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Research Article · Volume 5, Issue 1, Pages 47–55, 29 January 2017 · Open Access

Effect of Alcoholic Extract of Salvia officinalis Leaves on some Physiological Parameters Aspects in Acrylamide-Treated Rats

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Advances in Animal and Veterinary Sciences
Published:
29 January 2017
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Abstract

Khalisa Khadim Khudiar, Ghasag Jawad Hussein

Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Baghdad, Iraq.
 
Abstract | This study was carried out to explore the effects of alcoholic extract of Salvia officinalis (SO) leaves on some physiological parameter including: protein profile, antioxidant status,some immunological and proinflammatory biomarkers in acrylamide (ACR) comparing to cyclosporine (Cys) treated rats. Thirty adult male rats were selected randomly and equally allocated into six gropes and treated daily for 45 days with oral manner as follow: Group G1: (control group) received tap water), G2: rats in this group were received (150 mg/kg /B.W) of alcoholic extract of SO leaves,G3: rats of this group were received (1 mg/kg /B.W) of acryl amide in drinking water, G4: rats in this group were received (1mg/kg /B.W) of cyclosporine, G5: rats in this group were received (150 mg/kg /B.W) of Salvia officinalis leaves extract and acryl amide(1 mg/kg /B.W), G6: rats in this group were received the same mentioned dose of SO and cyclosporine as in G2 and G4 groups. At the end of experiment, animals were sacrificed and blood was drawn by cardiac puncture technique for measuring the following parameters: serum reduced glutathione (GSH), peroxynitrite radical, total protein, albumin, globulin concentrations as well as phagocyte index (%) and mitotic index (%). Serum immunoglobulin G (IgG), interleukin-6 (IL-6) and C – reactive protein (CRP) concentrations were also recorded. The results of the current study revealed the beneficial effect of alcoholic extract of Salvia officinalis against deleterious effect of ACR and cyclosporine illustrated by its antioxidant, immunostimulatory and anti-inflammatory effect. Significant increase in serum TSP, albumin and globulin concentration, as well elevation in serum GSH and depression in peroxynitrite radical concentration was observed after oral intubation of SO alone or in combination with ACR or Cys comparing to the ACR or cyclosporine treated rats which showed controversial result. Concerning immune-stimulatory and anti-inflammatory effect of Salvia officinalis, significant elevation in phagocytic index % (PI), mitotic index % (MI) and in serum (IgG), as well as significant depression in serum IL-6 and CRP concentrations was observed following extract intubation comparing to the immune-supperion and pro inflammatory effect of ACR and cyclosporine. On conclusion, alcoholic extract of Salvia officinalis (SO) leaves alleviate the detrimental effect of ACR and cyclosporine correlated with their pro oxidative, immune suppressive and pro-inflammatory effect. Non-significant differences between ACR and Cys were observed in all measure issue.

Keywords | Salvia officinalis, Cyclosporine, Acrylamide, Phagocytic index, Mitotic index, IgG

 

Introduction

Salvia officinalis (garden sage, common sage) or Dalmation sage enjoys the reputation of being a panacea because of its wide range of medicinal effects. The genus Salvia is one of the most important genera in the Labiatae family and includes over 900 species all over the world. Salvia species are aromatic plants, rich in essential oils which have been used in food, cosmetics, perfumes and pharmaceutical products . The plant antioxidant , antinociceptive and anti-inflammatory ; and diuretic activities are recorded. In addition, to its anticancer and antidiabetic effects .

Acrylamide (ACR) is a reactive, small organic molecule with very high water solubility. These properties facilitate its rapid absorption and distribution through the body . ACR has become one of the major public health concerns since it was detected in widely consumed food items for example, fried bread (breakfast cereals), potato chips, and any carbohydrate-rich food items cooked at high temperatures (higher than 200°C) . The harmful effects of acrylamide have been proposed to be caused by its neurotoxicity , mutagencity and carcinogenicity as well as oxidative stress . Researches also reported toxic effect of ACR on reproductive , and skeletal muscle . Beside, acrylamide-induced locomotors defects and neurotoxicity are associated with Parkinson’s disease .

Cyclosporine A (Cys) is a fungal metabolite with potent immunosuppressive properties. It down-regulates the production of interleukin-2 by T lymphocytes affecting both T helper and T effector cell functions . Because of this action, Cys has been extensively used for the prevention of organ rejection in transplant patients as well as for the treatment of autoimmune diseases . Cyclosporine A inhibits the proliferation of human gastric cancer cells and can induce their apoptosis . Beside increased production of ROS, lipid hydroperoxides and a significant decrease in total antioxidants with Cys treatment confirms the role of oxidative stress in Cys induced organ toxicity .

