Research Article

Anti-Inflammatory and Analgesic Potential of Hot Water Extracts of Mulberry Leaves

Aamir Ali, Hafiz Muhammad Tahir*, Azizullah, Shaukat Ali, Muhammad Summer, Ali Haidar Gormani, Saira Nawaz and Ayesha Muzamil

Department of Zoology, Government College University, Lahore.

Received | January 09, 2022; Accepted | March 24, 2023; Published | May 22, 2023

*Correspondence | Hafiz Muhammad Tahir, Department of Zoology, Government College University, Lahore; Email: [email protected]

Citation |Ali, A., Tahir, H.M., Azizullah, Ali, S., Summer, M., Gormani, A.H., Nawaz, S. and Muzammil, A., 2023. Anti-inflammatory and analgesic potential of hot water extracts of mulberry leaves. Journal of Innovative Sciences, 9(1): 120-131.

DOI | https://dx.doi.org/10.17582/journal.jis/2023/9.1.120.131

Keywords | Mulberry, Inflammation, Plant extract, Mice, Hot water extract

Copyright: 2023 by the authors. Licensee ResearchersLinks Ltd, England, UK.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

1. Introduction

Inflammation is a complex and dynamic response that can be defined by heat (hyperemia), redness (erythema), swelling (exudation), pain and loss of function (Placha and Jampilek, 2021; Pei et al., 2023). It is of two basic types: Acute that starts rapidly, becomes severe in a short time and chronic inflammation that is slow and cause many chronic diseases (Ginwala et al., 2019). Inflammatory processes are initiated by cell injury, infection (microbial) and trauma or toxins (Deshpande and Zou, 2020). Oxidative stress can also lead to inflammation (Hu et al., 2020).

Inflammation is a common feature in most of the modern human diseases (Kotas and Medzhitov, 2015). Due to the enormous shift in the disease spectrum over the previous century, the World Health Organization (WHO) catalogued inflammatory disorders as the highest risk to human wellbeing (Kotas and Medzhitov, 2015; Logie and Vanden, 2020). Furthermore, most of the age-related diseases share an inflammatory pathogenesis (Franceschi and Campisi, 2014).

Inflammatory processes cause immune cells to release different molecules that sensitize nociceptor sensory neurons and induce pain and swelling (Pinho-Ribeiro et al., 2017). Leukocytes, particularly neutrophils are responsible for the initiation and maintenance of inflammation and the leukocytes that have infiltrated tissues continuously produce reactive chemicals that harm the structural and cellular components of tissues (Goldring et al., 2011; Franceschi and Campisi, 2014). Damaged cells and activated immune cells produce cytokines that alter the normal tissue function and phenotypes of nearby cells (Franceschi and Campisi, 2014). Tumor necrosis factor (TNF) and interleukins (IL-1, IL-6, and IL-12) produced by helper T cells and macrophages function as pro-inflammatory cytokines and blocking of either TNF or IL-1 or both leads to reduction in inflammation (Boleto et al., 2020; Rezagholizadeh et al., 2022; Shafeghat et al., 2022).

Currently non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to cure inflammation, but they also have a greater risk of heart attack, renal disease, and stomach ulcers and bleeding (Fanelli et al., 2013). Plant products are gaining popularity as natural remedies for the cure of different ailments including inflammation (Salehi et al., 2019, 2020; ; ). Plants are a rich source of medically important phytochemicals such as polyphenols, flavonols etc. (; ).

Due to the higher therapeutic potential, low risk of side effects, availability, and connection to cultural practices, the herbal remedies are favored (Shah et al., 2018; Erarslan and Kültür, 2019; Süntar, 2020; Okaiyeto and Oguntibeju, 2021).

Moraceae family of flowering plants is ecologically important having 38 genera and 1500 species (Christenhusz and Byng, 2016; de Sousa et al., 2016). Genus Morus of this family includes 24 species and widely distributed across Asia, Europe, America, and several areas of Africa (Ionica et al., 2017). Plants of this genus can be grown under cultivation and contain some medically important species, particularly red mulberry (M. rubra), white mulberry (M. alba) and black mulberry (M. nigra) (Sarkhel et al., 2020; Jan et al., 2021).

