Effect of Nigella sativa oil on postoperative peritoneal adhesion formation Ahmet Sahbaz1, Firat Ersan2 and Serdar Aydin2 1School of Medicine, Department of Obstetrics and Gynecology, Bulent Ecevit University, Kozlu/Zonguldak, and 2Department of Obstetrics and Gynecology, Kanuni Sultan Suleyman Research and Training Hospital, Istanbul, Turkey Abstract Aim: We aim to evaluate the effect of Nigella sativa oil (NSO) on postoperative peritoneal adhesion formation in female rats. This experimental study is the first on the prevention of postoperative adhesion formation by NSO. Methods: Twenty-four Wistar albino female rats were randomly assigned to three groups of eight rats each. Rats in group 1 were each injected i.p. with 1 mL of NSO. In group 2, an adhesion model was created with no injection of NSO. In group 3, an adhesion model was created and the area was covered with 1 mL of NSO. The rats were killed on postoperative day 8, and the severity of adhesions was evaluated macroscopically and histopathologically. Results: There was a statistically significant difference in adhesion scores between group 2 (control) and group 3 (NSO-treated) (P = 0.003). Statistically significant differences in angiogenesis, fibrosis and inflammation were observed between the control and Nigella sativa groups (P = 0.002, P = 0.001 and P = 0.004, respectively). Conclusion: Covering peritoneal surfaces with NSO after peritoneal trauma is effective in decreasing peritoneal adhesion formation. Key words: adhesion, Nigella sativa oil, peritoneal adhesions, peritoneum, prevention. Introduction Postoperative peritoneal adhesion (PPA) formation is a common sequela of abdominopelvic surgery. The Sur- gical and Clinical Adhesions Research (SCAR) group stated that approximately one-third of patients who underwent open abdominal or pelvic surgery were readmitted an average of two times over the subse- quent 10 years for conditions directly or possibly related to adhesions.1,2 Infertility, pain, bowel obstruc- tion and increased technical difficulty in subsequent abdominal or pelvic surgery are some undesired results of PPA.3,4 Adhesions also have major financial implications. In the USA, adhesion-related health-care costs exceed $US 1 billion annually.5 Although numer- ous adjunctive treatments comprising a variety of strat- egies to prevent the development or recurrence of adhesions have been investigated, no satisfactorily effective adjuvant has yet been found. Adhesions are the consequence of trauma to the monolayer mesothelial cell surface of the peritoneum and may result from mechanical, sharp or thermal injury; infection; radiation; ischemia; desiccation; abra- sion; or foreign body reaction. Such trauma disrupts stromal cells, which release vasoactive substances, such as histamine and kinins, which increase vascular per- meability. This leads to extravasation of serum and cel- lular elements. Inactive fibrinogen turns into a fibrin matrix where leukocytes, erythrocytes, platelets, mast cells and surgical debris accumulate to repair the two Received: August 22 2012. Accepted: April 26 2013. Reprint request to: Dr Ahmet Sahbaz, School of Medicine, Department of Cardiology, Bulent Ecevit University, 67600, Kozlu/Zonguldak, Turkey. Email: drsahbazahmet@yahoo.com bs_bs_banner doi:10.1111/jog.12172 J. Obstet. Gynaecol. Res. Vol. 40, No. 2: 532–537, February 2014 532 © 2013 The Authors Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology mailto:drsahbazahmet@yahoo.com adjacent injured peritoneal surfaces.6 At this stage, if normal local fibrinolysis is insufficient, macrophages persist and fibroblasts proliferate at the affected site. The recovering mesothelial cells, fibroblasts and peri- toneal macrophages can signal the deposition of exces- sive extracellular matrix via cell growth factors and cytokines.7 Adhesion fibroblasts develop a myofibro- blast phenotype.8 Fibroblasts and myofibroblasts secrete massive amounts of extracellular matrix molecules, including fibronectin, hyaluronic acid, gly- cosaminoglycans and proteoglycans. This process establishes a weak fibrous bridge between tissues. Vas- cularization and collagen deposition strengthen this bridge, forming a tough adhesion between the two tissues.7 The two major strategies for PPA prevention or reduction are adjustment of the surgical technique and application of an adjuvant. Improvements in sur- gical technique alone will help to decrease, but not prevent, adhesion formation because of the adhesio- genic nature of postoperative peritoneal repair. It seems that adjuvants, which can be categorized as either drugs or barriers, are necessary for prevention of PPA. In animal models, many products