Advance Pharmaceutical Journal 2016; 1(5): 119-125 119 Review Article

A Review on Medicinal Stricta Decne Aisha Al Maharooqi, Mariya Al Hilali, Zainab Al Hinai, Dhanalekshmi Unnikrishnan* Medical College (In academic partnership with West Virginia University), Muscat, Sultanate of Oman

Received: 14 December 2016 Revised: 25 December 2016 Accepted: 07 January 2017 Abstract Objective: Medicinal with its numerous bioactive compounds such as alkaloids, flavonoids, phenolics, etc., are nature's gift to the world. It is time to revisit our thinking towards natural remedies to find useful natural products with interdisciplinary approach. Conventional allopathic drugs prescribed for the treatment of diseases are associated with numerous side effects and so there is a need for valuable, safe and superior drugs for different ailments. Considering Rhazya stricta plant, there is a large scope for scientific evaluation based on the active principles it possess as per different scientific reports. This plant has extraordinary medicinal potential to hit upon new chemical leads for pharmaceutical use. The research work done with this plant by various scientists should be appreciated. The main aim of this article is to review most of the scientific reports available for Rhazya stricta Decne ( R. Stricta ), an arid plant available and grown a lot in Middle East countries. Conclusion: This review consolidated the main phytochemical and pharmacological activity reported on R. Stricta . Based on this review, we concluded that there is a lacuna of research on other aspects of R. stricta such as toxicology, safety and genomic studies. More intricate studies are needed for other pharmacological activity also for reaching precise conclusion. As there is a need for developing new drug, this plant may act as a potent source for promising lead molecule in support of upcoming researchers. Keywords: Rhazya stricta, phytochemicals, pharmacological, alkaloids.

Introduction about a single plant in detail that helps to focus on future Nature is the world's best medicine. Most of the bioactive study about the plant with novel technology. With the advent components present in the natural plants and food may delay or of genomics, proteomics, glycomics and metabolomics and prevent the onset of many diseases such as cancers, diabetes and with major advances in techniques for analyses (e.g. arthritis etc. It has been reported since long about the medicinal surface-enhanced laser desorption ionization time-of-flight potency of herbal plants. Many herbs used for medical purposes mass spectrometry), chemical synthesis and high- come from common plants only. There are times when it might throughput screening of active compounds, there is an be smarter to use an herbal remedy than pharmaceuticals unprecedented opportunity to evaluate and explore the huge because natural medicine offers a safer alternative. We should medicine chest that is embedded in herbs. So, this review respect the power that many natural plants can have on our consolidated most of the scientific report available for health. In fact, many pharmaceutical drugs are based on the Rhazya stricta Decne ( R. Stricta ), an arid plant available and synthesized versions of naturally occurring compounds found in grown a lot in Middle East countries. plants. In recent years, interest in herbal medicine has Description of the Plant skyrocketed leading to a greater scientific interest in the The genus Rhazya comprises mainly of two species, namely medicinal use of plants. Many research studies and clinical trials Rhazya stricta Decne and Rhazya orientalis (Ali et al., have shown that plants are capable of treating disease and 2000a). Rhazya stricta Decne ( R. stricta ), commonly known improving health, often without any significant side effects. By as Harmal, Ishrik etc., is a parched plant belongs to the keeping the above mentioned points in mind, it is good to know family . It is widely distributed throughout *Address for Corresponding Author: Western Asia from to Arabia throughout the Middle Dr. Dhanalekshmi Unnikrishnan East, to the North West Province of , South Asia and Oman Medical College (In academic partnership with West Virginia abundantly found in various regions of (Gilani et University), Muscat, Sultanate of Oman al., 2007; Imededdine et al., 2016; Nabih et al., 2010). E-Mail: [email protected] Rhazya species were called after the name of a Muslim

