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ANTI-INFLAMMATORY ROLE OF PEPTIDES ISOLATED FROM VENOM OF ANDROCTONUS FINITIMUS (POCOCK, 1897) (SCORPIONES: BUTHIDAE).

Byline: R. Yaqoob, H. M. Tahir, A. Rasheed, M. M. Ahsan and M. Arshad

Keywords: inflammation, peptides, venom, scorpions, Androctonus finitimus, cytokines.

INTRODUCTION

Scorpion's venom has drawn much attraction of medical researchers because of its toxic properties. During the 400 million years of evolution, scorpion has developed a complex mixture of mucoproteins, various biochemically active water soluble enzymes, enzyme inhibitors, amines, histamine, lipids, glucose-aminoglycanes, small peptides and various salts in their venom (Zlotkin et al., 1978; Gwee et al., 2002; Nisani et al., 2007; Adiguzel, 2010; Gomes et al., 2010). Though venoms are inducers of many patho-physiological effects but their modified use turn them into healer of several pathologies. Researchers are trying to intricate pathophysiological effects of venom to discover some logical application of venom toxin for developing therapeutically potent agents. Scorpion venom contain bioactive peptides with variety of therapeutic applications (Chen and Ji, 2002; Garcia et al., 2003; Fiske et al., 2006; Gomez-Varela et al., 2007; Zhao et al., 2008; Pillozzi et al., 2009; Cheong et al., 2010).

Many scientists have reported cytotoxic and anti-inflammatory potentials of scorpion venom and its components (Salarian et al., 2012), which may be helpful in the treatment of cancers of numerous types (Incesu et al., 2005; Zhang et al., 2009; Di-Lorenzo et al., 2012; Joseph and George, 2012). Some peptides from scorpion venom are immunosuppressive agents (Chen and Chung, 2012). Anti-inflammatory effects of venom from Heterometrus laoticus and Androctonus bicolor have also been reported (Ayed et al., 2013; Hoang et al., 2014).

After scorpion envenomation a cascade of inflammatory responses occurs immediately (Fabiano et al., 2008), including initiation of antibodies production against venom antigens and induction of a wide variety of cytokines and other mediators of inflammation by T lymphocytes (Mosmann et al., 2005). Hence, cytokines are the direct mediators of inflammatory process (Romgnani, 1994). The cytokines are of two types i.e., pro-inflammatory and anti-inflammatory. Production of both type of cytokines have been reported in severe scorpion envenomation cases (Petricevich, 2004). However, this process is slightly biased towards production of anti-inflammatory cytokines (Petricevich, 2006). Anti-inflammatory cytokines such as IL-4, IL-10, IL-5 and IL-6 down regulates hyperactive inflammatory process (Bone, 1996; Fisher and Zheng, 1996). Secretion of IL-4 initiate differentiation of Th cells into Th2 sub-populations which are capable of secreting more IL-4 and IL-10 (Mosmann et al., 2005).

Interleukin-6 plays dual role in an inflammatory response, as it has both pro-and anti-inflammatory effects (Barton, 1997). IL-6, down regulate the production of IL-1 and tumor nacrosis factor-[alpha] (TNF-[alpha]), the pro-inflammatory cytokines, inhibits production of granulocyte-macrophage colony stimulating factor (GM-CSF) and interferon I3 (IFN-I3) (Gay et al., 2006) and also has little role in IL-10 production (Xing et al., 1998). IL-10 is produced by several immune cells (Asadullah et al., 2003), and probably the most important anti-inflammatory cytokine of human immune response. It is the compelling inhibitor of Th1 derived cytokines, including IFN-I3, TNF-[alpha], IL-1[beta], IL-2, IL-6, IL-8, and IL-12 (Asadullah et al., 2003; Mosmann et al., 2005).

It also down regulates other mediators of inflammation such as, prostaglandin as well as macrophage originate production of free oxygen radicals and nitric oxide (Goldman et al., 1996), platelet activating factor and leukotrienes (Bogdan et al., 1991; Malefyt et al., 1991). Increased production of IL-10 is believed to counteract the inflammation process so that hemostasis can be reestablished. Keeping in view of the ample therapeutic applications of scorpion venom present study has been designed. Aim of the study was to evaluate anti-inflammatory potentials of selected low molecular weight fractions of scorpion venom.

