Indian Journal of Animal Research

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Full Research Article

Biocompatibility, Antimicrobial and Wound Healing Activities of Lavandula dentata Leaves Extract

Nahed Ahmed Hussien 1,*, Hanan Ramadan Hamad Mohamed 2
1Department of Biology, College of Science, Taif University, Taif 21944, Saudi Arabia.
2Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt.

ABSTRACT

Background: The human skin is a natural barrier that protects against external stress, but its physiological structure can be compromised when it gets damaged. In the field of medical science, wounds are a significant issue that requires immediate attention. Lavandula species are used in the food, perfume and cosmetics industries due to their antimicrobial, anti-inflammatory and wound-healing properties. 

Methods: The present study was done to assess the biocompatibility, antimicrobial and wound-healing potential of L. dentata leave methanolic extract (LE) that is cultivated in the Taif region of Saudi Arabia. The biocompatibility of LE was analyzed against the normal human skin fibroblast (HSF) cell line using SRB assay. A quarter of LE IC50 was used for wound healing assay. Finally, Escherichia Coli, Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyogenes were used to determine LE antibacterial potential through the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) measurement. 

Result: LE appears safe on HSF cell line with IC50 = 97 mg/mL. LE decreased wound width, wound area and the mean cell migratory rate of wound border cells during scratch closure, while increased the wound closure% in a time-dependent manner compared to negative control. LE shows antimicrobial potential against all four strains at MIC and MBC>3.0 mg/mL, except for Streptococcus pyogenes MIC= 3.0 mg/mL. In conclusion, LE offers therapeutic benefits against wound healing with an antimicrobial effect, however, higher concentrations of LE should be used to assess its effect.

INTRODUCTION

The skin is a barrier to protect the body against microorganisms’ infection, environmental damage, dehydration, temperature regulation and sensation. Unfortunately, the skin is exposed to various risks that cause abrasion, tearing, or even abrasion, resulting in wounds that disrupt the normal structure and functions of the skin (Lee et al., 2006; Ehterami et al., 2018). Acute wounds heal normally, while chronic wounds last longer and cause tissue infection, damage and other diseases such as diabetes or venous ulcers (Izzah Ibrahim et al., 2018).
       
Although reactive oxygen species (ROS) are normally produced and act as cellular messengers to stimulate key processes associated with wound healing, including cell motility, cytokine action and angiogenesis (Rodrigues et al., 2012). However, impaired wound healing due to nutrition, age, infection, gender and oxygenation increases the formation of ROS and reduces various enzymatic and non-enzymatic free radical scavengers that delay wound healing and cause further tissue damage (Rodrigues et al., 2012). Consequently, medicinal herbs, plants and extracts with strong antioxidant and antimicrobial activity are promising healing agents (WHO, 2004).
       
Lavender (Lavandula dentata L.), belonging to the Lamiaceae family, is a widely distributed plant extensively cultivated worldwide. Lavandula species extract and oil contain different components including geraniol, linalool, ursolic acid, linalyl acetate and others that are used in various medicinal applications including skin sores treatment, inflammation, pain, gastrointestinal, rheumatic and nervous disorders (Hajhashemi et al., 2003). Lavender exhibits strong antioxidant, antibacterial and antiviral activities because many extracts and essential oils derived from lavender have shown potent anti-inflammatory, antibacterial and antioxidant activities (Altaei, 2012; Al Sufyani et al., 2019; Schweitzer, 2021). Mori et al., (2016) report that lavender oil accelerates granulation and wound contraction through transforming growth factor-b induction in vivo.  For example, Lavender oil consists mainly of terpenes and terpenoids, with linalool (19-48%), 1, 8 cineole (21-42%) and camphor (5-17%) (Rota et al., 2004). Three main Lavandula species are principally cultivated to produce essential oils worldwide: L. angustifolia (fine lavender), L. latifolia (spike lavender) and the sterile hybrid L. intermedia (lavandin) due to their extensive and important cosmetic and pharmaceutical applications (Oueslati et al., 2020). A systematic review from Saudi Arabia by Ahmad et al., (2022) and others in the public domain (Giuliani et al., 2020) have reported the medicinal uses and pharmacological properties of Lavender. Here emphasis on the wound-healing potential of Lavandula dentata should be done. The current study was undertaken to evaluate the biological (cytotoxic and antimicrobial) and wound-healing activities of Lavandula dentata leaf extract that is cultivated in the Taif region of Saudi Arabia.