Depending on the available information reveled that antioxidant supplementation protected the body against oxidative stress induced by different case including pollution, exposure to different oxidant and causing several diseased condition, inflammation and immunosuppression, the present study was designed to investigate the effect of alcoholic extract of Salvia officinalis against different aspects related to oxidative stress damage induced by ACR comparing to cyclosporine.

Materials and Methods

Preparation of Ethanolic Extract of S. officialis

Twenty g. of Salvia officialis powdered leaves were taken and extracted with soxhlet apparatus ethanol 70%. The solvent was removed under reduced pressure in a rotary evaporator until they become completely dry. The residue was stored at 4°C for further use .

Animals and Experimental Design

Thirty mature male Wistar rats (aged 90 days and weighted 190±10 g), were allowed to acclimatize to the animal house environment before beginning of the experiment. Animals were housed in polypropylene cages inside a well-ventilated room. Male rats were fed on the standard chow and drinking water ad libitum throughout the experiment. Room temperature was maintained at 23±2ºC, the light-dark cycle was on a 12 hr. light/dark cycle with light on at 06:00 p.m. and off at 06:00 a.m. during the experimental periods. Rats were randomly selected and equally divided in to six groups as follows G1, G2, G3, G4, G5 and G6. They were treated orally (daily) for 45 days as follows G1: control group, were given distilled water G2: rats of this groups were given Salvia officinalis (150 mg/Kg B.W.) G3, rats of this groups were received acrylamide (1 mg/kg B.W.), G4, rats of this groups were given cyclosporine (1mg/Kg B.W.) for 45 days, G5, rats of this groups were given orally Salvia officinalis and acrylamide (1 mg/kg B.W. +150 mg/kg B.W.) daily for 45 days, G6, rats of this groups were given orally Salvia officinalis and cyclosporine (1 mg/kg B.W. +150 mg/kg B.W.) daily for 45 days.

Blood samples were collected at end of experiment, blood was drawn by cardiac puncture technique from anesthetized rats. Then serum samples were separated and frozen at -20°C until analysis of the following parameters: Serum total protein and albumin concentrations was measured using total protein and albumin kits (Biomaghreb- Germany) immunoglobulin G (IgG) concentration was measured using IgG kit ELISA (Hcusabio- China) serum peroxynitrite radical concentration was determined according to reduced glutathione (GSH) concentration was measured according to . Furthermore, determination of bone marrow cellularity (Mitotic index %) has been determined as described by Savage (1975) and determination of Phagocytic Index % according to Weber and Osborn (1982). Serum Interluekin-6 (IL6) concentration was measured using ELISA Interluekin-6 kit (RayBio-USA), also C-Reactive protein (CRP) concentration was estimated by using CRP kit (Spectrum-UK). Statistical analysis of data was performed according for One-Way analysis of variance (ANOVA) utilizing a significant level of (P<0.05) specific groups differences were identified utilizing least significant differences (LSD) as described by Snedecor and Cochran (1973).

Results

The results in Table 1 showed that oral intubation of Salvia officinalis alone (G2 group), or concurrently with acryl amide in drinking water (group G5) or cyclosporine (group G6) caused significant elevation (P> 0.05) in serum GSH and significant decrease (P<0.05) in serum peroxynitrite concentration comparing to the value in Acryl amide (group G3) or cyclosporine (G4) treated groups. A statistical analysis indicated that the mean values of TSP and albumin concentration is significantly decreased (P<0.05) after Acryl amide exposure or cyclosporine treatment for 45 days comparing to the value in other treated groups. on the other hand serum TSP and albumin concentration significantly increased (P<0.05) after oral intubation of Salvia officinalis to normal, acrylamide or Cys treated groups comparing to the value in G3 and G4 treated groups (Table 1). Significant increase (P>0.05) in serum globulin concentration was observed after oral intubation of Salvia officinalis concurrently with acrylamide or cyclosporine comparing to the value in G2,G3 and G4. The value in group G5 and G6 tend to normalize that of the control at the end of the experiment (Table 1).

