|Year : 2019 | Volume
| Issue : 1 | Page : 58-65
Protective action of picroliv isolated from Picrorhiza kurroa against radiation clastogenecity on mice and cyclophosphamide-induced cytotoxicity in Allium cepa Root
Papiya Bigoniya1, Ankita Warathe2, Chandra Shekar Singh3
1 Department of Pharmacology, Dr. Satyendra Kumar Memorial College of Pharmacy, RKDF University, Gandhinagar, India
2 Department of Pharmacology, Radharaman College of Pharmacy, Ratibad, Bhopal, Madhya Pradesh, India
3 Department of Pharmacology, Kamla Nehru Institute of Management and Technology, Faculty of Pharmacy, Sultanpur, Uttar Pradesh, India
|Date of Web Publication||22-May-2019|
Dr. Papiya Bigoniya
Department of Pharmacology, Dr. Satyendra Kumar Memorial College of Pharmacy, RKDF University, Gandhinagar
Source of Support: None, Conflict of Interest: None
Objective: Wide-scale cell death, following chemo and radiation therapy, is a major concern in clinical therapy of cancer. The need to identify agents with a potential for chemo and radioprotective potential has assumed great importance. The study aims at the evaluation of the efficacy of picroliv, a potent antioxidant derived from the plant Picrorhiza kurroa, as cyto- and radioprotector. Materials and Methods: Picroliv was fed to mice in a dose of 20 and 30 mg/kg, i.p. daily for 15 days following 4 Gy gamma rays exposure. Body weight, mortality, and hematology were assessed along with endogenous spleen colony-forming unit (CFU) and micronucleus (MN) scoring. In vitro cytoprotective activity was assessed on Allium cepa root meristem growth parameters against cyclophosphamide-induced genotoxicity by determination of mitotic index (MI) and chromosome aberrations (CA). Results: Picroliv treatment resulted in reduced body weight loss, recovery of hematological parameters, increased CFU preservation, and reduced MN expression. Picroliv caused an increase in root length and number of A. cepa simultaneously exposed with cyclophosphamide. Cyclophosphamide-induced cellular damage as measured by MI, and CA was significantly less. Picroliv at 10 mg/ml concentration showed normal dividing cells with few fragments, and sticky chromosome reversing the severe cytotoxicity of cyclophosphamide expressed with chromosome fragmentation, vagrant, sticky, and C-anaphase chromosomes. Conclusion: The results of this study strongly suggest picroliv to be a promising agent for ameliorating injury, following radiation and chemotherapy. The potent antioxidant, hepatoprotective, and immune-modulatory properties of picroliv may be responsible for the apparent cyto- and radioprotective activity.
Keywords: Cytoprotective, picroliv, Picrorhiza kurroa, radioprotective
|How to cite this article:|
Bigoniya P, Warathe A, Singh CS. Protective action of picroliv isolated from Picrorhiza kurroa against radiation clastogenecity on mice and cyclophosphamide-induced cytotoxicity in Allium cepa Root. J Radiat Cancer Res 2019;10:58-65
|How to cite this URL:|
Bigoniya P, Warathe A, Singh CS. Protective action of picroliv isolated from Picrorhiza kurroa against radiation clastogenecity on mice and cyclophosphamide-induced cytotoxicity in Allium cepa Root. J Radiat Cancer Res [serial online] 2019 [cited 2019 Dec 7];10:58-65. Available from: http://www.journalrcr.org/text.asp?2019/10/1/58/258715
| Introduction|| |
The medicinal plants have enormous therapeutic potential looking into the herbal boom worldwide. In India, the traditional medicine system has a large number of herbal remedies that have potential therapeutic claims used from the ancient times. These medications, however, suffer from a lack of standardization parameters and documentation based on scientific screening procedure. The 21st century has seen a paradigm shift toward the therapeutic evaluation of herbal products for various diseases by careful exploration of the traditional systems of medicine based on the modern concept of evaluation and standardization of phytocompounds. Cancer is characterized by uncontrolled cellular growth, local tissue invasion, and distant metastases. Several therapies were there to combat cancer mainly chemotherapy and radiation therapy, but the associated side effects of these therapies were still a big hurdle. Chemotherapy is one of the most potent tools used to fight cancer, but the side effects from treatment can be as debilitating as the disease itself. Since cancerous cells multiply rapidly, many chemotherapy drugs target cell reproduction mechanisms, which harm healthy cells that also are in the process of division. In recent years, much interest has developed worldwide in the area of chemoprotectors. Despite intense global research in the field of chemoprotectors, very few synthetic compounds have been able to meet the criteria of a clinically acceptable chemoprotector. This has shifted the focus of researchers toward the holistic approach for natural compounds as chemoprotectors in search of new compounds in view their safety and multifaceted mode of action.