have been demonstrated to decrease postoperative adhesion for- mation, including corticosteroids,9 non-steroidal anti- inflammatory drugs,10,11 reactive oxygen species (ROS) scavengers,12–14 fibrinolytic agents,15 flotation agents and semisolid barriers,16 and mechanical barriers.16–18 Because many of the adhesion-preventing mechanisms of these drugs are among the therapeutic properties of Nigella sativa oil (NSO), we hypothesized that NSO may be an ideal anti-adhesion agent. N. sativa (NS) is an annual herbaceous plant belonging to the Ranuncu- laceae family. It grows in countries bordering the Medi- terranean Sea, Pakistan, India and Turkey. The seeds or oil of NS, commonly known as black seed or black cumin, have been used as a natural remedy for a number of diseases and conditions.19 NS seeds contain more than 30% fixed oil, 0.4–0.45% volatile oil, amino acids, proteins and carbohydrates.20 Many of the phar- macological activities mentioned in the published work have been attributed to quinone constituents in the seed. Thymoquinone is the major active component of the volatile oil. Several pharmacological properties of NS seed extract and/or NSO have been reported, including antioxidant, anti-inflammatory, antihista- minic, antimicrobial, antitumor, immunomodulatory, antinociceptive, uricosuric, choleretic, antifertility and antidiabetic activities.19,21 Wound healing and adhesion formation are medi- ated through similar pathways.22 The mechanism underlying the shift from a normal healing process to adhesion formation remains unclear. The inflamma- tory system, the fibrinolytic system and extracellu- lar matrix deposition with remodeling are three intertwined host processes that cause adhesion devel- opment. We hypothesized that NS affects all of these processes by means of its antioxidant, anti- inflammatory, antihistaminic, antimicrobial and immu- nomodulatory properties. In this study, we thus aimed to determine the effectiveness of NSO in preventing adhesion formation in a traumatic peritoneal adhesion model in rats. Methods This study was performed at the Experimental Animal Production and Research Laboratory of Istanbul Uni- versity Medical School, Istanbul University, and was approved by the local Animal Ethics Committee. All protocols were in accordance with the regulations gov- erning the care and use of laboratory animals of the Declaration of Helsinki. Twenty-four Wistar outbred female albino rats (mean weight, 250 � 25 g; mean age, 6 months) were randomly assigned into three groups of eight rats each. Rats were kept at a maximum of four per cage, in standard 40 cm ¥ 25 cm ¥ 25 cm cages with plastic sides and bottoms covered with stainless steel woven wire. The floor of each cage was covered with wood shavings, which were replaced every 2 days. Rats were fed with pellet feed manufactured specifi- cally for small animals. A 12:12-h light : dark cycle was used to illuminate the room where the rats were placed. Approximately 10–12 h before each operation, the feeding boxes were removed to assure gastric emptying prior to surgery. To assess the potential toxic effects of NSO, rats in group 1 were injected i.p. with 1 mL of NSO that had been sterilized in an autoclave (Nigellae Oleum 250 mL, Arifoglu, Avcilar, Istanbul) using a 22-Fr syringe through a point over the midline of the abdomen and 3 cm below the xiphoid. We injected 1 mL of NSO into the peritoneal cavity of eight rats in the i.p. group. Because an incision may have led to adhesions, yielding false-positive results, we did not administrate NSO to this group by means of laparotomy. The rats were anesthetized with 75 mg/kg body- weight of i.m. ketamine (Ketalar; Parke-Davis, Detroit, MI, USA) and 40 mg/kg i.m. xylazine (Rompun; Bayer, Efficacy of NS for prevention of adhesions © 2013 The Authors 533 Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology 14470756, 2014, 2, D ow nloaded from https://obgyn.onlinelibrary.w iley.com /doi/10.1111/jog.12172 by B ezm -I A lem V akif U niversity, W iley O nline L ibrary on [08/10/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense Berlin, Germany). Each rat in group 2 was placed on its back on an operating table, and its extremities were fixed to the table using sticking plaster. After antisepsis with povidone iodine (Betadine; Kurtsan, Istanbul, Turkey), a 3-cm long vertical median incision was made. The terminal ileum and cecum were mobilized and placed onto the left index finger of the surgeon. The anterior surface of each cecum was scraped with dry gauze to induce serosal petechiae (scraping model).23 The cecum was replaced in the abdomen, and the incision was closed with 3-0 polypropylene sutures (Prolene; Bicakcilar, Istanbul, Turkey) using a continu- ous suture technique. The rats in group 3 were treated in a manner identical to that used for those in group 2. In group 3, 1 mL of NSO was applied into the perito- neal cavity immediately after generation of adhesions. All animals were killed on day 8 by i.p. injection of 200 mg/kg sodium pentothal. Evaluation of adhesion formation The laparotomies comprised reverse-U incisions. Any adhesions observed in the peritoneal cavity were scored using the modified scale devised by Evans et al.24 According to this scale, 0 = no adhesions, 1 = smooth adhesions splitting spontaneously or with weak traction, 2 = firm adhesions splitting by traction, and 3 = dense adhesions requiring sharp dissection. The same individual, who was blinded to the groups, determined the adhesion scores. The strongest adhe- sion identified was accepted as the adhesion grade for that individual animal. Other detected intraperitoneal pathologies were also recorded. Pathological evaluation For histopathological evaluation, the adhesion model area of each cecum was resected and preserved in 10% formaldehyde. After routine dehydration and paraffinization processing, cross-sections of 5-mm thickness were prepared using a microtome. Sections were examined under a light microscope after hematoxylin–eosin staining. In the areas of granula- tion tissue formation, inflammation was investigated by quantifying the density of inflammatory cells and inflammatory cell types, neovascularization was inves- tigated by determining the density of the newly formed branched capillary vessels with prominent endothelium, and fibrosis was investigated by exam- ining collagen accumulation and fibroblast prolifera- tion. A single pathologist – who was blinded to the study groups – conducted the histopathological evalu- ation. In the cecum of the adhesion model, accumula- tion of polymorphonuclear and mononuclear cells, which reflects inflammation, was assessed in terms of absent or normal in number (0 points), slight increase (1 point), marked infiltration (2 points) or massive infiltration (3 points). Neovascularization was investi- gated by scanning for capillary vessel proliferation with prominent endothelium in an area comprising 10 middle-power fields. In every middle-power field (¥20 plus objective), the number of vessels was evalu- ated semiquantitatively as 0 points if neovasculariza- tion was absent, 1 point if one to two vessels were counted, 2 points if three to nine vessels were counted and 3 points if 10 or more vessels were counted. The mean of 10 middle-power fields was accepted as the final result. In the assessment of fibrosis, the increase in fibroblast numbers and the presence of collagen were quantified together. Samples were evaluated and scored as 0 if fibrosis was absent, as 1 for slight fibrosis and hyalinization, as 2 for moderate fibrosis and hyalinization, and as 3 for dense fibrosis and hyalinization.25 Statistical evaluation Statistical analyses were performed using MedCalc software ver. 11.5. The Mann–Whitney U-test was used to compare groups 2 and 3. Categorical data are expressed as mean � standard error of the mean. The criterion for significance was accepted as a value of P < 0.05. Results Re-laparotomies in group 1 revealed no adhesion, and no abnormalities were observed during the histopatho- logical examination of the biopsies collected from the anterior surfaces of the cecum walls. In addition, no indication of a toxic reaction in the peritoneal cavity was found. Application of NSO to the peritoneal surfaces of rats in group 3 after creation of the adhesion model resulted in a significant reduction in postoperative macroscopic adhesion and microscopic fibrosis scores. Inflamma- tion and vascularization scores were lower in the rats in this group. As shown in Table 1, the mean adhesion score in group 2 was significantly higher than that in group 3 (P = 0.003). Group 3 had lower microscopic fibrosis scores than group 2 (P = 0.002). Statistically significant differences in microscopic inflammation and vascular- ization scores were found between groups 2 and 3 (P = 0.001 and P = 0.004, respectively). A. Sahbaz et al. 534 © 2013 The Authors Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology 14470756, 2014, 2, D ow nloaded from https://obgyn.onlinelibrary.w iley.com /doi/10.1111/jog.12172 by B ezm -I A lem V akif U niversity, W iley O nline L ibrary on [08/10/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense Discussion Multiple mechanisms may underlie the NSO-mediated reduction in adhesion formation. Although the etiol- ogy of pelvic adhesion formation is not completely understood, the