The results in Table 2 showed a significant increase (P<0.05) in phagocytic index % and MI% index after exposure to acrylamide (G5) and oral intubation of cyclosporine (G6) concurrently with Salvia officinalis comparing to the value in G3 and G4 groups which received acrylamide or cyclosporine alone which showed significant (P<0.05) depression in these parameters. Oral intubation of Salvia officinalis to normal (G2), or concurrently with acrylamide (G5) or cyclosporine (G6) treated groups showed significant (P<0.05) increase in serum IgG concentration as compared to G3 and G4 groups (Table 2). The results also showed that oral intubation of Salvia officinalis to normal (G1), G2, SO+ACR(G5) and SO+ Cys (G6) treated groups caused significant increase (P<0.05) in IL-6 and CRP concentration comparing to the value in ACR (G3) and Cys (G4) groups (Table 2).

Discussion

Effect of S. Officinalis on Total Serum Protein Concentration in Acrylamide or Cyclosporine Treated Rat

Here in study indicated that treatment with alcoholic extract of SO concurrently with ACR or Cys caused significant increase in TSP, albumin and globulin concentration comparing to Cys and ACR treated rats. Such result demonstrated the hepatoprotective activity of Salvia officinalis and thus supports the usage of this plant for treatment of liver disorders . Sage constituents with their antioxidant properties overcame the lower in the total protein content perhaps by preventing oxidative stress and protein fragmentation and enhancing protein synthesis . Depression in protein carbonyl content (an indicator for cellular protein oxidation) after SO supplementation (Osman and El–Azime, 2013) could be a mechanism for elevation serum protein.

Table 1: Effect of ethanolic extract of Salvia officinalis on serum GSH, peroxynitrite, total albumin, globulin and albumin concentration in normal, acrylamide and cyclosporine treated rats

Group

G

G2

G3

G4

G5

G6

Parameter

Reduce GSH

55.58±0.4 B

58.208±0.7 A

42.786±0.7 D

44.994±1.2 D

50.228±0.8 C

51.05±0.5 C

Peroxynitrite radical

31.63±0.6 D

28.89±0.7 E

40.896±0.5 A

40.474±0.8 A

33.39±0.6 C

34.76±0.6 B

Total protein

6.608±0.2 A

7.577±0.6 A

5.616±0.7 B

5.531±0.8 B

6.264±0.7 A

6.27±0.6 A

Albumin

2.41±0.03 B

3.122±0.1 A

1.81±0.1 D

1.85±0.02 D

2.19±0.02 C

2.16±0.02 C

Globulin

4.198±0.1 A

3.935±0.1 B

3.806±0.1 B

3.681±0.02 C

4.074±0.02 A

4.11±0.02 A

Values expressed as mean ± SE; n: 5; Different capital letter represent a significant difference between groups (p <0.05) vs. Control; G1: Control; G2: Salvia officinalis (150mg/kg B.W); G3: Acryl amide (1mg/kg B.W); G4: Cyclosporine (1mg/kg B.W); G5: Salvia officinalis (150mg/kg B.W) + Acryl amide (1mg/kg B.W); G6: Salvia officinalis (150mg/kg B.W) +A cyclosporine (1mg/kg B.W)

Table 2: Effect of ethanolic extract of Salvia officinalis on phagocytic index (%), mitotic index (%) and serum immunoglobulin G (IgG), interlukin-6 (IL-6) (pg /ml) and C-reactive protein (CRP) concentrations in normal, acrylamide and cyclosporine treated rats

Group

G

G2

G3

G4

G5

G6

Parameter

Phagocytic index

22.4±0.3 B

26.68±0.7 A

16.62±0.3 C

15.52±0.2 D

21.42±0.4 B

21.32±0.2 B

Mitotic index

23.726±0.7 B

28.008±0.5 A

16.71±0.3 D

15.42±0.3 E

22.022±0.3 C

22.654±0.7 C

IgG

4.38±0.09 B

4.75±0.2 A

3.21±0.07 B

3.23±0.05 B

4.77±0.07 A

4.90±0.1 A

IL-6

22.64±0.2 B

24.45±0.4 A

28.99±0.4 D

29.42±0.3 D

21.63±0.2 C

21.59±0.2 C

CRP

6.94±0.3 C

7.97±0.3 A

10.98±0.05 D

10.91±0.1 D

7.52±0.1 B

7.40±0.2 B

Note: For details see Table 1

Significant decreases of the total protein, albumin, and globulin levels reported in the current study after exposure to ACR are going in line with study by Hammad et al. (2013) and Mahmood et al. (2015). A steady decrease in hepatic protein levels with higher doses of ACR could be attributed to retarded protein synthesis, change in protein metabolism, or to the leakage of protein reserves from hepatocytes . Significant decrease of serum albumin and TSP were noticed after 2 weeks of treatment with Cys that indicated hepatotoxicity . Based on in vitro, cyclosporine could inhibits hepatic protein synthesis and then depression in protein, probably at the translation level . Besides, over production of ROS after Cys exposure may accompanied decrease in liver protein level (Gala´n et al., 1999) and then depression in serum.

Effect of Acrylamide on Serum Antioxidant Status (Glutathione and Peroxynitrite Radical Concentration) in Normal, Acrylamide or Cyclosporine Treated Rats

Significant elevation in serum GSH and depression in peroxynitrite radical concentration after oral intubation of Salvia officinalis indicated its antioxidant capacity. Antioxidant and free radical scavenging activity of alcoholic and water extract of SO were studied in vivo and in vitro ; study as well as in SO nanoparticles , Carnosic acid, carvacrol, thymol (Tenor et al., 2011) α-thujone and camphor as well as rosmarinic acid and its dimer (salvianolic acid), showed a high antioxidant activity and is a very significant scavenger of free radicals . The ability of sage to increase basal GSH levels and depressed peroxynitrite concentration could be probably due to induction of glutathione synthesis and scavenging the nitrogen oxide or their radical derivatives with depression in peroxynitrite level (Alkan et al., 2012).

The current study showed significant decrease in serum GSH concentration and elevation in peroxynitrite radical concentration after ACR treatment indicating a case of oxidative stress, which is in line with recent study reported by Abd El-Ghaffar et al. (2015), Al-Agele and Khudiar (2016) and Sabeeh (2016 ) in rats. Acrylamide is well known to generate free radicals, induce lipid per oxidation disturbing the antioxidant status and ultimately leading to oxidative stress ; . Accumulation of free radicals such as superoxide, NO after ACR exposure can react together to produce peroxynitrite, the highly reactive oxidizing agents have the ability to attack and damage cell membranes and biomolecules .

It has been shown that Cys toxicity in kidney, liver and nervous system is accompanied by increased both H2O2 production and lipid peroxidation, and concominantly decreased cellular level of reduced glutathione . Reduction in the content of protein sulfhydryl groups and formation of protein thiol oxidation by Cys , leading to GSH depletion , could be another possible mechanism. It has been demonstrated that Cys-induced local production of hydroxyl radical, a highly active and detrimental radical, with elevation in superoxide radical could be attributed to production of peroxynitrite radical.

Effect of S. officinalis on Phagocytic Index (%) in Acrylamide or Cyclosporine Treated Rat

The present study demonstrated significant increase in phagocytic index after oral intubation of SO concurrently with ACR or Cys treated rats which showed significant decrease indicating immune stimulatory effect of SO. Active component of SO (essential oil) caused an elevation in blood phagocytic activity in rabbits , and in broiler chickens . Water soluble polysaccharide are active SO compound are claimed to possess immune modulatory activity , including anti-inflammatory, macrophage phagocytic stimulation and induction of cytokine as well as mitogenic activity . While numerous studies revealed that macrophage functions, e.g. phagocytic activity, chemotactic migration, superoxide and peroxide production and protein secretion, to be reduced in the presence of Cys .

Effect of S. officinalis on IgG Concentration in Acrylamide or Cyclosporine Treated Rats

Elevation in serum IgG concentration after SO supplementation improved immunostatus of the body and reflected its boosting the humeral immune response.

Many protective function of immune cells depend upon the fluidity of cell membrane, depression in fluidity of membrane by LPO -induced by many toxicant (including ACR) lead to marked atrophy of thymus and B cell dysfunction . So intake of dietary antioxidant enhance body immunity and protect it from harmful effect of FRs and oxidative stress that could be induced by ACR. Active compounds of sage extract act on augmentation of humeral and cellular immune response. Through its effect on neutrophil, macrophage, B and T lymphocyte. These active compounds act synergistically or separately in enhancing responsiveness of these cells directly or indirectly . Significant decrease in serum IgG concentration after ACR exposure indicating toxic effect of ACR on humeral immune function . A lot of information pointed to the role of FRS that could be produced after ACR exposure in affecting immune-defence mechanism and weakening of immunity . Immune suppression effect of cyclosporine is depicted in some situation ; .Cyclosporine treatment completely or partially abrogated IgG production in rat model and human . Treatment of hamster with Cys and prednisolone lowered levels of circulating IgG against worm crude antigen .

Effect of S. officinalis on Mitotic Index % in Acrylamide and Cyclosporine Treated Rat

Significant increase in percentage of mitotic activity after treatment with Salvia water extract in low concentrations was recorded by Gateva et al. (2015) indicating its antimutagenic effect (Bouaziz et al., 2015). Sage extract caused significant increase in bone marrow mitotic index in mice comparing to cystosor . On the contrary, different result were observed by others, where prolong use of high concentration of plant may increase its mutagenic toxic material , delay cell division leading to decrease in MI%. Polysaccharides (mutagenic agent) and other active component of SO have been found to stimulate the immune function of bone marrow cells by inducing cell division presence of mutagenic compound in the extract might be related to its action on spindle assembly or cell cycle regulator . Besides, Cytogenetic effect of plant may be due to its ability to act as FR scavenger so it can captures ROS release from toxic substance like ACR .

ACR cytotoxicity indicated by decrease in MI % and genotoxicity could be occur due to decreasing in oxidative defense system , as well as elevation in ROS production and its known to be clastogenic and mutagenic in vivo and in vitro . Reduction in MI after ACR could be due to DNA damage and inhibition of DNA synthesis , and blocking of cell from entering mitosis . General speaking MI could be disrupted either by inhibitory process of cell division, disturbing normal function of mitotic spindle and producing chromosomal aberration lead to reduction in mitosis . Beside increase in number of interphase or dead cells leading to its accumulation, induced DNA damage by ACR could be claimed.

Significant decrease in MI activity after Cys treated indicated its mutagenic activity. cyclophosphatimide treatment has been shown to cause an elevation of micronuclei function in bone marrow of mice and significant decrease in interphase index (MI) . This may be due deleterious effect of Cys on bone marrow cell due its free radical producing activity, or it may be due to defect in mitotic spindle composition during cell division and consequently causing mitosis deficiency . Cyclosporine is thought be decrease breakage of Anaphase Bridge during cell division and DNA damage . Furthermore, Cyclosporine may cause abnormalities in lymphocyte receptor involved in mitagenic recognition, resulting in inhibition of blastogenic and mitotic index .

Effect of S. officinalis on IL-6 and CRP Concent-ration in Acrylamide or Cyclosporine Treated Rat

Reduction in serum IL-6 and CRP concentration after SO supplementation indicating the anti-inflammatory effect of the sage ; . Supplementation of Salvia officinalis cause significant decrease in CRP concentration in healthy comparing to obese patient (Hernandez-Saavedra et al., 2015). Increased circulating lipids due to obesity lead to an increased inflammatory state, through an augmented production of cytokines like IL-6 as well as CRP , accordingly, hypolipidemic and the anti-inflammatory effect of SO could reduce CRP and IL-6 level. The impact of elevation in serum IL-6 concentration after exposure to ACR in the current study are in line with those of ; Abdel-Diam et al., 2015). IL-6 is labeled as anti-inflammatory as well as pro-inflammatory mediator and can modulate immunosuppressive functions . Oxidative stress induced after ACR exposure drives proinflammatory cytokine expression like IL-6 may be attributed to its elevation. Different doses of ACR (15-50 mg /kg B.W) caused significant increase in CRP concentration in rats exposed to low fat diet comparing to those kept on high fat diet and control . This could be related to the lowering of the reserves of an important cellular antioxidant, GSH, by acrylamide . An elevation in CRP and IL-6 serum levels regarded as propensities value in assessing progression of some chronic disease like coronary heart disease (CHD) (Lopez et al., 2006), which are expected to occur following exposure to ACR . Besides, their elevation is an indicator of infection in immune suppressed subject ; . The result of the current study showed significant increase in serum IL-6 and CRP concentration after cyclosporine treatment comparing to SO. Patients with immune suppression therapy have been shown to have elevated level in the serum IL-6 . The pro-inflammatory effect of Cys and its effect on expression of IL-2 drives IL-6 secretion was documented. In contrast to the current result long term treatment (more than one year) with cyclosporine caused significant decrease in serum IL-6 and CRP . The discrepancy in the result may be reflected that toxic compounds response is under the influence of several mediation, in addition to the role of duration of exposure in philosophy of result discussion.

Acknowledgments

Authors of this study would like to thank College of Veterinary Medicine, University of Baghdad, Iraq for their support.

Conflict of Interest

There do not exist any conflict of interest.

Authors’ Contribution

Khalisa Khadim Khudair designed the experiment . Ghasag Jawad Hussein analyzed and interpreted the data and performed the experiment. Khalisa Khadim Khudair gave technical support , wrote the paper and conceptual advice.

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