Cinnamic acid and cinnamaldehyde ameliorate ...

Cinnamic Acid and Cinnamaldehyde Ameliorate Cisplatin-Induced Nephrotoxicity in Rats. El-Sayed M. El-Sayed a, Ola M. Abd El-Raouf b, Hala M. Fawzyb, Mohamed F Manie b a Pharmacology & Toxicology Dept., Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt b Pharmacology Dept., NODCAR, Egypt, Cairo, ABSTRACT: Cinnamic acid (CA) and Cinnamaldehyde (CD) are the major constituents of cinnamon species. These compounds have been reported to possess various pharmacological properties of which their antioxidant activity is a prime one. Therefore, it is rational to hypothesize that they may mitigate oxidative stress induced by cisplatin (Cisp), a widely used chemotherapeutic agent. A single dose of Cisp (5mg/kg) injected i.p. to male rats caused a significant increase in serum urea and creatinine levels with a significant decrease in serum albumin as well as marked elevation in lipid peroxides measured as malondialdehyde (MDA) with significant reduction in reduced glutathione (GSH) kidney content and the activity of antioxidant enzymes; catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) of kidney as compared to control group. However, administration of CA (50 mg/kg p.o.) or CD (40 mg/kg p.o.) for 7 days after Cisp administration ameliorated Cisp-induced nephrotoxicity as indicated by restoration of kidney function and oxidative stress parameters. Furthermore, CA and CD reduced the histopathological changes induced by Cisp. In conclusion, CA and CD ameliorated Cisp-induced nephrotoxicity where CA was more effective than CD; effects that might be attributed to their anti-oxidant activities. Keywords: cinnamic acid; cinnamaldehyde; anti-oxidant; cisplatin; nephrotoxicity Abbreviations: CA, Cinnamic acid; CAT, Catalase enzyme; CD, Cinnamaldehyde; Cisp, Cisplatin; DMSO, Dimethylsulphoxide; DTNB, 5;5-dithiobis-2-nitrobenzoic acid; GPx, Glutathione peroxidase; GR, Glutathione reductase; GSH, Reduced glutathione; MDA, Malondialdehyde; NBT, Nitro blue tetrazolium; PMS, Phenazine methosulfate; SEM, Standard error of the means; SOD, Superoxide dismutase; TBA, Thiobarbituric acid.

INTRODUCTION: Cisplatin (cis-diamminedichloroplatinum) is one of the most effective chemotherapeutic agents widely used in treatment of a variety of malignancies, including head and neck, ovarian and testicular cancers (Rabik and Dolan, 2007). However, the full clinical utility of cisplatin is limited by its nephrotoxicity (Schrier, 2002). Approximately 28 to 36% of patients receiving an initial dose (50–100 mg/m2) of cisplatin developed acute renal failure. The vigorous hydration has not been effective in eliminating cisplatin toxicity. Moreover, the use of diuretics may complicate the electrolyte disturbance induced by cisplatin. Discontinuation of cisplatin remains the only option in cases of progressive renal failure (Lebwohl and Canetta, 1998). In addition to the direct tubular toxicity in the form of apoptosis and necrosis (Arany and Safirstein, 2003), the vascular factors (Luke et al., 1992) and inflammation (Ramesh and Reeves, 2003) that have been implicated in the pathogenesis of cisplatinmediated nephrotoxicity, several other studies have also demonstrated that cisplatin-induced oxidative stress is involved in the development of renal tubule

injury (Chirino and Pedraza-Chaverri, 2009).The involvement of oxidative stress was further supported by the fact that free radical scavengers and antioxidants may mitigate cisplatin-induced nephrotoxicity (Gulec et al., 2006). Many antioxidant agents were investigated for their preventive abilities against cisplatin-induced nephrotoxicity. Some researches advised the use of enriched diets with natural antioxidants like vitamin E, ascorbic acid and methionine (Appenroth et al., 1997). Other study reported the use of sulfhydryl-containing drugs such as captopril, diethyldithiocarbamate, sodium thiosulfate, N-acetylcysteine and lipoic acid that could also exert antioxidant activity (El-Sayed et al., 2008). Cinnamon, scientifically named Cinnamomum spp, is a plant with many uses as a herbal medicine, containing mucilage, tannin, sugar, resin, and essential oil, among which the essential oil is the most important part, a substantial portion of which is made up of cinnamaldehyde which possesses antioxidant, antibacterial and anti-inflammatory effects (Molania et al., 2012 ). In addition, Cinnamic acid, a major active phenolic ingredient in cinnamon displays many pharmacological properties, such as antioxidant and antimicrobial activity (Chen et al., 2011). In this study, we have investigated the ameliorative potential of CA and CD against Cisp-induced nephrotoxity toxicity in rats.