inflammatory response has long been recognized as a common denominator in all pathways of adhesion formation. ROS, such as the superoxide anion radical (O2 –), hydrogen peroxide (H2O2), the hydroxyl radical (OH–) and hypochlorous acid (HOCl–), are produced at high levels during the first few minutes of tissue ischemia created by surgery.26 These electrically charged molecules damage cellular structures, resulting in cytolysis. As a result of cytolysis and lipid peroxidation of the cellular membranes, vascular permeability increases, which leads to the formation of serosanguineous exudate; this in turn ini- tiates adhesion formation. ROS scavengers have been described as reducing the inflammatory reaction and thus adhesion formation in rats19,20 and rabbits.18 These published findings provide clear evidence that both NSO and the active ingredients of NS, particularly thy- moquinone, exert reproducible antioxidant effects by enhancing the oxidant scavenger system.27,28 This anti- oxidant activity may be one of the mechanisms by which NSO reduces adhesion formation. Progression and persistence of an acute or chronic state of inflammation are mediated by eicosanoids, oxi- dants, cytokines and lytic enzymes. These are secreted by macrophages and neutrophils. In addition to that induced by ROS, inflammation is also mediated by two principal enzymes: cyclooxygenase (COX) and lipoxy- genase (LO). COX catalyzes production of arachidonic acid, prostaglandins and thromboxane, while LO cata- lyzes the formation of leukotrienes. These inflamma- tory mediators may play an important role in adhesion formation.29 Anti-inflammatory drugs have been widely accepted to reduce adhesion formation in mice,30 rats16,17 and rabbits.31,32 Several in vitro studies reproducibly reported the inhibitory effects of NSO and the active ingredients of NS on the production of these mediators. Inhibition of both the COX and 5-LO pathways and exertion of an anti-inflammatory effect may also mediate the adhesion-preventing effect of NSO. Because pathogen contamination can enhance the inflammatory response in the peritoneum, and because this response may enhance adhesion formation, locally and systemically administrated antibiotics have been tested in terms of PPA prevention.33,34 NS seeds have been reported to exert antimicrobial activities,35,36 which may contribute to their anti-adhesion effect. The viscosity of NSO may mediate, at least in part, its anti- adhesion effects, by causing formation of a layer that prevents contact between peritoneal surfaces and those exposed to trauma. Table 1 Mean adhesion, fibrosis, inflammation and vascularization scores Parameters Group 2 (n = 8) Group 3 (n = 8) P Count Mean � SEM Count Mean � SEM Adhesion score 0 0 2.75 � 0.16 0 1.75 � 0.16 0.003 1 0 2 2 2 6 3 6 0 Fibrosis score 0 0 2.63 � 0.18 0 1.38 � 0.18 0.002 1 0 5 2 3 3 3 5 0 Inflammation score 0 0 2.63 � 0.18 0 1.13 � 0.12 0.001 1 0 7 2 3 1 3 5 0 Vascularization score 0 0 2.00 � 0.18 0 1.13 � 0.12 0.004 1 1 7 2 6 1 3 1 0 SEM, standard error of the mean. Efficacy of NS for prevention of adhesions © 2013 The Authors 535 Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology 14470756, 2014, 2, D ow nloaded from https://obgyn.onlinelibrary.w iley.com /doi/10.1111/jog.12172 by B ezm -I A lem V akif U niversity, W iley O nline L ibrary on [08/10/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense In conclusion, this study is to our knowledge the first to assess prevention of PPA formation by NSO. Our results show that application of NSO after cecal abra- sion led to significant reductions in the macroscopic adhesion, microscopic fibrosis, inflammation and vas- cularization scores. Considering its many beneficial effects and its use in folk medicine, NS is a promising agent for the prevention of PPA. Further studies should assess the effects of NSO in human subjects in comparison with other agents that prevent adhesion formation. Disclosure The authors have nothing to disclose. References 1. Ellis H, Moran BJ, Thompson JN et al. Adhesion-related hospital readmission after abdominal and pelvic surgery: A retrospective cohort study. Lancet 1999; 353: 1476–1480. 2. 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Studies on the antimicrobial activity of Nigella sativa seed (black cumin). J Ethnopharmacol 1991; 34: 275–278. Efficacy of NS for prevention of adhesions © 2013 The Authors 537 Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology 14470756, 2014, 2, D ow nloaded from https://obgyn.onlinelibrary.w iley.com /doi/10.1111/jog.12172 by B ezm -I A lem V akif U niversity, W iley O nline L ibrary on [08/10/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense