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Assignment on Literature review Submitted by, Ms. Bini Balakrishnan 079/ July 2012 Department of Physiology, Yenepoya Medical College. Topic: Effect of Nigella sativa in Endosulfan induced toxicity in Wistar albino rats Review of literature: I. Endosulfan Pesticides are economically important chemicals and their use in agriculture has increased crop yields leading to a decrease in food costs. Endosulfan is a widely used insecticide belonging to the cyclodiene group of organochlorine pesticides1.This chemical is sometimes found to affect non-target organisms including human, in the course of its application. 2 Reports are available on the physical and chemical as well as toxicological effects of endosulfan in animals3.Population that are usually susceptible to endosulfan include the unborn and neonates, the elderly and people with liver, kidney, immunological haematological or neurological disease 2. Endosulfan is highly toxic, regardless of route of its exposure 1.causing in-coordination, imbalance, difficulty in breathing, gagging, vomiting, diarrhoea, agitation, convulsions, loss of consciousness, and central nervous system disorders 2. Chronic exposure results in liver enlargement, seizures, reduced growth and survival, changes in kidney structure and blood parameters. Endosulfan is known to get excreted from the mammary gland via the human breast milk in a comparatively higher rate than other pesticides 1. This is a highly toxic pesticide and a potential endocrine disruptor. Its half-life ranges from few months to years in soil and 1-6 months in water depending on pH and other climatic conditions. The Environmental Protection Agency (EPA) has classified endosulfan as a toxicity class Ib chemical and is a major environmental concern because of its persistent nature 4. Endosulfan persists in the environment and bio accumulates in animals and plants, leading to instances of food contamination and eventually dietary exposure in humans 5 II. Endosulfan induced toxicity in experimental animals In a short term toxicity test of endosulfan on amphibian animal models revealed that low concentrations can be very highly toxic to amphibians and have suggested that this mortality may exhibit important lag effects 6. In a recent study they found that sub lethal dose (0.32 ppm/kg-1 bw) of endosulfan after15, 30 and 45 days of exposure to five week of albino rats resulted in histopathological changes in renal tissue and endosulfan induced severe renal damages. They concluded that endosulfan is a nephrotoxic chemical and that exposure produces significant renal toxicity, in rats4. According to a recent study endosulfan decreases reproductive parameters such as sperm count, motility and testicular weight. The concentration of hormones such as LH and FSH were significantly more while testosterone underwent a meaningful decrease. Hence this study found that the above may lead to infertility due to the changes in sex hormones concentration and sperm count and motility 7. Following intravenous administration of endosulfan in Sprague–Dawley adult rats under urethane anesthesia at doses from 0.5 to 4 mg/kg resulted in increase in electro encephalogram (EEG) power and the evoked potentials (EP) and large increase of cortical evoked potentials at low doses of endosulfan8. Consumption of endosulfan at low dose for longer duration can ultimately lead to differential alterations of Monoamines (an important class of neurotransmitters) in various regions of the rat central nervous system. An acute neurotoxicity study in rats (gavages) showed a greater sensitivity of females compared to males9. In a study following single oral administration of 14C-Endosulfan to male Sprague – Dawley rats and multiple oral dosages resulted in cell death in rat and human glial and neuronal cell cultures, α - endosulfan manifested selective neurotoxicity 10. A recent study of investigation of the activities of Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in the adult rat brain, after subchronic endosulfan treatment resulted in systemic toxicity in mammals and induces reactive oxygen species (ROS) and lipid peroxidation (LPO). Oxidative stress was manifested by induction of LPO as determined by higher malondialdehyde levels. This was accompanied by elevation of Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) activities. They also found the protective measures of Vitamins E and C, well-known antioxidants, protected the brain from these effects11. In a study it is found that endosulfan reduced ovarian size in mice associated decrease in healthy ovarian follicles, corpora lutea and increase in atretic follicle 12. III. Protective measures from endosulfan toxicity: In a recent literature, they had studied the hazardous impacts of endosulfan on olfactory system, which play a major role in analyzing and perceiving the sense of smell, choice of mate, and food localization in Swiss mice. The deleterious effects caused by endosulfan have been linked to its ability in alterations of ATPase levels. Hence, there is an urgent need to establish a counter policy by means of food regime which can check oxidative stress caused as a result of environmental stressors. Antioxidants like resveratrol, alpha lipoic acid and vitamin E as potential therapeutic agents in counterbalancing negative health hazards of endosulfan on the normal functioning of brain. The result had found the inherent potential of antioxidants against endosulfan induced neurotoxicity in the olfactory lobe of mice13. In a study of possible protective effects of vitamin E and C against endosulfan induced toxicity in rats showed that Vitamin C and E ameliorated the endosulfan induced oxidative stress oxidative stress and sperm toxicity in rats.14 In an in vitro study effect of antioxidant vitamin E on rat erythrocytes against endosulfan toxicity showed the effectiveness of Vitamin E15. Recent studies are showing the protective effects of phytochemicals in pesticide induced toxicity. In endosulfan induced toxicity, some studies proved that protection is possible. A recent study revealed the protective effect of Ocimum sanctum against endosulfan induced immunotoxicity in male Wistar rats. It is found that Ocimum sanctum has immunomodulatory effect.16 IV. Nigella sativa Nigella sativa is one among the indigenous medicinal plants with lot of health benefits. Nigella sativa is an annual flowering plant, native to South West Asia .It grows to 20-30 cm in tall , finely divided linear leaves .The flowers are delicate ,and usually coloured pale blue and white, with 5-10 petals, the fruit is a large and inflated capsule composed of 3-7 united follicles, each containing numerous seeds .This seed is used as spice. Kingdom : Planate Division : Magnoliophyta Class : Magnoliopsida Order : Ranunculales Family : Ranunculaceae Genus : Nigella Species : Sativa Seed vessels contain seeds, usually three cornered, with two sides flat and are convex, strong agreeable aromatic odour like that of nutmegs and a spicy pungent taste. Nigella sativa has been used for medicinal purposes for centuries both as a herb and pressed into oil in Asia, Middle East and Africa. It has been traditionally used for a variety of conditions and treatment related to respiratory health, stomach and intestinal health, kidney and liver function, circulatory and immune function support, and for general wellbeing. In Islam, it is regarded as one of the greatest forms of healing medicine available. The Islamic prophet Muhammed once stated that the black seed can heal every disease except death. In the Unani Subsystem of medicine, Nigella sativa is regarded as a valuable remedy for a number of diseases. The seeds have been traditionally used in the Middle East and South East Asian countries to treat ailments including, asthma, bronchitis, rheumatism, and related inflammatory diseases, to increase milk production in nursing mothers, to promote digestion and to fight parasitic infections. Its oil has been used to treat skin condition such as eczema and boils and to treat cold symptoms. Nigella sativa Seeds are used as a carminative, stimulant, diuretic, anthelmintic, galactogogue. It is useful in indigestion, loss of appetite, diarrhea, amenorrhea and dysmenorrhea. To arrest vomiting, seeds are roasted and given internally. Seeds contain, numerous ester of structurally unusual unsaturated fatty acids with terpene alcohols (7%), trace of alkaloids are found which belong to two different types, isochinoline alkaloids are represented by nigellimin and nigellimin -n-oxide and nigellicin. In the essential oil, thymoquinone was identified as the main component (up to 50%). 17 In a study it is found that confirmed the gastric antisecretory and antiulcer activity of Black seed in a well-conceived, nicely designed and perfectly executed experimental study. It provides the most recent and intricate details of the pathogenesis of gastric ulcers and the target of effective antiulcer drugs. They administered black seeds aqueous suspension to experimental animals. The biochemical parameters determined the etiopathology of ulcer disease and the mechanism of drug induced gastroprotection further strengthen the finding of the study. 18 In another study it is found that Nigella relieves the deleterious effect of ischemia reperfusion injury on liver. Intraperitoneally infused NS is administered before ischemia and before reperfusion. Blood samples and liver tissues were harvested, enzymes were measured. They concluded that, NS treatment protects the rat liver against to hepatic ischemia-reperfusion injury. 19 According to a recent study found the role of NS and a number of its antioxidant constituents towards azoxymethane-induced genotoxic effects and colon cancer in rats. Result showed that, NS revealed inhibitory effects on DNA damage in the azoxymethane -treated rat. Thymoquinone the constituent of NS inhibited maloandialdehyde (MDA) content in the liver. They concluded that the inhibitory effects might depend on the combined competitive inhibition of various antioxidant constituents of this plant. 20 One recent study had done the role of nigella in diabetes. It showed the multiple molecular targets underlie the antidiabetic effect of NS seed extracts in skeletal muscle, adipocyte and liver cell. They found that Nigella sativa seed Ethanol extract(NSE)induces an important insulin like stimulation of glucose uptake in C2C12skeletal muscle cell and 3T3-L1 adipocytes following 18 hrs treatment. They concluded that, NS seed oil can be used as a treatment for diabetes, for obesity and metabolic syndrome. 