Corresponding author Ola.raoof @hotmail.com

J. Drug Res. Egypt, Vol. 34, No.1 (2013) 57

MATERIALS AND METHODS: Animals Male adult Sprague-Dawley rats weighing 230-260g were obtained from the breeding colony maintained at the animal house of the National Organization for Drug Control and Research, NODCAR, Egypt. Animals were caged in seven groups, given food and water ad libitum and maintained at 21–24˚C and 40–60% relative humidity with 12-h light–dark cycles. Animals were subjected to an adaptation period of 2 weeks in the animal house before experiments. The experiments were conducted in accordance with the ethical guidelines for investigations in laboratory animals and were approved by the Ethical Committee of Faculty of Pharmacy, Cairo University, Egypt and comply with the Guide for the Care and Use of Laboratory Animals (ILAR, 1996). Chemicals Cisplatin (Cisp) was obtained from EIMC United Pharmaceuticals, Egypt and was given i.p. in a single dose of 5 mg/kg (Naghizadeh et al., 2008). Cinnamic acid (CA) was obtained from Qualikem Fine Chemicals (New Delhi, India), given orally in a dose of 50 mg/kg daily for 7 days before Cisp injection (Kasetti et al., 2012). Cinnamaldehyde (CD) was obtained from LLUCH Essence (Spain), given orally in a dose of 40 mg/kg daily for 7 days before cisplatin injection. Cinnamic acid and Cinnamaldehyde were dissolved in dimethylsulphoxide 50% (DMSO) which was obtained from Sigma-Aldrich Corp. (France). All other chemicals were of the highest analytical grades available commercially. Experimental design Fifty-six male adult Sprague-Dawley rats were allocated into 7 groups (8 rats / each), two rats from each group were used for histopathological examination as follows: Group 1: Received saline and served as control. Group 2: Received DMSO 50% (as a solvent). Group 3: Received cinnamic acid in a dose of 50 mg/kg p.o. Group 4: Received cinnamaldehyde in a dose of 40 mg/kg p.o. Group 5: Received cisplatin in a single dose of 5 mg/kg, i.p. Group 6: Treated with cinnamic acid in a dose of 50 mg/kg, p.o. for 7 days, after a single dose of cisplatin (5 mg/kg, i.p.). Group 7: Treated with cinnamaldehyde in a dose of 40 mg/kg, p.o. for 7 days, after a single dose of cisplatin (5 mg/kg, i.p.). Serum and tissue preparation On the seventh day after Cisp injection, blood samples were withdrawn from the retro orbital plexus of each rat via glass capillaries. Serum was separated by centrifugation for 20 min at 4000 r.p.m. and stored at 20oC. The kidneys were rapidly isolated and washed with icecold isotonic saline (0.9%). Then, they were stored at 80ºC till they were homogenized in 50 mM phosphate buffer (pH 7.4) using electronic homogenizer (Ezister Daihan Scientific Co., Ltd., Korea) to prepare 10 %

w/v homogenate. The homogenate was then made into aliquots and was used for the determination of kidney contents of MDA and GSH and enzymatic activities of CAT, SOD and GPx. Biochemical Analysis Serum urea nitrogen, creatinine and albumin were estimated colorimetrically according to the methods of Fawcett and Scott (1960), Bartles et al. (1972) and Doumas and Peters (1971), respectively. The kidney homogenate was used for the determination of thiobarbituricacid-reactive substances levels measured as malondialdhyde (MDA) according to the method of Satoh (1978) (using 1,1,3,3tetraethoxypropane as a standard). Reduced glutathione (GSH) contents were assessed by the method of Beutler et al. (1963), using 5-5’ dithiobis (2nitrobenzoic acid) as a substrate. Catalase (CAT) activity was determined colorimetrically using hydrogen peroxide as a substrate according to the method of Aebi (1984). Superoxide dismutase (SOD) activity was determined using the method of Nishikimi et al. (1972) which relies on the ability of the enzyme to inhibit the phenazinemethosulphate mediatedreduction of nitrobluetetrazolium dye. Glutathione peroxidase (GPx) activity was measured by applying the method of Paglia and Valentine (1967) using hydrogen peroxide as a substrate. Histopathological examination of the kidney Autopsy samples were taken from the kidney of rats in different groups and were fixed in 10% neutral buffered formalin for twenty four hours and decalcification was occurred on formic acid. Washing was done under tap water, and then serial dilutions of alcohol (methyl, ethyl and absolute ethyl) were used for dehydration. Specimens were cleared in xylene and embedded in paraffin at 56oC in hot air oven for twenty four hours. Paraffin bees wax tissue blocks were prepared for sectioning at 4 microns thickness by sledge microtome. The obtained tissue sections were collected on glass slides, deparaffinized, stained by hematoxylin & eosin stain and then examination was done through the light electric microscope (Banchroft et al., 1996). Statistical analysis of data All values were presented as means ± standard error of the means (SEM).Statistical analysis was performed using GraphPad Prism version 5 (GraphPad, San Diego, CA, USA). Comparison between different groups was carried out using one-way analysis of variance (ANOVA), followed by Tukey-Kramer's multiple comparison tests. Difference was considered significant when P ≤ 0.05.

RESULTS: Table 1 shows that injection of cisplatin (i.p.) in a single dose of 5 mg/kg caused significant increases in serum urea (401%), creatinine (938%) and kidney/body-weight ratio (102%) and significant decrease in serum albumin level (68%) and body weight (14%) after seven days of treatment as compared to control group.


Moreover, cisplatin (5 mg/kg) produced a significant increase in MDA (124%) and significant decrease in GSH renal content (69%) and enzymatic antioxidant parameters in kidney; SOD, CAT & GPx (56%, 57% & 77%, respectively in comparison with the control group) (Table 2). In contrast, administration of CA for seven days after a single dose of cisplatin, significantly reduced the elevated serum levels of urea and creatinine by 79% and 82%, respectively as well as kidney/body-weight ratio (31%) while significantly increased the serum albumin level by 191% (in comparison with cisplatintreated group). Further, it decreased MDA content by 53% and increased GSH content (484%) as well as SOD and GPx activities (184% & 522%) in kidney tissue, respectively, in comparison with cisplatintreated group (table 1&2). Similarly, treatment of animals with CD (40 mg/kg) for seven days after a single dose of cisplatin significantly reduced the elevated serum levels of urea and creatinine by 76% and 83%, respectively as well as kidney/body-weight ratio (18%) while significantly increased the serum albumin level by 196% (in comparison with cisplatintreated group), while it decreased MDA content by 62% and increased GSH content (305%) as well as SOD and GPx activities (79% & 334%, respectively) in kidney tissue, in comparison with cisplatin-treated group. Histopathological findings of kidney tissues are illustrated in Table 3 & Figure 1. The histopathological examination of kidney sections of the control group (saline) showed a normal histopathological structure (Figure 1A). On the other hand, administration of cisplatin to rats revealed degenerative changes, inflammatory cell infiltration between the cystic dilated and necrosed tubules, and focal haemorrhage detected in between the tubules at the corticomedullary junction (Figure 1B). Treatment of rats with CD (Figure 1C) or CA (Figure 1D) obviously mitigated the histopathological changes induced by cisplatin.

DISCUSSION: Cisplatin is a major antineoplastic weapon used for the treatment of solid tumors. Its chief dose-limiting side effect is nephrotoxicity which requires a reduction of dose or discontinuation of treatment (Kuhad et al., 2006). The present study was designed to investigate whether CA or CD administration before cisplatin could afford protection against cisplatin-induced nephrotoxicity. Our results revealed that cisplatin produced significant elevation in serum creatinine, urea levels and kidney/body-weight ratio and significant decrease in serum albumin level. The increased urea and creatinine levels suggest the reduction of glomerular filtration rate (Naziroglu et al., 2004). Also, the increase in kidney/body-weight ratio could be attributed to reduction of body weight. Furthermore, cisplatin caused significant decline in the activity of the antioxidant enzymes (CAT, SOD and GPx), significant depletion of GSH and enhancement of MDA production in renal tissue. These findings are consistent