MATERIALS AND METHODS

Venom and treatments: Venom was extracted from Androctonus finitimus (Pocock, 1897) by electric stimulation of telson (Ozkan and Filazi, 2004). Crude venom as well as following bioactive protein fractions eluted from crude venom by native-Polyacrylamide gel electrophoresis (Native-PAGE) (Arndt et al., 2012) were used in experiment.

AF1: fraction containing proteins of ~54 kilo Dalton (KDa)

AF2: fraction containing proteins of ~36KDa

AF3: fraction containing proteins of ~8.5KDa

Model animals: Mus musculus (Swiss Webster albino mice) with an average weight of 30-35 grams were used as a model organism. Animals were purchased from National Institute of Health (NIH), Islamabad, Pakistan. Five to seven animals were kept in one cage (24"x12"). Each cage was lined with saw dust as bedding material. Animals were maintained at controlled environmental conditions i.e., light (325 lux), humidity (40-50%), temperature (26-30AdegC) and 12 hours alternating light-dark cycle. All animals were provided with standard food and water.

Determination of median lethal dose (LD50) for mice: Lethal potency of venom was determined by probit analysis method as recommended by World Health Organization (WHO, 1981). Dried crude venom was dissolved in double distilled water to prepare three venom doses i.e., 0.1mg/ml, 0.05mg/ml and 0.02mg/ml. Intravenous injections of treatments were given to mice in tail. Volume of injection was kept constant i.e., 100ul/mice. An equal volume of 5% normal saline was injected to control group. Percent mortality was recorded for 24 hours post injection.

Evaluation of Anti-inflammatory potential of venom: Albino mice were divided into 6 groups of 3 animals each. Paw edema was induced in animals of all groups. To induce edema 50ul of 1% carrageenan in saline solution was injected to left hind tibio-tarsal joint. After 1 hour of injecting cargeenan, Group 2 received Betamethasone (50ul) as standard treatment after induction of paw edema and considered as positive control group. Animals of group 1 were considered as negative control, thus received 50 ul of normal saline only. Different venom fractions and sub lethal dilutions of whole venom were injected to remaining groups as a treatment. Treatment given to each group were as follow:

* Group 1 (Negative control): 50ul of 1% carrageenan + 50ul of normal saline

* Group 2 (Positive control): 50ul of 1% carrageenan + 50ul of Betamethasone

* Group 3: 50 ul of 1% carrageenan + 50 ul of AF1

* Group 4: 50 ul of 1% carrageenan + 50 ul of AF2

* Group 5: 50 ul of 1% carrageenan + 50 ul of AF3

* Group 6: 50 ul of 1% carrageenan + 50 ul of A. finitimus whole venom

Diameter of tibio-tarsal joint of each animal was recorded before the treatment. The swelling of ankle joints (tibio-tarsal) was measured at 1, 2, 4, 6, 12 hour intervals post treatment. After 48 hours, animals were sacrificed and blood was drawn via heart puncture. The blood withdrawn was used for total leukocyte count (TLC) and differential leukocyte count (DLC). Experiment was replicated thrice and results were compared through one way ANOVA by using SPSS 13. Normality of the data was determined by using Kolmogorov-Smirnov test.

Effect of venom on cytokine levels: Blood serum from above described groups was collected and stored at -20AdegC for determination of anti-inflammatory cytokine level. Levels of IL-4, IL-6, IL-10 and IL-13 in mice serum were determined by sandwich-enzyme-linked immuno sorbent assay (ELISA) (Schumacher et al., 1988). Qiagen kit (Mouse Inflammatory Cytokines Multi-Analyte ELISArray Kit: MEM-004A) was used for this purpose. Solutions were prepared according to manufacturer's instruction and after preparation of plates the absorbance was recorded at 450nm. One way analysis of variance (ANOVA) followed by Tukey's test was used to compare the level of cytokines in the treated and control groups.