21 It is found that Non opioid drug Nigella sativa is effective in long term treatment of opioid dependence. It not merely cures the opioid dependence but also cures the infections and weakness from which majority of addicts suffer.22 References: 1. Manjula S D, Benjamin S and Laxminarayana K. Modulatory Effect of Vitamin C on Genotoxic Effect of Endosulfan in Developing Albino Rats Iranian journal of pharmacology and therapeutics. 2006; 5:113-116 2. Khan S and Kumari D. Analytical study of histopathological changes induced by of endosulfan in kidney of Albino rats Asian journal of pharmaceutical and clinical research 2012; 5(1):113-114 3. Khan S and Kumari D. Biochemical effects of Endosulfan in liver of albino rats. International journal of pharmacy and pharmaceutical sciences. 2011; 3(4):290-291 4. Vimala Vemireddi. Immunotoxic and Oxidative Effects of Endosulfan and Permethrin on Murine Splenocytes, in vitro. Toxicology. 2006; 5(3): 129-140 5. Victer Briz et.al, Differential estrogenic effects of the persistent organochlorine pesticides dieldrin, endosulfan and lindane in primaryneuronal cultures. Toxicological sciences. 2011; 4: 119-122 6. Jones D K, Hammond J I and Relyea R A. Very highly toxic effects of endosulfan across nine species of tadpoles: lag effects and family-level sensitivity. Environmental Toxicology and Chemistry. 2009; 28(9): 1939–1945 7. Modaresi M, Seif MR. Effects of Endosulfan on the Reproductive Parameters of Male Rats. Journal of Reproductive Infertility. 2011; 12(2):117-122 8. Scremin O U, Chialvo D R, Lavarello S, Berra H H and Lucero M A. The environmental pollutant endosulfan disrupts cerebral cortical function at low doses. NeuroToxicology. 2011; 32: 31–37 9. Li D, Liu J, Li J. 2010. Genotoxic evaluation of the insecticide endosulfan based on the induced GADD153-GFP reporter gene expression. Environ Monit Assess. 2010; 5(3): 142-146 10. Chan M P L, Morissawa S, Nakayama A and Yoneda M. Evaluation of health risk due to the exposure to endosulfan in the environment. AATEX. 2007; 5(2): 543-548 11. Zervos IA et. al, . Endosulfan-induced lipid peroxidation in rat brain and its effect on t-PA and PAI-1: ameliorating effect of vitamins C and E. J Toxicol Sci. 2011; 36(4):423-33 12. Azarnia L et. al, Histological examination of endosulfan effects On follicular development of balb/c mice. Bulgarian Journal of Veterinary Medicine. 2008; 12(1): 33−41 13. Preeti Singh and Habiba Bano. A Study Showing the Ameliorative Potential of TransResveratrol, α- Lipoic Acid and Vitamin E on Endosulfan Induced Alterations in the ATPase in Olfactory Lobe of Male Swiss Albino Mice. Toxicology Journal. 2012; 2(2): 219-21 14. Vol 37, No 3, September Takhshid M A, Tavasuli A R, Heidary Y, Keshavarz Y, Kargar H. Protective Effect of Vitamins E and C on Endosulfan-Induced Reproductive Toxicity in Male Rats. IJMS 2012; 37(3): 113-115 15. Saxena R, Garg P, Jain D K. In vitro antioxidant effect of Vitamin Eon oxidative stress induced due to pesticides in rat erythrocyte. Toxicology international. 2011; 18(1): 125-129 16. Bharath B.K et, al. Imuuno-modulatory effect of Ocimum sanctum against endosulfan induced immunotoxicity. Veterinary World 2011;4 (1):25-27 17. Gargari P M, Attary V E, Gorbani M R A. Effect of dietary supplementation with Nigella sativa Lin. on serum lipid profile, lipid peroxidation, and antioxidant defence system in hyperlipidemic rabbits. Journal of Medicinal plants Research. 2009; 3(10):815-821 18. Al Mofleh IA, Al Haider AA, Mossa JS, Al-Sohaibani MO, Al-Yahya MA, Rafatullah S. Gastroprotective effect of an aqueous suspension of black cumin Nigella sativa on necrotizing agents-induced gastric injury in experimental animals. Saudi J Gastroenterol. 2008;14(3):128–34. 19. Yildiz F, Coban S, Terzi A, Ates M, Aksoy N, Cakir H, Ocak AR, Bitiren M.Nigella sativa relieves the deleterious effects of ischemia reperfusion injury on liver. World J Gastroenterol. 2008; 14(33):5204-9. 20. Al-Johar D, Shinwari N, Arif J, Al-Sanea N, Jabbar AA, El-Sayed R, Mashhour A, Billedo G, El-Doush I, Al-Saleh I. Role of Nigella sativa and a number of its antioxidant constituents towards azoxymethane-induced genotoxic effects and colon cancer in rats. Phytotheraphy Res. 2008; 22(10):1311-23 21. Benhaddou-Andaloussi A, Martineau LC, Vallerand D, Haddad Y, Afshar A, Settaf A, Haddad PS. Multiple molecular targets underlie the antidiabetic effect of Nigella sativa seed extract in skeletal muscle, adipocyte and liver cells. Diabetes Obes Metab. 2009; 3(10):815-21 22. Sangi et, al. A new and novel treatment of opioid dependence: Nigella sativa 500 mg. Ayub J Med Coll Abbottabad 2008;20(2):1136-39 23. Ebru U, Cardioprotective effects of Nigella sativa oil on cyclosporine A-induced cardiotoxicity in rats. Basic Clin Pharmacol Toxicol. 2008 Dec;103(6):574-580. 24. El-Bahai MN, Al-Hariri MT, Yar T, Bamosa AO. Cardiac inotropic and hypertrophic effects of Nigella sativa supplementation in rats. Int J Cardiol. 2009 Jan 24;131(3):e115-7. Epub 2007 Nov 1 25. Ebru U, Burak U, Yusuf S, Reyhan B, Arif K, Faruk TH, Emin M, Aydin K, II, Semsettin S, Kemal E. Cardioprotective effects of Nigella sativa oil on cyclosporine A-induced cardiotoxicity in rats. Basic Clin Pharmacol Toxicol. 2008 Dec;103(6):574-580.