with those of Ali et al. (2007), Fouad et al. (2010) and Yadav et al. (2010). It was evident that cisplatin nephrotoxicity occurs as a result of oxidative stress and increased generation of superoxide anion, hydrogen peroxide and hydroxyl radicals due to increased activity of NADPH oxidase, xanthine oxidase and adenosine deaminase (Gulec et al., 2006; Chirino et al., 2008). These free radicals damage the lipid components of the cell membrane via peroxidation and denaturing its proteins, which subsequently lead to enzymatic inactivation (Lalila et al., 2001). Moreover, cisplatin induced tubular damage could be explained by the fact that as fast as cisplatin is in the interior of the cells, the hydrolysis product (chloride atoms replaced by water molecules) reacts with glutathione in the cytoplasm and DNA in the nucleus (Boulikas and Vougiouka, 2003). The produced cisplatin-DNA intrastrand cross-links results in cytotoxicity (apoptosis/necrosis) (Galea and Murray, 2002). The present study demonstrated that treatment with CA or CD ameliorated cisplatin-induced alterations in serum creatinine, urea and albumin levels and kidney/body-weight ratio. In addition, CA or CD significantly mitigated lipid peroxidation in the rat kidney induced by cisplatin as manifested by the decreased MDA level, accompanied by increased GSH content and enhanced activities of SOD, and GPx. These results could be attributed to the potential antioxidant effect of CA (Dai et al., 2012) and CD (Molania et al., 2012) and are in agreement with those obtained by Patra et al. (2012) who demonstrated that CA protects mice from cyclophosphamide-induced hepatotoxicity and myelotoxicity. Moreover, our results are consistent with Molania et al. (2012) who revealed the promising protective effect of CD against gamma radiation-induced mucositis. The histopathological findings demonstrated that administration of cisplatin induced various degenerative changes in kidney cells which confirmed the biochemical evidence of oxidative stress. In contrast, treatment with CA or CD obviously mitigated the histopathological changes induced by cisplatin. Our data revealed that CA was more effective than CD as a therapeutic agent regarding the antioxidant activity (O’Grady et al., 1993) in a number of ways: 1. Phenolic hydroxyl groups in CA are good hydrogen donors (Valentão et al., 2003), which can react with reactive oxygen and nitrogen species (Valentão et al., 2002) and break the cycle of generation of new radicals (Choi et al., 2002). 2. Following interaction with the initial reactive species, a radical form of the antioxidant is produced and has a greater chemical stability than the initial radical (Choi et al., 2002). 3. The antioxidant capacity of phenolic compounds is also attributed to ability to chelate metal ions involved in production of free radicals (Yang et al., 2010). 4. Hydrophobic benzenoid rings and hydrogen bonding potential of phenolic hydroxyl groups interact with protein and give cinnamic acid capacity to inhibit some enzymes involved in radical generation (Yang et al., 2010). Conclusion: CA or CD ameliorated cisplatin-induced nephrotoxicity in rats, where CA was more effective


than CD. The antioxidant activities can be considered the main factors responsible for such beneficial effect. Therefore, CA or CD represents a potential candidate for renal injury therapy which is a major and doselimiting problem during cisplatin therapy.

Conflict of interest: The authors declare that there are no conflicts of interest. Acknowledgments: We thank Professor Dr. Adel B. Kholoussy, Department of Pathology, Faculty of Veterinary.

Table 1: Effect of treatment with cinnamic acid (CA) and cinnamaldehyde (CD) on serum urea, creatinine and albumin levels and kidney/ body-weight ratio in cisplatin (Cisp)-treated rats. Parameters Groups

Urea (mg/dl)

Creatinine (mg/dl)

Albumin (mg/dl)

Final body weight (g)

Kidney/bodyweight ratio (1000×)

Control saline DMSO CA CD Cisp Cisp +CA Cisp +CD

25.37 ± 2.11 27.15 ± 2.30 25.25 ± 2.22 23.64 ± 0.60 127.10± 0.79 a 27.27 ± 2.52 b 29.91 ± 2.15 b

