig. 2A and B). Similarly, the non-selective, non-steroidal anti-inflammatory drug IND, also reduced only the second phase of formalin-induced nociceptive behavior. Additionally, EESM dose-dependently reduced the LPS-induced mechanical hyperalgesia. The lowest dose used (10 mg kg^− 1) did not change the LPS-induced mechanical hyperalgesia while higher doses, 18 mg kg^− 1 and 30 mg kg^− 1, reduced and completely abolished LPS-induced hyperalgesia (Fig. 3A). As expected, IND also reduced this response (Fig. 3A). This extract also showed anti-inflammatory activity. EESM 100 mg kg^− 1 significantly reduced the carrageenan-induced edema (Fig. 3B), particularly 5 h after Cg injection. The steroidal anti-inflammatory drug DEX significantly reduced edema formation at time points 3 and 5 h after Cg injection (Fig. 3B). As mentioned above, the main compound found in EESM was rosmarinic acid (5).

The analgesic and anti-inflammatory activity of rosmarinic acid (5) is well documented. Using similar models, Boonyarikpunchai et al. (2014) showed that rosmarinic acid (5), isolated from Thunbergia laurifolia, also significantly reduced acetic acid-induced writhing, while 100 mg kg^− 1 additionally inhibited the first and second phases of formalin-induced nociception and carrageenan-induced edema. This study also showed that rosmarinic acid (5) reduced heat-induced nociception, an effect that was blocked by naloxone, suggesting that rosmarinic acid (5) is effective against inflammatory pain and has an effect dependent of opioid release. However, other mechanisms may be involved since the isolated compound was effective in reducing carrageenan-induced edema, which is not reduced by opioid drugs. Our results show that EESM, which contains rosmarinic acid (5), was effective mostly in the inflammatory pain and edema. We did not observe a reduction in the first phase of formalin-induced pain, suggesting that the extract, at the doses used, is not acting through opioid release. The highest dose of EESM we tested was 100 mg kg^− 1 and, therefore, the amount of rosmarinic acid (5) in the extract is certainly lower than that used by Boonyarikpunchai et al. (2014) to reduce formalin-induced nociception. Other mechanisms for rosmarinic acid (5) to reduce inflammatory pain and edema have been proposed involving the cholinergic systems, the L-arginine-nitric oxide pathway, the reduction in the release of inflammatory cytokines particularly in neuropathic pain (Guginski et al. 2009; Ma et al. 2020; Rahbardar et al. 2017; 2018; Areti et al. 2018; El Gabbas et al. 2019, Borgonetti and Galeotti, 2022). The effect of rosmarinic acid (5) on formalin-induced nociception and LPS-induced mechanical hyperalgesia cannot be attributed to motor impairment since even high doses of this compound did not alter the motor performance of the animals, as showed in previous studies (Yu et al. 2022). Therefore, the anti-inflammatory and antinociceptive effect of EESM was expected and confirmed by these studies and is related, at least in part, to the presence of rosmarinic acid (5).

Differently from EESM, EDSM was only tested in the inflammatory hyperalgesia since the evidences in the literature suggested that oleanolic acid (1) and ursolic acid (2) are mainly related to the blockage of the release of inflammatory mediators. EDSM also significantly reduced the LPS-induced mechanical hyperalgesia observed at 3 h and 5 h after the injection of LPS in the hind paw (Fig. 4A) without interfering with the motor performance of the animals (Fig. 4B). As mentioned before, oleanolic acid (1) and ursolic acid (2) were the main triterpenes found in EDSM and are also commonly found in other Salvia species (Jassbi et al. 2016; Ortiz-Mendoza et al. 2022).