In Asia, various mulberry plant parts, including the fruits, leaves and root bark have often been used as traditional medicines to cure a variety of human health impairments (Yuan and Zhao, 2017). Mulberry leaves are palatable, low cost and valuable materials that are used for raring silkworm (Bombyx mori) and as feed for dairy animals (Rohela et al., 2020; Jaiswal et al., 2021). Different mulberry leaves-derived products such as ice-cream and tea are now commercially available (Thaipitakwong et al., 2018). These leaves are also used for reducing the risks associated with cardiovascular system, nervous system and obesity (Ignat et al., 2021; Weng et al., 2021). Mulberry leaves extracts have anti-inflammatory, anti-hyperglycemic and antimicrobial activity in addition to lowering the blood lipids in mild hyperlipidemic patients (Sharma et al., 2020; Hao et al., 2022; Zhang et al., 2022). Mulberry leaf hot water extracts and methanolic extracts prevent oxidative damage and reduce the level of inflammatory cytokines (Hameed et al., 2020; Boro et al., 2021).

M. alba and M. nigra are originated in China and Iran respectively but frequently farmed widely in subtropical and tropical areas of the world (Aljane et al., 2016; Luo et al., 2019). Different mulberry species especially Morus nigra, M. alba, M. laevigata and M. macroura are present in Pakistan and their leaves are extensively used for silkworm rearing (Mutebi, 2022). The aim of the current study was to assess the nociceptive and anti-inflammatory properties of a hot water extract of M. nigra and M. alba leaves against carrageenan induced inflammation and formalin induced pain by using Swiss albino mice as model animal.

2. Materials and Methods

2.1 Plant material

The leaves of the two mulberry species Morus nigra and M. alba were obtained from Government College University Lahore Botanical Garden (31° 33’ 24.102’’ N and 74° 19’ 40.8432’’ E). Leaves were rinsed with tap water and shade dried for 3 days at 30°C. Dried leaves of both plant species were ground to fine powder and kept in a hermetic seal separately until further use (Katsube et al., 2009).

2.2 Preparation of extract

Mulberry powder (10g) was added to 100ml of distilled water and solution was heated on hot plate at 40°C for 20 minutes. Further extraction was done by mixing the solution in Flask Shaker for 24 hours at room temperature. The Whatmann’s filter paper (9cm Diameter and 11µm Particle retention) was used to filter the extract and filtrate containing soluble constituents was obtained (Arabshahi-Delouee and Urooj, 2007). Extracts were mixed with distilled water to prepare the required dose of 200mg/kg, 100mg/kg and 50mg/kg.

2.3 Model animal

Mus musculus (Swiss albino mice) with an average weight of 25-30gm were chosen as model animal. Mice were bought from Veterinary Research Institute Lahore, Pakistan. They were kept in standard-sized boxes (28” x 18” x 18”) with regulated climatic conditions, such as 26 to 30 ºC temperature range, humidity range of 40 to 50%, and a 12-hour cycle of light and dark alternatively. All the animals were given a regular diet. Saw dust was utilised as bedding which was changed on daily basis. The experiment was performed at Animal House of Government College University Lahore after ethical approval from Institutional Bioethics Committee of GC University, Lahore (No. GCU-IIB-450) (Bayliak et al., 2021).

2.4 Evaluation of anti-inflammatory potential

Carrageenan solution (1%) was freshly prepared before the experiment. Animals were starved for 2 hours and divided into eight groups with five animals each. Treatment doses were given orally to animals of each group with help of oral gavage. Positive and negative control groups were treated orally with indomethacin (5mg/kg) and water respectively. Out of six treatment groups, three were treated with 200mg/kg, 100mg/kg and 50mg/kg of M. alba leaves hot water extract mixed in dH2O and remaining three groups with hot water extracts of M. nigra leaves. After 1 hour of treatment dose 50µl of 1% carrageenan in 0.9% saline solution was injected to left hind tibio-tarsal joint of all animals. The diameter of ankle joints was utilized to assess the level of inflammation (Winter et al., 1962). Paw circumference was assessed by cotton thread at 0, 1, 2, 3, 4, 5 and 6 hours post carrageenan injection to assess the inflammation or paw edema (Akindele and Adeyemi, 2007; Gupta et al., 2015).

2.5 Effect on leukocytes and complete blood count

After 6 hours of carrageenan injection the blood was drawn directly by a cardiac puncture and stored in EDTA. K3 vacuum tubes at 4°C for 2 hours. Complete blood count was performed in auto blood analyzer.

2.6 Histopathology of Paw

Animals were sacrificed at 6 hours post treatment and to assess histopathological changes their paws were taken precisely. Paw samples were decalcified after being washed with 10% Formalin. Furthermore, tissues were fixed in paraffin and cut into thin pieces. Hematoxylin-Eosin (HE) stain was used to determine the level of inflammation in these thin sections.

2.7 Analgesic activity

A day before experiment, each animal was habituated for an hour in the observation chamber. Experimental design was similar as mentioned in anti-inflammatory assay except positive and negative control groups that were treated orally with Diclofenac sodium (10mg/kg) and water respectively. Formalin induced method of nociception is used to access analgesic activity (Hunskaar and Hole, 1987). After 30 minutes of oral dose, 20 µl (10ml/kg) of 1% formalin prepared in normal saline was injected subcutaneously into the planter tissue of dorsal hind paw of the mice with a 26-gauge needle. Individual animal was then put back into the chamber and licking response time was measured with stop watch for 30 min.

Intensive licking activity was divided in two distinct periods and both periods were scored separately. The first period for 0-5 minutes and the second period for almost 15-30 minutes after the injection of formalin. Acute pain in first period is non-inflammatory and due to the direct activation of nociceptors by formalin, while pain in second period is inflammatory and appears due to the combination of inflammatory reactions in tissue (Warren, 1990).

2.8 Statistical analyses

Results were observed as decrease in licking time and increase in paw edema. Results of both anti-inflammatory and analgesic activity were computed by using one way ANOVA followed by Tukey’s test to assess the differences between treatment groups and negative control. P ˂ 0.05 was considered as significant value.

3. Results and Discussion

3.1 Formalin induced nociception

Formalin injection in paw tissues resulted in severe pain and paw licking activity immediately after the administration. Licking response was severe during first 5 minutes and then decreased afterwards. There was a latency period of almost 10 minutes when animals did not show nociception responses. After the latency period, animals again showed licking response from 15-30 minutes post formalin injection. Mulberry leaves extracts of M. alba and M. nigra (200mg/kg, 100mg/kg and 50mg/kg) caused non-significant (P>0.05) decrease in licking and biting activity of mice in the first phase of acute pain (0-5 minutes) as compared to negative control (Figure 1A). In second phase of nociceptive activity (15-30 minutes) there was significant (P<0.05) reduction of licking response in treated groups as compared to negative control. However, Diclofenac Sodium showed highest anti-nociception activity in second phases (Figure 1B).

 

 

3.2 Anti-inflammatory activity

The injection of carrageenan into planter tissues of tibio-tarsal joints of mice paw resulted in immediate swelling of paw. The paw circumference increased gradually with time and was the highest in all groups at 4th hour of post carrageenan injection (Table 2). Mice of negative control showed highest increase in paw width (3.14mm ± 0.148) while positive control (Indomethacin) showed lowest increase (2.2mm ± 0.119) at 4th hour post treatment. Just after the carrageenan injection (0 hour), there were non-significant differences of paw width among all groups (F7, 32= 0.409; P>0.05). However, there were statistically significant differences (P<0.01) in paw width of all treatment groups against negative control at 1st (F7, 32= 0.409), 2nd (F7, 32= 2.464), 3rd (F7, 32= 4.071), 4th (F7, 32= 3.597), 5th (F7, 32= 5.087) and 6th (F7, 32= 0.409) hours, post carrageenan injection. However, there were non-significant differences (P>0.05) among Indomethacin and mulberry extracts treated groups.

3.3 Histological results

The histological sections of paw edema tissues after the carrageenan injection were observed and the results of histological changes including different inflammatory markers are shown in Figure 2. High tissue damage was observed in negative control as compared to treatment groups. The level of swelling and collection of fluid was also high in negative control. Moreover, there was accumulation of infiltrating cells, especially polymorphonuclear leukocytes (PMNs) in intercellular spaces. While the treatment groups showed less damage and swelling. The number of infiltrating cells was reduced as well as the intercellular spaces. Infiltrating cells were only confined to spaces near to vascular areas. Indomethacin, a standard drug had shown similar results to treatment groups.