www.apjonline.in Advance Pharmaceutical Journal 2016; 1(5): 119-125 120 scientist Abu Bakr Mohammed bin Zakariya Al-Razi, known in 1994). The R. stricta leaves have been shown to contain Europe mostly under the Latinized name of Rhazes (Batanouny flavonoids, glycosides, triterpenes, tannins, volatile bases et al., 1999). The plant is a glabrous erect shrub, about 90 cm and probably other substances (Ahmed et al., 1983; high (Jafri, 1966), with a smooth central stem and dense semi- Baeshen et al., 2010). erect branches (Western, 1989); leaves alternate, 6 to 10 × 1 to 2 Review report submitted by different groups cm, elliptic–lanceolate, thick or leathery, sessile, turning yellow with age; flowers white in short branched cymes; fruit pale Gilani et al. (2007) reviewed the phytochemical, yellow follicles; seeds shortly winged (Jafri, 1966). Some pharmacological and ethnobotanical studies of R. stricta . research proceedings mentioned R. stricta as an evergreen They reported phytochemical and pharmacological aspects poisonous shrub, has covered large hilly areas of Pakistan. R. of the species have been investigated by many research stricta like other weeds compete with the main crops for groups but pharmacological activities are evaluated only nutrients and other resources and hamper the healthy growth for a few of the isolated alkaloids from R. stricta . There is a ultimately, reducing the yield both qualitatively and particular need for ethnobotanical studies of R. Stricta in quantitatively (Khan et al., 2011). various regions of Middle Eastern countries and in South Asia where the species grows. Gilani et al. (2007) Folklore claims for medicinal use concluded that more ethnomedical and pharmacological R. stricta is a medicinal plant used in folk medicine to treat studies are recommended for R. stricta with the ultimate diseases such as diabetes mellitus, fever, sore throat, and syphilis goal of benefiting local communities in regions where this (Adam, 1998; El-Ghonemy, 1993). It's used in the treatment of plant grows. This should be accomplished by sharing diseases like boils, eruptions, red sore, infected and swollen knowledge and also through the manufacture of herbal eyes, skin rashes, colic and stomach pain etc. It is also used as a drugs from R. stricta 's active chemical constituents general coolant and is famous for treating jaundice, anemia like following the World Health Organization's guidelines for symptoms in pregnant women and problems associated with safety and efficacy. child development, also effective for treatment of Khan et al. (2012) reviewed the phytochemistry, biological gastrointestinal parasites, such as round worm and flat worms. It and pharmacological activities, and ethno medicinal uses of is also used for drying up haemorrhoids (Ahmad et al., 2007). R. stricta. Appreciable pharmacological and biological Leaves and roots are useful for moth blisters, dysentery, jaundice activities are mainly due to the presence of more than 100 (Tareen et al., 2010), diabetes, general debility, chronic alkaloids and a few non alkaloids in the plant. They rheumatism and tumour (Qureshi et al., 2012). Extract of leaves reviewed that phytochemicals in the plant have been is prescribed in folkloric medicine for the treatment of various reported to exhibit ambulatory, antifungal, antimicrobial, disorders such as diabetes, sore throat, helminthiasis, antioxidant, endogenous monoamine oxidase (MAO) A and inflammatory conditions and rheumatism (Mohammed N B inhibitory and herbicidal activities. Those Baeshen et al., 2015). It is widely used in traditional medicine as phytochemicals also showed effects on arachidonic acid a reputed tonic and curative for rheumatic pain, sore throat, (AA) metabolism, blood pressure, central nervous system syphilis, diabetes, helminthiasis, inflammatory conditions, fever (CNS), immunity, smooth muscles and glucose and other diseases (Ali et al., 1995; Ali et al., 1998). homeostasis. Sarfaraz Khan et al. (2012) suggested doing Documented Phytochemicals- Brief Note more research work for exploring its medicinal importance R. stricta is an important medicinal species that is rich in due to its richness of phytochemicals. R. stricta has alkaloids containing mostly anticancer alkaloids and few non immense potential as an antimicrobial; therefore, such alkaloidal compounds (Gilani et al., 2007). Over 100 alkaloids studies are highly suggested for research activity. have been isolated from R. stricta , but the pharmacological Ali et al. (2000b) reviewed the phytochemical, activities are known for only a few of these compounds. It is an pharmacological and toxicological properties of the important medicinal species used in indigenous medicinal medicinal plant R. Stricta . Other than alkaloids they herbal drugs to cure various diseases in South Asia and the reported the presence of few flavonoids also. However, they Middle East (Gilani et al., 2007). Most of the activities of the reported that the biological activity of these compounds has plant reside in its alkaloidal fractions (Khan et al., 2012). A few not been studied clearly. R. Stricta alkaloids which cause flavonoids have been isolated and their structures and depression of the central nervous system and hypotension stereochemistry are characterized (Ali et al., 2000b). The leaves have not been explored completely. Extracts of R. stricta of the plant contain alkaloids with β-carboline nucleus namely appear to have low toxicity also, so it's inadvisable to be akuammidine, rhazinilam and tetrahydrosecamine (Bashir et al., used by pregnant women.