Table 1. Effect of A. finitimus venom and its protein fractions on different blood parameters of Mice.

Treatments###TLC###Neutrophils(%)###Lymphocytes(%)###Monocytes(%)###Eosinophils(%)

###(10-3/ul)

Negative control###3.33c +- 0.17###60a +- 5.77###23.33ab +- 2.02###2.67a +- 0.67###3b +- 0.57

Positive control###4.75cd +- 0.18###70a +- 2.88###31.33b +- 3.75###2a +- 0.57###1.33ab +- 0.33

ACV###1.53a +- 0.17###54.66a +- 5.17###14.66a +- 1.45###1.33a +- 0.33###1.67ab +- 0.33

AF1###5.1d +- 0.17###63a +- 1.73###26.33ab +- 2.33###3a +- 0.57###1.67ab +- 0.33

AF2###2.4b +- 0.21###66.66a +- 1.45###34b +- 3.21###3a +- 0.57###1a +- 0

AF3###7.1e +- 0.17###94b +- 2.3###27b +- 1.15###3a +- 0.57###1.33ab +- 0.33

F 5,12###131.89###14.42###7.34###1.52###3.77

P###<0.05###<0.05###0.002###0.256###0.028

Table 2. Dynamics of Anti-inflammatory cytokines in serum of mice injected with whole venom and various ve nom fractions of A. finitimus.

Treatments###IL-4###IL-6###IL-10###IL-13

Negative control###0.216b +- 0.011###0.219c +- 0.002###0.245a +- 0.002###0.216a +- 0.028

Positive control###0.276e +- 0.009###0.24e +- 0.000###0.293c +- 0.002###0.25e +- 0.016

ACV###0.181a +- 0.006###0.231d +- 0.006###0.246a +- 0.020###0.218a +- 0.002

AF1###0.246d +- 0.014###0.212b +- 0.004###0.291c +- 0.004###0.227b +- 0.001

AF2###0.278e +- 0.006###0.201a +- 0.004###0.284b +- 0.003###0.233c +- 0.006

AF3###0.23c +- 0.010###0.25f +- 0.008###0.336d +- 0.008###0.24d +- 0.004

F5,12###607.43###264.46###1420.459###214.46

P###<0.05###<0.05###<0.05###<0.05

RESULTS

Results of Probit analysis showed that median lethal dose of A. finitimus venom was 0.019mg of venom/g of body weight and a dose of 0.031mg/g was sufficient to kill 95% of treated animals. Injection of carrageenan resulted in remarked swelling of tibio-tarsal joints within one hour of injection (Fig. 1). Paw swelling in negative control animals increased progressively up to 3 hours post treatment and then decreased gradually but do not return to normal size even after 12 hours. When effect of venom and its protein fractions on carrageenan induced paw edema was recorded, decline in paw swelling was observed in all treated groups as compared to negative control. Increase in paw diameter was observed in ACV and AF1 treated animal during first hour after treatment which settle down within 4 hour post treatment. Although increase in paw size was more obvious in ACV injected group as compared to AF1 treated group.

Animals treated with AF2 and AF3 protein fractions there is reduced paw swelling during first hour of treatment and recovery in paw size was more apparent in AF2 treated group.

Results of the study showed that injection of A. finitimus venom (ACV) and its protein fractions AF1 significantly affected the total leukocyte count (TLC) in relation to negative control (F5,12 = 131.89; P: <0.05) (Table 1). Highest TLC was recorded in animals which receive protein fraction AF3. On the other hand neutrophil and lymphocyte levels elevated significantly in all venom treated groups except ACV (F5,12 = 14.42; P <0.05 for neutrophils; F5,12 = 7.37; P = 0.002 for lymphocytes). There was no significant difference in monocyte number (F5,12 1.52; P = 0.256) however, eosinophil levels significantly decreased in venom treated animals (F5,12 = 3.77; P = 0.028).