3.4 Hematology

Results of the hematological studies (Table 1) showed that the total number of leukocytes, platelets, RBCs, lymphocytes and neutrophils in blood of negative control group mice were significantly lower than mulberry treated and positive control groups (F7, 23= 13.026; P<0.01; F7, 23= 18.86; P>0.05; F7, 23= 17.92; P<0.01; F7, 23= 3.47; P<0.05; F7, 23= 9.19; P<0.01). However, there were non-significant differences in level of monocytes (F7, 23= 1.49; P>0.05) and eosinophils (F7, 23= 1.25; P>0.05) in the mice of all experimental groups (P>0.05). The total number of leukocytes, lymphocytes and platelets did not differ significantly

 

Table 1: Effect of mulberry leaves extracts on different blood parameters of mice injected with carrageenan solution.

Treatments	RBCs (1x106/µl)	TLC (1x103/µl)	Lymphocytes (1x103/µl)	Neutrophils (1x103/µl)	Monocytes (1x103/µl)	Eosinophils (1x103/µl)	Platelet count (1x108/µl)
Negative Control	6.4a ± 0.11	4.56a ± 0.2	3.48a ± 0.08	1.72a ± 0.04	0.056a ± 0.004	0.059a ± 0.004	961.53a ± 11.32
Indomethacin	8.8c ± 0.08	6.38b ± 0.16	4.92b ± 0.07	2.60b ± 0.1	0.092a ± 0.004	0.096a ± 0.003	1219 b ± 12.97
M. alba (200mg/kg)	8.37bc ± 0.2	6.07b ± 0.1	4.01ab ± 0.12	2.24a ± 0.09	0.072a ± 0.01	0.076a ± 0.01	1181.33 b ±12.74
M. alba (100mg/kg)	7.92b ± 0.1	5.95b ± 0.08	3.88ab ± 0.11	2.12a ± 0.12	0.069a ± 0.005	0.071a ± 0.004	1154.22b ± 14.21
M. alba (50mg/kg)	7.81b ± 0.17	5.72b ± 0.09	3.76ab ± 0.13	2.06a ± 0.13	0.067a ± 0.007	0.069a ± 0.007	1143b ± 20.7
M. nigra (200mg/kg)	8.46bc ± 0.12	6.1b ± 0.11	4.07ab ± 0.13	2.15a ± 0.1	0.072a ± 0.007	0.075a ± 0.009	1189.67b ± 11.77
M. nigra (100mg/kg)	8.13bc ± 0.12	6.03b ± 0.1	3.97ab ± 0.11	2.04a ± 0.12	0.071a ± 0.01	0.072a ± 0.009	1161.67b ± 17.19
M. nigra (50mg/kg)	7.97bc ± 0.12	5.84b ± 0.09	3.83ab ± 0.13	2.01a ± 0.12	0.068a ± 0.008	0.069a ± 0.01	1153b ± 14.43

 

Note: Data shows Mean ± SE; Similar superscripts on each value within a column show non-significant differences, while different superscripts show significant differences.

 

Table 2: Effect of mulberry leaves extracts on paw edema or increase in paw circumference of mice in control and treatment groups.

Groups	Increase in paw circumference
	0 h	1 h	2 h	3 h	4 h	5 h	6h
Negative Control	4.56a ± 0.186	2.32a ± 0.130	2.46a ± 0.128	2.89a ± 0.154	3.14a ± 0.148	2.53a ± 0.138	2.18a ± 0.112
Indomethacin	4.1a ± 0.159	1.47b ± 0.184	1.59b ± 0.175	1.86b ± 0.107	2.2b ± 0.119	1.42b ± 0.163	0.79b ± 0.074
M. alba (200mg/kg)	4.31a ± 0.152	1.59ab ± 0.172	1.9ab ± 0.178	2.05b ± 0.148	2.31b ± 0.144	1.55b ± 0.127	0.83b ± 0.081
M. alba (100mg/kg)	4.36a ± 0.177	1.6ab ± 0.162	1.72ab ± 0.165	2.14b ± 0.155	2.36b ± 0.148	1.57b ± 0.131	0.85b ± 0.087
M. alba (50mg/kg)	4.38a ± 0.197	1.63ab ± 0.176	1.8ab ± 0.172	2.28ab ± 0.157	2.35b ± 0.120	1.75b ± 0.113	0.87b ± 0.077
M. nigra (200mg/kg)	4.29a ± 0.195	1.51b ± 0.151	1.64b ± 0.149	1.96b ± 0.149	2.27b ± 0.171	1.53b ± 0.166	0.81b ± 0.091
M. nigra (100mg/kg)	4.34a ± 0.128	1.57ab ± 0.088	1.68ab ± 0.095	2.11b ± 0.097	2.34b ± 0.084	1.56b ± 0.110	0.82b ± 0.058
M. nigra (50mg/kg)	4.38a ± 0.213	1.6ab ± 0.157	1.82ab ± 0.174	2.02b ± 0.150	2.35b ± 0.167	1.6b ± 0.157	0.86b ± 0.068

 

Note: Data shows Mean ± SE; Similar superscripts on each value within a column show non-significant differences, while different superscripts show significant differences.

 

(P>0.05) among mulberry treated groups and positive control group. While there were non-significant differences (P>0.05) in the level of neutrophils among mulberry treated groups and negative control. The number of RBCs was significantly lower in mice treated with lower concentrations of M. alba leaves extract (100mg/kg and 50mg/kg) as compared to mice treated with mulberry leaves extracts of M. nigra and positive control group.

The anti-inflammatory potentials of mulberry leaves were investigated by using carrageenan induced mice paw edema as it is considered the most suitable inflammatory model to evaluate various anti-inflammatory products (Pathak et al., 2020; Nigussie et al., 2021). Carrageenan induced inflammatory response is non-specific and biphasic, characterized on the basis of mediator release (Meacock and Kitchen, 1976; Hvattum and Ekeberg, 2003). Serotonin and histamine are released in the first phase and cause increase in vascular permeability, kinins in second phase while various pro-inflammatory mediators including prostaglandins, TNF-α and different cytokines in third phase (Sriramula, 2020; Zhang and Kurashima, 2021; Mo et al., 2022). Anti-inflammatory effects of various extracts of mulberry leaves had already been reported (Souza et al., 2018). However, these extracts were prepared in toxic solvents like methanol and ethanol that further require complete separations.

Results of our study showed that the hot water extracts of mulberry leaves have suppressive effects on carrageenan induced edema. Chung et al. (2003) had also reported similar effects. In the present study the inhibition was mild in first four hours of post carrageenan injection, but more intense at 5th hour and onward, as suggested by Aouey et al. (2016). The decrease in edema during the first phase could be due to inhibition of histamine and serotonin as well as neutrophil migration (Channa et al., 2006; Patil et al., 2019). While the possible mechanism for the intense late inhibition in our study could be due to inhibition of cyclooxygenases (involved in prostaglandin synthesis), cytokines and other pro-inflammatory mediators (Channa et al., 2006; Babu et al., 2009). Anti-histaminic effect may be related to inhibition of degranulation of mast cells (Barbosa et al., 2009; Vanderlei et al., 2011). While Sadeghi (2013) reported that the reduction in pro-inflammatory mediators is due to decreased influx of inflammatory cells like neutrophils. Moreover, the effectiveness of M. nigra and M. alba leaves extracts against inflammation was similar to Indomethacin, a standard anti-inflammatory drug.

The TLC was decreased in mice injected with carrageenan solution. It may be due to migration of leukocytes towards the inflammatory sites, causing the decreased leukocyte count in peripheral blood (Eric and Dick, 1996; Patil and Suryavanshi, 2007). In our study the mice treated with mulberry leaves extracts and Indomethacin showed higher TLC. Vaisbuch et al. (2002) reported that anti-inflammatory drugs like Betamethasone lower the clearance of leukocytes from peripheral blood and increase their production and release from bone marrow. The mulberry leaves extracts in our study showed increased TLC level. Chen et al. (2013) reported that oxyresveratrol present in mulberry leaves inhibits leukocyte migration and suppress inflammation. On the contrary it had been reported that some anti-inflammatory substances i.e., plant extracts cause the decrease in TLC (Rached et al., 2010; Al-Sadoon et al., 2012; John and Shobana, 2012).

RBCs level of untreated mice in our study was low as inflammation causes clearance of RBCs. According to Straat (2012) the possible mechanisms involved could be phagocytosis and increased adherence of RBCs to endothelial walls. In our study the mice treated with mulberry leaves extracts showed comparatively high levels of RBCs. The exact possible mechanisms responsible for this effect are unknown. While the platelet level of mice in our study increased significantly in mulberry leaves extract treated groups. However, Henriques (1987) reported the great increase in circulating platelets after 48 hours of carrageenan injection. Histopathological observations of mice paw tissue showed that the carrageenan induced various histological alterations such as swelling and influx of inflammatory cells (Ma et al., 2013). Paw tissues of treated mice exhibited reduced histological alterations. According to Sadeghi (2013) the reduction in histological alterations is due to the inhibition of vascular permeability and pro-inflammatory mediators production.

In present study the formalin induced licking response in mice was used to evaluate the analgesic effect of mulberry leaves extracts as previous studies have suggested that this model has the ability to differentiate between peripheral and central analgesic mechanism (Bouaziz et al., 2005). Formalin 1% solution was used for induction of pain because lower concentrations did not induce biphasic pain (Rosland et al., 1990; Hasriadi et al., 2022). Pain during the first phase is due to peripheral inflammatory response and central sensitization of pain stimuli; while histamine, serotonin, bradykinin and prostaglandins are involved in pain of second phase (Dou et al., 2021; Miranda et al., 2022). It had been reported that the flavonoids, 1-Deoxynojirimycin (DNJ) and phenols present in mulberry leaves are responsible for their functional properties (Thaipitakwong et al., 2018; Eruygur and Dural, 2019).

In our study the hot water extracts of M. alba and M. nigra leaves did not show significant analgesic effects during the first phase of acute pain. However, all the doses of hot water extracts of both mulberry species as well as Diclofenac Sodium showed significant analgesic response during second phase of pain. Parr and Bolwell (2000) reported the NSAIDs are also not effective to reduce pain in the first phase but significantly reduce the pain during second phase. Mohammadifar et al. (2016) reported that alcoholic extract of M. alba leaves showed analgesic effect in both first and second phase of pain. Analgesic potential of other mulberry leaves extracts like ethanol had also been reported (Chauhan et al., 2015). According to Denny (2013) the flavonoids and phenols of mulberry leaves could be responsible for analgesic potentials. The exact mechanisms are still needs to be identified. It has been reported that the possible mechanism involved could be dual inhibition of arachidonic acid pathway and inhibition of prostaglandin synthesis (Duarte et al., 1988; Ferdous et al., 2008). The analgesic activity of mulberry leaves extracts was not as strong as Diclofenac Sodium, a standard analgesic drug. It is concluded that the crude extract of leaves of M. alba and M. nigra possess anti-inflammatory and analgesic potentials. However, further mechanistic studies are required in this regard to find exact constituents and their mechanisms responsible for these potentials.

Conclusions and Recommendations

It is concluded that the crude extract of leaves of M. alba and M. nigra possess anti-inflammatory and analgesic potentials. However, further mechanistic studies are recommended in this regard to find exact constituents and their potential mechanisms responsible for these results.

Acknowledgement

We acknowledge Prof. Dr. Hafiz Muhammad Tahir (Department of Zoology, Government College University Lahore) for his supervision as well as for his assistance in reviewing the manuscript for English language and grammar correction. We are also thankful to Dr. Azizullah and Dr. Shaukat Ali (Department of Zoology, Government College University Lahore) for providing us assistance during experimental trial.

Novelty Statement

The Hot Water Extract of Mulberry Leaves (Mulberry Tea) has the potential to reduce inflammation.

Author’s Contribution

Aamir Ali: Designed the study, executed the experimentation.

Hafiz Muhammad Tahir and Azizullah: Designed and supervised the study.

Shaukat Ali and Muhammad Summer: Analyzed the data and wrote the manuscript.

Ali Haidar Gormani and Saira Nawaz: Edited the manuscript.

Ayesha Muzamil: Analyzed the data and wrote the manuscript.

Conflict of interest

The authors have declared no conflict of interest.

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