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Baeshen et al. (2015) reviewed the therapeutic potential of actions of the plant extract may be due to folkloric medicinal plant Rhazya stricta in detail and reported immunomodulatory capacity and it was tested in peritoneal that extract contains alkaloids, glycosides, flavonoids, tannins macrophage-derived cytokines in mice. Each mouse and triterpenes. They stated that several preclinical studies received an alkaloidal fraction of R. stricta and peritoneal reported that the leaves extract causes sedation, analgesia, anti cells were isolated, cultured and assayed for IL-1 alpha and cancer, decreases motor activity and have anti-depressant, anti- TNF alpha using an Enzyme Linked Immunosorbent Assay oxidant activity, complex effect on brain endogenous (ELISA) technique. The alkaloidal fraction of R. stricta monoamine oxidase activity and central mediated hypotension. significantly increased the production of these two The genotoxicity of Rhazya stricta leaves was demonstrated by proinflammatory cytokines (Tanira et al., 1998). Baeshen and colleagues in a battery of tests. They also Effect on arachidonic acid (AA) metabolism demonstrated the effect of Rhazya stricta in insulin insensitivity, Rhazimine alkaloid isolated from R. stricta leaves has been MDRs (multi-drug resistant organisms), cardiovascular diseases, studied to describe the effect on AA metabolism in human obesity and some other ailments. They revealed that their blood. It has dual and selective inhibitor effect on platelet research group is presently involved in extensive studies on the activating factor (PAF)-induced platelet aggregation and whole genome of Rhazya stricta which may lead to future AA metabolism in vitro (Saeed et al., 1993). These effects Natural Products Genomics and PDT (Phytodynamic Therapy). might provide additional beneficial anti-inflammatory and Pharmacological Activities anti-PAF effects by comparison with classical non steroidal Antihyperglycemic Studies anti-inflammatory drugs (Saeed et al., 1993). Lyophilized The leaves extract of R. stricta have been used for the treatment and butanol extracts of R. stricta shown significance of diabetes mellitus (Western, 1989; Gonemi, 1992). The reduction in carrageenan-induced inflammation in the rat beneficial effect of R. stricta in diabetes was studied by oral paw edema test, and decrease rectal temperature of pyrexic administration of the decoction to streptozotocin-induced rats. Activity-guided fractionation indicated that the diabetic rats under different experimental conditions. The results potency of anti inflammatory action was about one tenth of showed no improvement in glucose homoeostasis (Wasfi et al., the standard anti-inflammatory drug phenylbutazone 1994). In another experiment, R. stricta leaf extract (Wasfi et al., 1994; Tanira et al., 1996). administrated sub chronically for 28 days (0.5 to 2 g/kg, p.o.) to Antioxidant Studies streptozotocin-diabetic rats showed no effect on either plasma Iqbal et al. (2006) reported the presence of high amount of glucose or insulin concentrations (Tanira et al., 1996a; Ali, 1997). phenolic content and antioxidant potential in the In the report of Ali et al, it was show that oral doses of the leaf methanolic extract of R. stricta leaves. The ethanolic extract extract (0.5, 2 and 4 g/kg) reduced the plasma glucose and of R. stricta fruit has shown significant lipoxygenase and increased insulin levels at 1 and 2 h following administration to acetylcholine esterase activities (Sultana and Khalid, diabetic rats (Ali et al., 2000b). From these research studies, it is 2010). The plant extract have shown good antioxidant clear that a conspiracy still remains in the antidiabetic activity of activity in the animal models of diseases (Ali et al., 1998). R. Stricta. The leaf extract R. stricta showed prominent dose Antihypertensive Studies dependent effect on reduced glutathione (GSH), lipid Lyophilized aqueous extract of R. stricta caused an inconsistent peroxidation (LP) and ascorbic acid (AA) concentrations in effect on heart rate, and a dose-dependent decrease in mean blood the liver and kidneys of rats. It was concluded that the R. pressure (MBP) of urethane-anaesthetized rats (Tanira et al., stricta extract, at some of the doses used, has antioxidant 1996). The maximum reduction amounted to 40% and the actions (Ali et al., 2000). alkaloidal fraction was found to be the most effective in this Herbicidal Activity action. Tanira et al. (2000) reported that using preparations such Kamel and Al-Mutlaq, proved that R. stricta extract has as frank pithed rat, and spinalized rats, it was found that the herbicidal activity by inhibiting the growth of wild radish extract acts centrally, rather than peripherally, to reduce blood without affecting the biological processes in the plant pressure. Recently, the alkaloidal fraction was injected into the (Kamel and Al-Mutlaq, 2004). cerebral ventricles (i.c.v.), and results were similar to those Effect on Smooth Muscles obtained from the i.v. injection (Khan et al., 2012). The lyophilized extract of R. stricta has been tested and Immunological Studies proved that it has relaxing effect on the isolated intestinal The possibility that some of the folkclore claimed therapeutic muscles of the rats (Tanira et al., 1996) because it increases

www.apjonline.in Advance Pharmaceutical Journal 2016; 1(5): 119-125 122 the production of proinflammatory cytokines (Tanira et al., significant effects on comet percent and the mean tail 1998). This plant is having highest antispasmodic drug potential moment value in single. R. stricta extract increased the character that will help in folk medicinal use of the plant (Ali et cytochrome p450 1A1 concentration in mice liver. al., 2000b). However, more work is needed, with the growing interest of the world in complementary and alternative medicines As Food supplements: d- tocopherol & c-tocopherol, feed applications, to investigate possible mechanisms of action stock, minerals of R. stricta leaves using the same method of extraction that R. stricta seed oil d-tocopherol and c-tocopherol, is potentially have been used by humans in the folk medicine (Almostady useful in food and pharmaceutical applications but the safety of et al., 2015). Baeshin et al., 2009 reported that R. stricta leaf this oil must be tested before use for human nutrition extract have strong mutagenic activities as compared with (Imededdine et al., 2016). R. stricta oil which is a potential the potent chemical mutagenic agent NTG (Baeshin et al., source of d-tocopherol is useful for the prevention, delay, or 2009). Their study showed that the increase in treatment of chronic and acute diseases (Imededdine et al., concentration of leaf extract and exposure time led to a 2016). Nutritive analysis of R. stricta revealed that the plant is a decrease in survival percentage and an increase in good source of minerals necessary for maintenance of normal auxotrophic mutation percentage by linear regression physiological parameters (Baloch et al., 2016). They also calculation method. reported that the plant is a rich source of iron, zinc, sodium, Cytotoxic and anticancer Activity potassium, magnesium and calcium which make it drug of choice in the management of anemia, dysentery and jaundice and related Zaman, 1990 reported that R. stricta plant having cytotoxic bone disease (Baloch et al., 2016). A recent study by Imededdine activity against the cell cultures human carcinoma MCF-7 et al. (2016) showed that R. stricta seeds are a source of cells. Cytotoxic action is mainly by the reduction in cell unsaturated oil which can be used as a feedstock for biodiesel proliferation. Depending on extract's type and production. concentration there are different antiproliferative profiles of R. stricta (Zaman, 1990). Antiproliferative effect proved Hypotriglyceridemic and hypocholesterolemic effect against MCF-7 and MDA-MB-231 cells effectively with Marked hypotriglyceridemic and hypocholesterolemic effect of the ethanol extract of Harmal. They potentially inhibited the plant is reported and it may have therapeutic implications on cellular growth and colony formation of human breast patients with hypertriglyceridemia and hypercholesterolemia cancer cell lines, MCF-7 and MDA-MB-231, in a dose- and (Baeshen et al., 2005). More research work is needed to explore time dependent manner (El-Awady et al., 2015). possible mechanisms of action of Rhazya stricta leaves in human Furthermore, it induced sequences of events marked by cardiovascular disorders. The aqueous extract of the R. stricta apoptosis, accompanied by a loss of cell viability, leaves significantly decreased concentrations of TGs, LDL-c, chromatin condensation, DNA fragmentation and cholesterol, uric acid and creatinin, but increased concentration proteolytic cleavage of poly (ADP-ribose) polymerase. of HDL-c. It triggered all these activities without affecting liver Harmal dependent apoptotic mechanisms involved an enzyme activities or kidney functions. These findings may have a increase in the Bax/Bcl-2 ratio and down-regulation of all c- positive impact on the cardiovascular patients and may provide a myc, human telomerase reverse transcriptase, and cyclin new therapeutic strategy to reduce hypertriglyceridemia D1 proteins (Baeshen et al., 2012). (Baeshen et al., 2005). Additionally, the extract significantly Harmal has anticancer activity which could be attributed in decreased concentrations of triglycerides, low density part to its inhibition of proliferation and apoptosis induction lipoprotein, cholesterol, uric acid and creatinine, without of cancer cells through up-regulation and down-regulation affecting liver or kidney functions in rats (Baeshen et al., 2010). of Bcl-2 proteins. Anticancer activitiy of R. stricta against Genotoxicity and antigenotoxicity Effect Hepato-cellular carcinoma (HepG2) and the colon cancer Genotoxic effect of R. Stricta was perceived by cytogenetical and (Caco cells) cell was reported. The results showed that molecular assays against wide range of cell types including extract produced a reduction in cell proliferation and Saccharomyces cervisae (Baeshen et al., 2005) and the primary showed different antiproliferative profiles regarding culture of human lymphocytes (Baeshin et al., 2009). R. stricta extract type and concentrations (El-Awady et al., 2015). extractions not showed any mutagenicity effect on the battery of This study inveterate the reports regard to natural products Salmonella typhimurium mutant tests strains TA98TA79a, to be the most effective in terms of their ability to alter the TA100, TA102 and TA1535. Comet assay results showed function of proteins relevant to cancer, forever (Muhtasib, genotoxicity effect of the R. stricta and its extract produced 2006). Medicinal plants have been curing various disorders

www.apjonline.in Advance Pharmaceutical Journal 2016; 1(5): 119-125 123 in human being from the time immemorial, among the human Conclusion diseases treated with medicinal plants more commonly is cancer This review consolidated the main phytochemical and (Koduru et al., 2007). Rhazya stricta treatment suppressed pharmacological activity reported on R. stricta . This review proliferation and colony formation and effectively induced also revealed that R. stricta has immense pharmacological morphological and biochemical features of apoptosis in U251 activity due to its richness of phytochemicals it possesses. cells. Apoptosis induction was mediated by release of There is a lacuna of research on other aspects such as mitochondrial cytochrome c, increased Bax: Bcl-2 ratio, toxicology and safety as well as intricate studies is needed enhanced activities of caspase-3 and -9, and PARP-1 cleavage. R. for other activity also for reaching precise conclusion. stricta treatment decreased expression levels of nuclear NF- Hence, further detailed research studies are recommended Bp65, survivin, XIAP, and cyclin D1 and increased expression in various parts of the countries especially in Arabian cape level of p53, p21, and Noxa This result provides a useful where it grows, as the nature of phytochemicals and foundation for studying and developing novel chemotherapeutic secondary metabolites composition in R. stricta plant varies agents for the treatment of GBM (Elkady et al., 2015). from one region to another. As there is a need for developing new drug, this plant may act as a potent source for promising Iqbal et al. (2006) proved that Harmal may be a good source of lead molecule in support of upcoming researchers. Further antioxidants. This fact deserves attention since considerable comprehensive study may still be necessary to elucidate the laboratory evidences from chemical, cell culture, and animal pharmacokinetics and pharmacodynamics behind the studies indicate that antioxidants may slow or possibly prevent therapeutic action of this plant. the development of cancer (Kaefer and Milner, 2008; Liu, 2004). Based on the preceding information and lack of any reported References scientific data elucidating the role of Harmal in prevention of Adam SEI. 1998. Toxicity of Rhazya stricta to sheep. human breast cancers, the impact of Harmal extracts on growth Veterinary and Human Toxicology, 40: 68-69. of breast cancer was also examined (Baeshen et al., 2012). Ahmad SS. 2007. Medicinal wild plants from Lahore- Effect on Central Nervous System Islamabad Motorway. Pakistan Journal of Botany, 39: 355-75. Aqueous lyophilized leaves extract of R.stricta showed dose dependent activities in antinociceptive tests and also they Ahmad Y, Fatima K, Le-Quesne PW. 1983. Further produced dose-dependent sedation effect, decreased motor alkaloidal constituents of the leaves of Rhazya stricta . activity, and impaired motor control (Ali et al., 1995). R. stricta Phytochemistry, 27: 1017-1019. has also CNS depressant effect due to present of b-carboline ring Ali AA, Alqarawi AK, Bashir, Tanira MO. 2000. in some phytochemical constituents (Bashir, 1994 and Ali, Antioxidant Action of Extract of the Traditional 1995). Alkaloids present in the plant extract have the ability to Medicinal Plant Rhazya stricta Decne. in Rats. reduce adrenaline concentration in the brain (Tanira et al., 1999). Phytotherapy Research, 14: 469-471. Antimicrobial Studies Ali BH, Al-Qarawi AA, Bashir AK, Tanira MO. 2000b. Rucker et al. (1992); Murakami et al. (1993) reported the Phytochemistry, Pharmacology, and Toxicity of antimicrobial property of R. stricta glycosides and ensures its use Rhazya Stricta Decne: A Review. Phytotherapy as an anti-infective agent. Coumarin which was present in all Research, 14: 229-234. plant extracts, are well known for its antitumor, antibacterial and Ali BH, Bashir AK, Banna NR, Tanira MOM. 1995. Central anthelmintic properties. R. stricta antimicrobial efficacy against Nervous System Activity of Rhazya stricta Decne in both bacteria and fungi revealed that plants have ability to kill or Mice. Clinical and Experimental Pharmacology and inhibit the growth of bacteria and fungi which experimentally Physiology 22: 248-253. support the use of this plant in traditional medicine by traditional Ali BH, Bashir AK, Tanira MO. 1998. Effect of extract of healer (Reddy et al., 2016). Crude methanolic extract (CME) Rhazya stricta, a traditional medicinal plant on rat brain showed effective antileishmanial activity with ED50 14.93 tribulin. Pharmacology Biochemistry & Behavior, 59: µg/ml. Furthermore, the phytochemical analysis of CME and its 671-675. fractions showed the presence of Alkaloids, Flavonoids, Ali BH. 1997. The effect on plasma glucose, insulin, and Phenols, Saponins and Diterpenes. The extract and fractions glucagon levels of treatment of diabetic rats with the were also appreciating for further investigations in future medicinal plant Rhazya stricta, and with (Muhammad et al., 2012). glibenclamide, alone and in combination. Journal of

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