Levels of cytokines in blood serum of mice treated with venom of A. finitimus are depicted in Table (2). Increased concentrations of IL-4 were recorded in all venom treated animals except ACV treated group, as compared to negative control. IL-4 was highest in AF2 treated animals (F5,12=607.43; P<0.05). IL-6 levels were elevated in ACV and AF3 injected groups (F5,12=269.460; P<0.05). Animals in negative control group had lowest IL-10 and IL-13 levels while positive control groups had comparatively high concentrations. IL-10 and IL-13 levels were lower in ACV treated animals while, high in AF3 treated animals amongst all venom fraction treatments (F5,12=1420.459; P<0.05 for IL-10; F5,12=214.460; P<0.05 for IL-13).

DISCUSSION

Inflammation is the body's typical response for the removal of unnecessary material from infested tissue (Mahat and Patil, 2007). Sometimes body encounters extended periods of inflammation that are considered as sign of chronic diseases. To deal such indications use of steroids and non-steroidal anti-inflammatory drugs (NSAID) is a common practice. Use of these chemicals is often associated with many hormonal and gastric complications (Suleyman et al., 2007) as well as liver and kidney malfunctioning (Wellehan and Gunkel 2004). Development of unique anti-inflammatory treatments and preparations is immediately required to resolve the complication associated with these drugs. In the proposed study, potential anti-inflammatory effect of scorpion venom and its protein fractions was investigated.

We observed a profound suppressive effect of protein fractions of venom on carrageenan induced paw edema. Previously, venom of Heterometrus laoticus and Mesobuthus eupeus has been reported to be involved in reducing carrageenan and adjuvant induced paw edema (Ahmadi et al., 2009; Hoang et al., 2014). During inflammation remarkable changes take place including edema, accumulation of white blood cells i.e., neutrophils, macrophages and monocytes and sensation of pain and fever (Gallin, 1989). Carrageenan induced paw edema is thought to be most suitable test for various investigations regarding evaluation of anti-inflammatory products because carrageenan is a strong inducer of various inflammatory and pro inflammatory mediators such as interleukins, leukotriene, histamine, bradykinins, etc. (Wills, 1960; D-Armour et al., 1965).

In the present study, decrease in the TLC was observed in crude venom treated animals compared to negative control. In case of inflammation, leukocytes migrate towards inflamed tissue. This may cause low levels of leukocytes in peripheral blood which in turn trigger the production of more WBCs under the influence of IL-1[beta]. IL-1[beta] induces the production of neutrophils (Eric and Lawrance, 1996; Kalpana et al., 2007). Decrease in leukocytes levels was reported by Jhon and Shobana, (2012) while evaluating potential anti-inflammatory role of some organic products by Rached et al. (2010) working on anti-inflammatory activity of bee venom and Al-Sadoon et al. (2012) who observed decline in WBCs during 24 post injection hours of snake venom (Walterennesia aegyptia).

A transient increase in TLC was recorded in positive control group. Similar results were observed by Ahmadi et al. (2009) while working on venom of M. eupeus. In our experiment, increase in leukocyte level was observed in animals injected with F1 and F2 protein fractions. This increased production of WBC may be due to the enhanced release of leukocyte from bone marrow and reduced clearance from peripheral circulation (Veiseh et al., 2009).

The extent of inflammation is determined by subtle balance in pro-inflammatory and anti-inflammatory cytokines. Anti-inflammatory cytokines down regulate pro-inflammatory cytokines to limit the inflammatory response (Petricevich, 2006). Scorpion venom contains peptides which are found to be associated with elevated levels of such anti-inflammatory cytokines. In our experiments we observed prominent increase in IL-4 levels in response to various venom protein fractions. According to another study an immediate increase in serum cytokine concentrations of rats treated with Androctonus australis venom was observed during one hour of exposure (Adi-Bessalem et al., 2008). Elevated levels IL-4 were also observed previously in serum of humans, envenomed by Tityus serrulatus (Magalheaes et al., 1999) and in the mice which were experimentally injected with venom and Ts2 fraction from venom of T. serrulatu (Petricevich et al., 2007; Zoccal et al., 2013).