0.48± 0.04 0.75± 0.06 0.74±0.06 0.50 ± 0.03 4.98± 0.34 a 0.90 ± 0.14 b 0.83 ±0.05 b

4.29 ± 0.19 4.37 ± 0.20 4.28 ± 0.09 3.98 ± 0.15 1.37± 0.06 a 3.98 ± 0.06 b 4.05 ± 0.13 b

235.30 ± 3.99 234.70 ± 1.76 243 ± 6.23 257.70 ± 4.05 202.2 ± 1.83 a 195.80 ± 2.32 a 218.80 ± 7.05 c

5.60±0.11 6.18 ± 0.14 6.22 ± 0.12 6.20 ± 0.09 11.3±0.17 a 7.75±0.50 a,b 9.32±0.47 a,b,c

Data are expressed as means±SEM of six rats per group. a Significantly different from control saline group. b Significantly different from the Cisp -treated group. c Significantly different from the CA + Cisp-treated group using one-way ANOVA followed by the Tukey-Kramer test for multiple comparison test at P ≤0.05.

Table 2: Effect of treatment with cinnamic acid (CA) and cinnamaldehyde (CD) on MDA and GSH contents and enzymatic antioxidant activities of kidney in cisplatin (Cisp)-treated rats. Parameters

MDA (nmole/g tissue)

GSH (mg/g tissue)

SOD (U/g tissue)

CAT (U/g tissue)

GPx (U/g tissue)

Groups 21.22 ± 0.84 14.79 ± 0.86 463.50 ± 20.76 1.38 ± 0.05 17.16 ± 0.89 Control saline 23.74 ± 0.16 13.63 ± 0.64 395 ± 16.86 1.39 ± 0.08 13.05 ± 0.73 DMSO 22.86 ± 0.87 12.85 ± 0.59 505.10 ± 35.60 1.01 ± 0.07 15.98 ± 1.08 CA 19.68 ± 0.69 14.04 ± 2.22 385 ± 13.88 0.88 ± 0.03 11.78 ± 1.80 CD 47.55 ± 2.56 a 4.64 ± 0.12 a 201.80 ± 21.66 a 0.60± 0.05 a 3.98 ± 0.19 a Cisp b a,b b a 22.54 ± 1.52 27.08 ± 2.31 572.20 ± 23.30 0.59 ±0.07 24.76 ±1.45 a,b Cisp + CA b b,c b,c a 17.90 ± 1.25 18.78 ± 3.55 360.90 ±32.54 0.55 ± 0.07 17.29 ±1.81 b,c Cisp + CD Data are expressed as means±S.E. of six rats per group. a Significantly different from control saline group. b Significantly different from the Cisp -treated group. c Significantly different from the CA + Cisp-treated group using one-way ANOVA followed by the Tukey–Kramer test for multiple comparison test at P ≤0.05.


Table 3: Effect of treatment with CD or CA on histopathological findings of kidney tissues of cisplatin (Cisp)-treated rats Groups CA (50 mg/kg) CD (40 mg/kg) Control Cisplatin + + Histopathological (saline) (5 mg/kg) Cisplatin (5 mg/kg) Cisplatin (5 mg/kg) Finding ++++ + ++ Tubular cougulative 0 None Very severe Mild Moderate necrosis ++++ + ++ Inflammatory cell 0 None Very severe Mild Moderate infiltration 0 ++++ + ++ Haemorrahage None Very severe Mild Moderate 0 ++ + ++ Renal casts None Moderate Mild Moderate 0 14(+) 4 (+) 8 (+) Total

A

B

C

D

Fig. 1: Histology of kidney samples of the control (saline), cisplatin-treated group, Cisplatin + CD-treated group, or Cisplatin + CA-treated group. (A) Control group: normal histological appearance of renal tubules (rt); (B) Cisplatin-treated group: inflammatory cells infiltration (m) in between the cystic (s) and necrosed (n) tubules; (C) Cisplatin + CD-treated group: necrosis (n) was detected in some tubules at the cortex (n); (D) Cisplatin + CA-treated group: degeneration and cystic (s) dilatation in few tubules at the cortex. Hematoxylin–eosin staining, magnifications: ×40.


