Oral administration of Nigella sativa oil ameliorates the effect of cisplatin on brush border membrane enzymes, carbohydrate metabolism and antioxidant system in rat intestine
Introduction
Cisplatin (CP) or cis-diamminedichloroplatinum II is one of the most extensively used antineoplastic drug containing a central platinum (II) atom, coordinated to two amine groups and two chloride ions, in cis configuration. It is used to treat various human cancers including oral, lung, head and neck, testicular, ovarian and advanced bladder cancer (Dugbartey et al., 2016, Kang et al., 2016). Unfortunately, its beneficial antitumor action is associated with numerous untoward side effects including gastrointestinal toxicity, that limit its application in clinical oncology. Gastrointestinal dysfunction is accompanied by delayed gastric motility, nausea and emesis with 67% of patients undergoing diarrhoea (Bearcroft et al., 1999, Song et al., 2012).
The BBM lining the epithelial cells of small intestine is one of the most sensitive and highly differentiated cellular membrane that performs a variety of digestive and transport functions. Histological examination of small intestine of CP treated rats has revealed that CP impairs the mucosal structure by causing degeneration and desquamation of the intestinal villi, culminating into acute epithelial necrosis and apoptosis (Chang et al., 2002).
Multiple lines of evidences suggest the role of free radicals and reactive oxygen species (ROS), such as superoxide anion and hydroxyl radical, in the pathogenesis of CP induced toxicity. These radicals react with cellular macromolecules including nucleic acid, proteins and lipids and cause extensive tissue damage (Katanic et al., 2015). ROS are considered as one of the major causative factors for CP induced mucosal lesions (Naqshbandi et al., 2011, Arivarasu et al., 2013). It has been previously shown that CP treatment results in lowered activities of BBM marker enzymes and various antioxidant enzymes along with an increased production of ROS in rat intestine (Arivarasu et al., 2007, Naqshbandi et al., 2011). In addition, CP has been reported to deplete protein bound sulfhydryl groups and glutathione, cause lipid peroxidation and mitochondrial dysfunction, thereby impairing fluid and electrolyte absorption in small intestine (Chang et al., 2002, Khan et al., 2012). Thus, it is imperative to explore effective preventive measures to protect the intestine from CP induced injuries and damage, that subjugate CP administration at tumoricidal doses.
In the past few years, several studies with combinatorial strategies have been attempted to curtail the side effects of CP therapy on normal tissues. 5-HT3 (5-hydroxytryptamine) receptor antagonists (Kishibayashi et al., 1993), anti-inflammatory agents (Roos et al., 1981), amino-acids (Tazuke et al., 2011) and vitamins (Bodiga et al., 2012) were tested against CP induced intestinal toxicity, however none of them were found to be clinically applicable.
Recently, much research effort is being focussed on the use of naturally occurring dietary antioxidants to counteract drug induced toxicities, especially where free radical generation is involved (Kang et al., 2016, Katanic et al., 2015, Khan et al., 2009). Several studies have reported the ameliorative potential of plant derived antioxidants such as caffeic acid (Arivarasu et al., 2013), chrysin (Khan et al., 2012), fucoidan (Song et al., 2012), flaxseed oil (Naqshbandi et al., 2011) and ferulic acid (Badary et al., 2006), against CP induced intestinal toxicity. Nigella sativa (NS), a member of family Ranunculaceae, is one of the promising medicinal plant that is known to possess health enhancing potential owing to its rich phytochemistry. NS seeds contain more than 30% of fixed oil, proteins (including 8–9 essential amino acids), alkaloids (nigellicine, nigellidine and nigellimine), saponins viz. α-heredin, bioactive phytosterols, and 0.4–2.5% essential/volatile oil (Ali and Blunden, 2003, Hosseinzadeh et al., 2007; Salem, 2005). The fixed oil is composed mainly of polyunsaturated fatty acids (PUFA), viz. ω-3 and ω-6 PUFA, in the recommended optimal dietary intake ratio of 1:4 (Yehuda and Carasso, 1993), while the volatile oil is rich in thymoquinone, thymol, thymohydroquinone, dithymoquinone, p-cymene and carvacrol (Ahmad et al., 2013). NS seed and its oil have been reported to exert a novel spectrum of pharmacological properties/activities such as antioxidant, anti-inflammatory, anti-diabetic, gastroprotective and hepatoprotective. Much of the biological activity of the NS oil has been attributed to its major bioactive constituent, thymoquinone, which is a potent scavenger of free radicals viz. superoxide anion and hydroxyl radicals (Ali and Blunden, 2003, Gholamnezhad et al., 2015). It has been reported previously that administration of NSO and/or its bioactive constituent thymoquinone, protects against gastric mucosal injury induced by ethanol and ischemia/reperfusion in rats (Kanter et al., 2005, El-Abhar et al., 2003). A.M. Fayez et al. have shown that thymoquinone and ω-3 fatty acids provide protection against renal dysfunction induced by intestinal ischemia/reperfusion (Fayez et al., 2014). Furthermore, thymoquinone was also found to enhance the anti-tumor activity of CP against Ehrlich ascites carcinoma, while ameliorating its nephrotoxic effects (Badary et al., 1997). We have recently shown that NSO protects against the CP induced deleterious effects on liver (Farooqui et al., 2016). However, to the best of our knowledge no study has been carried out, so far, to investigate the protective efficacy of NSO against CP induced intestinal damage. In view of this, the objective of the present study was to evaluate the potential of NSO to protect against CP-induced gastrointestinal toxicity.
Section snippets
Chemicals and drug
Nigella sativa oil: Mohammedia Products, Red Hills, Nampally, (Hyderabad, Andhra Pradesh, India), Cisplatin: Sigma-Aldrich Chemical Corp. (St. Louis, MO, USA). All other chemicals used were of analytical grade and were purchased either from Sigma Chemical Corp. or from SRL (Mumbai, India).
Diet
A nutritionally adequate laboratory pellet diet was obtained from Aashirwaad Industries, Chandigarh (1544, Sector 38-B, Chandigarh, India).
Experimental design
Animal experiments were conducted according to the guidelines of
Results
The present work was undertaken to study the effect of oral administration of NSO on CP induced changes in intestinal BBM enzymes, carbohydrate metabolism enzymes and the antioxidant status of rat intestine.
Discussion
CP is the most effective synthetic anticancer drug extensively used against diverse spectrum of malignancies (Dugbartey et al., 2016). However, gastrointestinal toxicity characterized by generalized mucositis of the gastrointestinal tract, is a major complication that reduces drug compliance in patients undergoing cancer chemotherapy with this drug (Arivarasu et al., 2013, Naqshbandi et al., 2011). Thus, there is a pressing need to investigate novel therapeutic agents against gastrointestinal
Conclusion
In conclusion, our results suggest that ROS and free radicals could contribute to the toxic effect of CP on the intestinal mucosa and that the treatment with NSO considerably alleviates the CP induced biochemical and histological changes in intestine. Prevention of CP induced oxidative damage is the underlying mechanism of NSO mediated protective effects on intestinal functions. Thus, NSO may have a potential for clinical application, to abrogate the accompanying gastrointestinal toxicity in CP
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgment
The authors gratefully acknowledge University Grants Commission (UGC), New Delhi for the award of Senior Research Fellowship (under MANF scheme) to F.S and Z.F.
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