IL-4 is secreted by T cells and found to supp ress various pro-inflammatory cytokines produced by monocytes which may help to quell hyperactive inflammatory process (Heller et al., 2008; Barros et al., 2009). Some studies also reported immunosuppressive effect of IL4 via activation of B and T lymphocytes (Rogler and Andus, 1998). IL-4 imposes an inhibitory effect on neutrophil and monocyte derived IL-8 and TNF (Lee et al., 2002) by inhibiting gene expression and mRNA degradation (Standiford et al., 1990).

IL-6 down regulate production of many pro-inflammatory mediators i.e., IL-1, TNF-[alpha], granulocyte-macrophage colony stimulating factor (GM-CSF) and interferon I3 (IFN-I3) as well as induce production of other anti-inflammatory cytokine i.e., IL-10 (Xing et al., 1998; Gay et al., 2006). IL-10 regulates damage caused by hyperactive immune response (Moore et al., 2001; Bazzoni et al., 2010). IL-10 is also a powerful inhibitor of various pro-inflammatory cytokines (Yokoyama et al., 2004) and known as "human cytokine synthesis inhibitor factor". Many of its target molecules are Th1 lymphocyte derived cytokines i.e., IFN-I3, TNF-[alpha], IL-1[beta], IL-2, IL-6, IL-8, and IL-12 (Asadullah et al., 2003; Mosmann et al., 2005). IL-6 and IL-10 were observed to be over expressed in venom fraction F3 treatment as compared to other fractions. An increase in IL-6 was also observed in rats exposed to M. eupeus venom (Jalali et al., 2015).

In patients envenomed by scorpion venom, a rapid increase in IL-6 was observed (Magalheaes et al., 1999; Petricevich and Pena, 2002; Pessini et al., 2003; Petricevich, 2006; Cruz et al., 2008) i.e., peaks at 15 minute of exposure, followed by return towards normal levels (Fukuhara et al., 2003).

Induced production of IL-10 in mice has also been documented by group of researchers while evaluating activity of A. australis (Adi-Bessalem et al., 2008). Another study suggested that venom of T. serrulatus and its different fractions (Ts2) enhance IL-6 and IL-10 production which may impose anti-inflammatory effect by acting on macrophages in a dose dependent manner. According to them, same fraction was responsible for inhibition of pro-inflammatory cytokines in presence of inflammation inducer (Lipopolyscharide) (Zoccal et al., 2011 and 2013). The increase in IL-10 in response to TsV is much rapid that within 6 hours of venom treatment considerable elevation could be observed (Fialho et al., 2011). Reduced sepsis and lung inflammation was found to be associated with augmented IL-10 that could be helpful in reducing lethality due to sepsis and lung inflammation (Gerard et al., 1993; Van-Der-Poll et al., 1995; Maciel et al., 2014).

IL-13 is another Th2 cell derived anti-inflammatory cytokine. It has the ability to inhibit production of multiple pro-inflammatory cytokines i.e., TNF, IL-1 and IL-8 (Zurawski and De-Vries, 1994) and enhance IL-1 receptor antagonist which is an anti-inflammatory cytokine. IL-13 shares many activities with IL-4 and receptors as well (Malefyt et al., 1993). In present study, we found little increase in IL-13 concentrations in positive control animals. This may be associated with reduction of inflammation. Previously involvement of IL-13 in reduction of NF-kB activation was found in lipopolysaccharide induced inflammation which was associated with decline in lethality (Di-Santo et al., 1997; Mijatovic et al., 1997; Muchamuel et al., 1997). IL-13 was also reported to play anti-inflammatory role in lung inflammation (Mulligan et al., 1997; Lentsch et al., 1999).

Conclusion: In current study, protein fractions extracted from scorpion venom are found to be effective in healing inflammation so, further study to modify them for synthesis of new and cheap drugs for curing edema/inflammation related diseases is recommended. Different fractions act in different manner so use of venom peptides in different combinations yet to be evaluated to get maximum curative effects. Furthermore, sequencing of these separated peptides is required to get better insight of mode of action of those peptides.

Acknowledgements: We acknowledge Higher Education Commission, Pakistan for provision of funds to conduct experimental work as this work is a part of PhD project under award of HEC indigenous scholarship.

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