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‫تقييم التأثيرات المعدلة المحتملة لحمض السيناميك و سينامالدهايد في الس ّمية الكلوية المحدثة بسيسبالتيه‬ ‫في الجرذان‬ **‫السيد محمد السيد * عال محمد عبد الرؤوف** هاله محمود فوزى** محمد فتحي حسه منيع‬ ‫ انقبْشح‬-ٍٍُ‫ ث‬-‫* أسزبر ٔ سئٍس قسى انفبسيبكٕنٕجى ٔ انسًٕو ثكهٍّ انصٍذنّ جبيعّ األصْـش‬ .ٍّ‫** قسى انفبسيبكٕنٕجى – انٍٓئّ انقٕيٍّ نهشقبثّ ٔ انجحٕس انذٔائ‬ ‫ ٔيٍ انًثجذ عهًٍب أٌ ْزِ انًشكجبد نٓب انعذٌذ يٍ انخصبئص‬.‫ٌحزٕي َجبد انقشفخ عهً يٕاد فعبنخ سئٍسٍخ ًْ حًط انسٍُبيٍك ٔسٍُبيبنذْبٌذ‬ ‫ أحذ انعالجبد انكًٍٍبئٍخ‬،ٍٍ‫ نزنك يٍ انًفزشض أَٓب قذ رخفف انس ًٍّخ انكهٌٕخ انزً ٌسججٓب سٍسجالر‬. ‫انذٔائٍخ انزً يٍ اِ يٓب كَٕٓب يعبداد أكسذح‬ ‫ كٍهٕجشاو) نزكٕس‬/ ‫ يٍههجشاو‬5( ٍٍ‫ ٔقذ أٔظحذ انُزبئج فً ْزِ انذساسخ أٌ حقٍ جشعخ ٔاحذح يٍ سٍسجالر‬. ‫انًسزخذيخ عهى َطبق ٔاسع‬ ً‫انجشراٌ رسجت فً صٌبد ح كجٍشح فً يسزٌٕبد انٍٕسٌب ٔانكشٌبرٍٍٍُ فً انذو يع اَخفبض يهحٕظ فً انجٕيٍٍ انذو ٔكزنك االسرفبع انًهحٕظ ف‬ ‫كًٍخ انذٌْٕ انًؤكسذح يع اَخفبض كجٍش فً َسجّ انجهٕربثٌٍٕ انًخزضل ثخالٌب انكهى َٔشبغ األَضًٌبد انًعبدح نألكسذح ثبنكهً ٔ انزي ٌشزًم‬ ‫ ٔرجٍٍ ْزِ انذساسخ أٌ يعبنجخ‬. ‫عهً اَضٌى انكبربالٌض ٔ اَضٌى سٕثشأكسٍذ دٌسًٕرٍض ٔانجهٕربثٌٍٕ ثٍشٔكسٍذٌض يقبسَخ ثبنًجًٕعخ انعبثطخ‬ ‫ أٌبو ثعذ جشعخ‬7 ‫ كٍهٕجشاو) نًذح‬/ ‫ يٍههجشاو‬40 ‫ كٍهٕجشاو) أٔ سٍُبيبنذْبٌذ (ثجشعخ‬/ ‫ يٍههجشاو‬50 ‫انجشراٌ ثحًط انسٍُبيٍك (ثجشعخ‬ ٌ‫ عالٔح عهى رنك فإ‬. ‫سٍسجالرٍٍ قذ أدي انً رقهٍم انس ًٍّخ انكهٌٕخ انًحذثخ ثسٍسجالرٍٍ كًب رجٍٍ يٍ اسزعبدح ٔظبئف انكهى ٔرقهٍم انزأثٍش انًؤكسذ‬ ٍ‫ ٔخزبيب ًٌكُُب أٌ َخهص ي‬.ٍٍ‫رعبغً حًط انسٍُبيٍك أٔ سٍُبيبنذْبٌذ ادي انً اَخفبض انزغٍشاد انزششٌحٍخ انًشظٍخ انُبجًخ عٍ سٍسجالر‬ ‫ْزِ انذساسخ ثأٌ حًط ا نسٍُبيٍك ٔ سٍُبيبنذْبٌذ قذ قبيب ةرحسٍٍ انس ًٍّخ انكهٌٕخ انًحذثخ ثسٍسجالرٍٍ فى انجشراٌ ٌرٍجخ نُشبغًٓب انًعبد‬ .‫نألكسذح‬