MATERIALS AND METHODS

The experiment took place at Taif University during the summer of 2023. L. dentata L. (fringed/ Toothed/ French lavender) leaves were freshly collected from Al Shafa area in Taif governorate (a high-altitude region located at an elevation of 1,879 m (6,165 ft) above sea level, with coordinates: 21°162 30.343 N 40°242 22.163 E), Saudi Arabia. They were identified and authenticated by Dr. Hussein, N. R. A. (Botany Department, Faculty of Science, South Valley University, Qena, Egypt) as Lavandula dentata L. Sp. Pl.: 572 (1753), Lamiaceae Martinov.
       
Before use, leaves were rinsed in water, dried away from the sun and ground to obtain fine powder (Fig 1). The powder was mixed with 200 mL of methanol (lab grade). The mixture was macerated overnight and then filtered using filter paper. Later, the marc (the damp solid material after filtration) was macerated again in 200 ml of methanol for 1 h and then filtered, this step was repeated twice. Finally, 600 ml of the collected methanol was evaporated under vacuum at 40°C, yielding 1.289 g of methanolic extract of lavender leaves (LE) (Labarbe et al., 1999). 
 

Fig 1: Steps of lavender leaves dryness, collection and grinding to obtain fine powder (A→C).


       
Human Skin Fibroblast (HSF) obtained from Nawah Scientific Inc., (Mokatam, Cairo, Egypt) was used to assess the cytotoxic effect of LE extract. Cells were maintained in Dulbecco’s Modified Eagle Medium (DMEM) media supplemented with 100 units/mL of penicillin, 100 mg/mL of streptomycin and 10% of heat-inactivated fetal bovine serum in humidified, 5% (v/v) CO2 atmosphere at 37°C. HSF cell viability against LE (0.1-1000 mg/mL) was assessed by using sulforhodamine B (SRB) assay according to Allam et al., (2018) and Skehan et al., (1990). Cisplatin (0.01-100 mg/mL) was used as a positive control. LE cytotoxic effect was calculated as:


Cell viability (%) = Mean OD570nm of treated cells/Mean OD570nm of control (untreated cells) ×100.


The data was plotted using OriginLab and the IC50 value for LE was determined.
       
For the wound healing assay, HSF cell lines were cultured in DMEM media, scratched and then treated with fresh media containing ¼ IC50 of LE (24.24 mg/mL) at 24, 48, 72 and 96h. Negative control wells were replenished with fresh medium (only). Images were taken using an inverted microscope at 24, 48, 72 and 96h intervals. At the end of each timing, the wound width, migration rate, wound area and wound closure % were calculated (as mean ± SD) using MII ImageView software version 3.7 according to Main et al., (2019) and Martinotti and Ranzato (2019).
       
The antibacterial effect of lavender leaf extract (serial two-fold dilutions of LE 3 mg/mL to 0.005 mg/mL) was determined by the Clinical and Laboratory Standards Institute (CLSI) methods. Four different bacterial strains were obtained from Nawah Scientific Inc. (Mokatam, Cairo, Egypt) and used in the present study: Escherichia Coli ATCC 8739, Staphylococcus aureus ATCC 29213, Pseudomonas aeruginosa ATCC 9027 and Streptococcus pyogenes ATCC 19615. Colony suspension and broth macrodilution were prepared according to EUCAST (2003). An antibiotic, ciprofloxacin (3 mg/mL to 0.005 mg/mL), was used as a positive control. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of LE against four different aerobic bacterial strains (Escherichia Coli, Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyogenes) were done. The MBC results of LE were analyzed using a one-way ANOVA test. The significance of all the statistical tests was determined at p<0.05 using GraphPad Prism 8.0.1 software.

RESULTS AND DISCUSSION

Lavender leaves extract biocompatibility
 
Lavandula genus plants have been widely used in traditional medicine due to their high content of bioactive compounds (Oueslati et al., 2020). Those bioactive compounds include monoterpenes, polyphenols and sesquiterpenes (Areias et al., 2000). Those constituents give lavender various properties such as antiseptic, anti-inflammatory, analgesic, antioxidant, antimicrobial and antifungal activities (Chrysargyris et al., 2016; El Abdali et al., 2022). Therefore, extracts of lavender have been used in the food, perfume and cosmetics industries (Wells et al., 2018). In the present study, we aimed to evaluate the biological properties of L. dentata L. leaves extract (LE) that are collected in Saudi Arabia, Taif region.
       
In the cell viability assay on human skin fibroblast (HSF), Figure 2A shows a high cytotoxic effect of Cisplatin (positive control, 0.001-100 mg/mL) in a dose-dependent manner with IC50 = 0.78 mg/mL, while LE appears to be safer on the same cell line. LE at concentrations of 0.01, 0.1, 1, 100 and 1000 mg/ml decreased cell viability dose-dependently with IC50 = 97 mg/mL (Figure 2B). Our data indicate that LE has low cytotoxicity in vitro at low concentrations, which agrees with Cardia et al., (2018). They have reported mice leukocytes viability>75% up to a concentration of 10 mg/mL of L. angustifolia oil (LAO) using MTT Assay. However, LAO at higher concentrations (30 and 90 mg/ml) affected cell viability. They concluded that LEO has a cytotoxicity dose-dependent manner and can vary with its constituents (Prashar et al., 2004). In addition, Alnamer et al., (2012) have reported the non-toxic potential of L. officinalis extract as an oral administration. L. dentata’s low cytotoxicity could be attributed to its antioxidant potential. Moroccan L. dentata oil consists of 16 constituents with the major component being linalool (45.06%), then camphor (15.62%) and borneol (8.28%) making it an effective natural agent against free radical damage (El Abdali et al., 2022).
 

Fig 2: Cell viability % of HSF for Cisplatin (A) and LE (B) treatment after 72 h.


 
Wound healing assay
 
The skin represents the largest organ in the body that acts as a biological barrier against injuries, burns, illness and any external stress (Mssillou et al., 2022). A wound is a tissue injury because of several chronic diseases including diabetes, trauma and cancer, which are among the major clinical problems (Shrivastav et al., 2018; Valente et al., 2019). Worldwide, 6 million people are suffering from non-healing wounds (85% of aged persons) resulting in enormous healthcare expenditures (Paladini and Pollini, 2019). The recovery period of a wound might take a few days in healthy people, which is prolonged in acute, while impaired in chronic wounds (Yadav et al., 2021). The wound healing process includes four phases: hemostasis, inflammation, proliferation and remodeling (Belachew et al., 2020). Several medicinal plants have been proven to increase the renewal rate of damaged tissues in vivo, in vitro and in excisional and incisional experimental models such as Nepeta dschuparensis, Chamaecostus cuspidatus, Nigella sativa, Aristolochia saccate and others (Bolla et al., 2019; Low et al., 2021; Naeimi et al., 2020; Ponnanikajamideen et al., 2019; Sallehuddin et al., 2020).
       
We have chosen one of the commonly used medicinal plants that are cultivated in KSA and used in numerous therapies, Lavandula dentata. Saudi Arabia has a diverse flora comprising different species that include numerous medicinal plants due to its vast area of diverse geographical landscapes and climates. Therefore, ethnomedical native plants are traditionally used in KSA for therapy, including wound healing Aati et al., (2019). According to Fig 3 (A-E), several parameters are measured to determine the wound-healing potential of LE methanolic extract (a quarter of IC50=24.24 mg/mL) at 0, 24h, 48h, 72h and 96 interval time. We have chosen ¼ of IC50 as a safe dose for LE treatment to prevent cell death (HSF cells) at higher doses. We have determined that LE decreased wound width (Fig 4A) and wound area (Fig 4B) in a time-dependent manner (0, 24h, 48h, 72h and 96h) in comparison to negative control. In addition, LE (24.24 mg/mL) decreased the mean cell migratory rate of wound border cells during scratch closure (Fig 4C) and increased the wound closure % (Fig 4D). However, for all parameters of the wound healing assay, there is a non-significant difference between LE treatment and the negative control group at different interval times. This could be returned to the selected very low dose of LE treatment for skin fibroblast cells. From a long time ago until now, different plants have been used in wound healing as a traditional medicine in KSA regions such as leaves and whole plant of Blepharons ciliaris L., leaves of Ecbolium gymnostachyum, leaves of Hypoestes forsskalii, whole plant of Euryops arabicus Steud (Al-Sodany et al., 2013), Adenium arabicum Balf, leaves of Centaurothamnus maximus, leaves of Verbesina encelioides, leaves and seeds of Diplotaxis acris (Forssk) Boiss (El-Shabasy, 2016), fruits of Tamarindus indica L. (Aly et al., 2022) and others (Aati et al., 2019).
 

Fig 3: Representative images from in vitro scratch wound healing assays for HSF cells treated by LE at 0 (A), 24h (B), 48h (C), 72h (D) and 96 (E) interval time.


 

Fig 4: Graph showing wound width (A) and wound area (B) in the presence of LE (24.24 ìg/mL) at different interval times (0, 24h, 48h, 72h and 96h) in comparison to control. Bar graph illustrating the mean cell migratory rate of wound border cells during scratch closure (C) and wound closure % at indicated time points (D) during the scratch wound assay.


 
Leaves and flowers of Lavandula dentata L. have been used for headache, relieve rheumatic pain and cold (Al-Sodany et al., 2013) but in our peer knowledge, it is the first time to assess the wound healing potential of Lavandula dentata cultivated in KSA. It was reported that L. dentata extracts consist of many compounds, but the major constituents are linalool, camphor and borneol which belong to oxygenated monoterpenes, b-farnesene which belongs to Sesquiterpene hydrocarbons and 1,8 cineole. It was reported that the concentration of LE constituents differs from one cultivated region to another such as in eastern Morocco (Imelouane et al., 2009), Moroccan middle Atlas (Soro et al., 2014), Brazil (Justus et al., 2018) and Italy (Giuliani et al., 2020). The chemical composition of LE varied depending on the mplant part (roots, leaves and flowers) from which it was extracted, geographical origins, seasonal changes, harvest time, genetic variability and growth conditions (Bouyahya et al., 2023). Natural compounds present in medicinal plants can accelerate the wound healing process by promoting epithelization (Farzaei et al., 2015), increasing vasculogenesis and angiogenesis (Caban and Lewandowska, 2021) and modulating the inflammatory cytokines (Hu et al., 2011) and finally enhancing wound contraction rates (Yin et al., 2015).
 
Antimicrobial potential of LE
 
 Four different bacterial strains were selected because they are common in wound infections: E. coli, S. aureus, P. aeruginosa and S. pyogenes (Puca et al., 2021). Antimicrobial resistance is considered a top ten threat to global health according to the World Health Organization (WHO, 2019). This resistance returns to the inappropriate use of antimicrobial drugs in humans and the unpleasant appearance of multi-drug resistant strains, which represents a public health concern. The WHO report indicates high annual deaths due to multi-drug resistant pathogens in Europe (25,000 deaths/year) and the United States (23,000 deaths/year). In addition, about 50% of infections are associated with K. pneumoniae, E. coli, S. aureus and P. aeruginosa (Pallavali et al., 2017; WHO, 2014). Therefore, the present study has been established for the antimicrobial assessment of the methanolic extract of LE.
       
Fig 5 and Table 1 show the antibacterial potential of LE against aerobic bacterial strains that infect wounds: Gram-negative (E. coli and P. aeruginosa) and Gram-positive (S. aureus and S. pyogenes). Table 1 shows that LE has a higher antimicrobial effect against all four strains at MIC and MBC> 3.0 mg/mL, except for Streptococcus pyogenes MIC= 3.0 mg/mL. However, ciprofloxacin has a higher antimicrobial effect at MIC<0.005 mg/mL. In agreement with our results, El-Said et al., (2021) in Saudi Arabia tested essential oil extracted from flowering aerial parts of L. pubescens against 13 strains of Gram-negative and Gram-positive bacteria using the agar diffusion assay. Their results revealed that LE had antimicrobial potential, but Gram-negative strains were more susceptible than Gram-positive ones. In addition, Hossain et al., (2017) tested the flowering part of L. angustifolia in Bulgaria against various pathogenic bacteria isolated from pet turtles belonging to seven species: Aeromonas hydrophila, Aeromonas caviae, Citrobacter freundii, Proteus mirabilis, Salmonella enterica, Aeromonas dhakensis and Ps. aeruginosa. Their results reported the LE antibacterial effect against all tested strains except Ps. aeruginosa.
 

Fig 5: Lavender leaf extract potential against E. coli (upper half of plates A,B), S. aureus (lower half of plates A,B), P. aeruginosa (upper half of plates C,D) and S. pyogenes (lower half of plates C,D).


 

Table 1: Minimum inhibitory concentration (MIC) and minimum bactericidal concentrations (MBC) of lavender leaf extract (LE).


       
The major chemical constituents of the LE (linalool, linalyl acetate and terpinen-4-ol) are responsible for the antimicrobial effect. These components damage the lipid layer of the cell membrane, which results in bacterial cell leakage and death (De Rapper et al., 2016). Recently, it has been reported that lavender essential oil induces oxidative stress on bacterial cells, disrupts their membrane and then dies through proteomic and genomic analyses (Yang et al., 2020, Yang et al., 2021). Further study is needed to report the specific mode of action of LE against bacterial strains.

CONCLUSIONS

The methanolic extract of L. dentata is safe for skin treatment, with low cytotoxic effects on skin fibroblast cells. It has potential in wound healing and as an antimicrobial agent, but further studies are needed to determine the optimal concentrations and the exact mechanism of action. Additional research is required to assess how the extract’s major constituents vary across different geographical regions.

ACKNOWLEDGEMENT

The authors extend their appreciation to Taif University, Saudi Arabia, for supporting this work through project number (TU-DSPP-2024-283).
 
Author contributions
 
The authors contributed to the practical part, writing the original draft, editing and accepting the final version of this article.
 
Funding
 
This research was funded by Taif University, Taif, Saudi Arabia (TU-DSPP-2024-283).

CONFLICT OF INTEREST

The authors declare no conflict of interest.

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