Several studies have shown that extracts from different plants that contain oleanolic acid (1) and ursolic acid (2) possess anti-inflammatory and antinociceptive activity, including the reduction of mechanical hyperalgesia (Azevedo et al. 2016; Kuraoka-Oliveira et al. 2020). Therefore, the presence of these compounds as main compounds in EDSM justifies the antinociceptive effect of EDSM. Ursolic acid (2) was also effective in neuropathic pain reducing mechanical and thermal hyperalgesia (Bhat et al. 2016), thermal pain, carrageenan-induced edema formation acting as, COX-2 inhibitors and/or glutamate receptors antagonist (Silva et al. 2017; Rodrigues et al. 2012). Additionally, Qasaymeh et al (2023) also showed that both oleanolic acid (1) and ursolic acid (2) inhibited the release of TNF-α and IL-12 in vitro. Due to this possible effect in glutamate receptors, we investigated if EDSM, at the doses used in the present study, could affect the motor performance of the animals, a common effect observed in drugs that affect the glutamatergic system. We did not observe any effect on the motor performance of the animals, suggesting that the antinociceptive effect observed in the mechanical threshold evaluation is not a bias due to a motor impairment, but does not exclude the possibility that the EDSM could be acting through both, blocking inflammatory mediators release and as NMDA antagonists. However, it is important to mention that previous studies also have shown that oleanolic acid (1) and ursolic acid (2) modulate the activities of several cytochrome P450 (CYP) enzymes suggesting that the consumption of herbal medicines containing these triterpenes can cause important pharmacological interactions (Kim et al. 2004).

Antioxidant assay

The antioxidant activity of the extracts from S. melissiflora was evaluated using the ORAC-FL method and measured in µmol Trolox equivalent (TE) per gram of dry extract (µmol TE g^− 1). Extracts with TE > 800.0 µmol TE g^− 1 are considered to have antioxidant activity (Prior et al. 2003). Among the extracts tested, only EESM showed antioxidant activity (Table 1). This result aligns with the findings of the phytochemical study, which identified rosmarinic acid (5) as the major constituent in this extract. In our assay 5 showed antioxidant capacity comparable to that of caffeic acid (Table 1). Rosmarinic acid (5) is a well-known compound with powerful antioxidant properties, including scavenging free radicals, activating enzymes, inhibiting lipid peroxidation, and protecting DNA. These properties enable it to effectively counteract oxidative stress-induced damage (Guan et al. 2022; Huang et al. 2019), and contribute to the anti-inflammatory and antinociceptive properties of this extract.

Table 1

Antioxidant capacity of *Salvia melissiflora* extracts
Sample	ORAC assay (µmol TE g^− 1)
EDSM (CH₂Cl₂ extract)	202.6 ± 38.10
EESM (EtOH extract)	2845.2 ± 2.70
Caffeic acid^a	2.85 ± 0.03^b
Chlorogenic acid^a	2.65 ± 0.03^b
Isoquercetin^a	5.15 ± 0.09^b
Quercetin^a	5.60 ± 0.08^b
Rosmarinic acid^a	3.00 ± 0.05^b
^a positive experimental control; ^b data of pure compounds are expressed as relative Trolox equivalent. The values are average of triplicate assays ± standard deviation.

Conflict of interest: There are no conflicts to declare

Acknowledgment

The authors are grateful to Élide P. Santos for collection and identification of the plant, and to CAPES (Finance Code 001), FAPESP (process numbers 06/06079-4; 09/05992-6, 15/03726-8, and 21/09693-5), and CNPq (process numbers #311166/2016-4, #304266/2017-5, and #427859/2018-2) for financial support.

Authors’ contributions

Conceived and designed the phytochemical analysis and analyzed the data: CSO and MEAS. Performed phytochemical analysis: CSO. Conceived and designed the pharmacological experiments and analyzed the data: FLB, CAE and ARZ. Performed pharmacological experiments: FLB and CAE. Conceived and designed the antioxidant assay and analyzed the data: TEBR and MJS. Wrote the paper: CSO, MEAS and ARZ.

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published 16 Nov, 2023

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Chemical constituents and anti-inflammatory, antinociceptive, and antioxidant activities of Salvia melissiflora Benth. aerial parts

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Journal Publication

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Abstract

Figures

Introduction

Materials and Methods

General experimental procedures

Plant material

Extraction and isolation of the compounds

Animals

Formalin-induced nociception

Mechanical hyperalgesia

Carrageenan-induced edema

Motor performance

Antioxidant assay

Statistical Analysis

Results and discussion

Phytochemical study

Antinociceptive and anti-inflammatory activity studies

Antioxidant assay

Declarations

References

Supplementary Files

Status:

Journal Publication

Version 1