Picrorhiza kurroa Benth (family Scrophulariaceae) is commonly known as Kutki. Kutki is a valuable medicinal plant found in the Himalayas at an altitude of 2700–4500 m. Picroliv or Kutkin is the main iridoid glycoside reported in P. kurroa rhizome responsible for the hepatoprotective activity, which is a mixture of picroside I and kutkoside.,,, As a century-old practice unlike modern medicines, the herbs are known to exert the desired therapeutic effects due to the presence of a group of components, as in the case of picroliv. It is normally obtained from 3- to 4-year-old roots and rhizomes containing an iridoid glycoside mixture having 60% picroside I and kutkoside in the ratio of 1:1.5. Literature and ethnopharmacological background of P. kurroa suggest that the primary active constituent picroliv is responsible for many pharmacological responses such as antiallergic, anti-anaphylactic, immunomodulatory, and antioxidant action.,, Immunostimulating, hepatoprotective and antioxidant activities of picroliv may also contribute to protection against radiation and alkylating chemicals, reducing immunosuppression, cytotoxicity, and genotoxicity that are side effects of chemotherapy. This study attempts an evaluation of in vivo radioprotective potential and in vitro cytoprotective activity on Allium cepa root meristem growth of isolated picroliv.
| Materials and Methods|| |
Isolation and authentication of picroliv
Picroliv was isolated and authenticated by high-performance liquid chromatography (HPLC), following our previously developed and reported method. The HPLC system (Shimadzu, Japan) was equipped with octadecylsilane column (15 cm × 4.6 mm) bonded to porous silica (5 μm) and a photodiode array detector. Isocratic solvent system of 1% v/v of orthophosphoric acid: acetonitrile in the ratio of 83:17 (v/v) was used after passed through 0.45 polyvinylidene difluoride filter and degassing at a flow rate of 1 ml/min, monitored at 280 nm.
The oral LD50 of picroliv in rat or mice was reported to be 2500 mg/kg, p.o. Experiments performed earlier on picroliv using different liver toxicant and hepatic models reports doses ranging from 1.5 to 200 mg/kg depending on treatment schedule from 1 to 45 days., The optimal hepatoprotective dose of picroliv is 20–30 mg/kg, i.p., as we have previously reported. Considering the above facts, an intraperitoneal dose of 20 and 30 mg/kg was adopted for this study. Isolated picroliv was suspending in 0.5% Tween 80 in water for injection and standard drug tocopheryl acetate was solubilized in corn oil.
The experiment was carried out on male albino mice weighing 25 ± 5 g. Animals were acclimatized to the standard laboratory conditions and housed in 25°C ± 2°C temperature, 55% ± 5% relative humidity, and 12:12 light and dark cycles during the experiment. Animals were fed with standard pellet diet and water ad libitum. The experimental was approved by the Institutional Animal Ethics Committee, and animals were taken care as per the committee for the purpose of control and supervision of experiments on animals (CPCSEA) guidelines.
The animals were whole-body irradiated to gamma rays with a 60Co Gammatron teletherapy unit (Theratron 780 C, Canada) at a dose rate of 0.77 Gy/min (4 Gy in 5.22 min). Dosimetry was done using a beam therapy dosimeter (Dose 1 Sweden Scanditronix and Unidose PTW, Germany) to calculate the dose. During irradiation, mice were kept immobilized in a well-ventilated perspex box (20 cm × 20 cm × 4.5 cm). The source surface distance was adjusted to 78.5 cm, depth 1.5 cm, and 25 cm × 25 cm of the equivalent area in an output rate of 77.324 Gy/min, and tissue maximum ratio of 0.99.
Mice were randomly divided into four groups containing 12 animals in each group. Group I – treated with vehicle (1 ml/100 g, i.p), Group II – tocopheryl acetate (300 mg/kg, i.p), and Group III and IV treated, respectively, with 20 and 30 mg/kg, i.p. picroliv. Dosing was started 1 h before the exposure of gamma radiation on day 0 and continued up to the 15th day. Six animals were kept for survival rate recording, and the remaining six experimented for the parameters of radiation exposure toxicity assessment. Body weight of the animals was recorded on 0, 10, 20, and 30th day. Hematological parameters were evaluated on 0th-day preradiation following blood withdrawal by retro-orbital puncture. On the 15th postirradiation day, six animals per group were sacrificed by cervical dislocation to estimate hematological parameters, endogenous spleen colony-forming unit (CFU), and micronucleus (MN) assay. Mortality was recorded at 10 days interval starting from 0 to 30 days.
Hemoglobin estimated using hemoglobinometer, and total white blood cells (WBCs) and red blood cells (RBCs) were counted using Neubauer hemocytometer (Feinoptik, Germany) in peripheral blood drawn from the heart for endogenous CFU assay spleens were dissected out and fixed in Bouin's solution for 24 h. Macroscopic CFUs visible to naked eyes were scored from each spleen. After sacrifice of the mouse, the epiphyses of femur bones were cut, and bone marrow cells were flushed with phosphate-buffered saline into centrifuge tubes. The cells were centrifuged once at 1000 rpm and resuspended in few drops of modified Eagle's media. Cell smears were drawn on clean glass slides, fixed with methanol for 30 min, and stained with Giemsa. At least 1000 cells were scored from each animal to determine the ratio of polychromatic and normochromatic erythrocytes (PCE and NCE). The number of micronucleated PCEs was expressed in percentage value to depict the MN frequency.
A. cepa bulbs of approximately equal size were divided into seven groups each containing four bulbs. Group I 0.5% Tween 80 in distilled water, Group II cyclophosphamide 10 mg/ml treated, Group III picroliv (1 mg/ml), Group IV picroliv (5 mg/ml), Group V picroliv (10 mg/ml), Group VI picroliv + cyclophosphamide (1 + 10 mg/ml), Group VII picroliv + cyclophosphamide (5 + 10 mg/ml), and Group VIII picroliv + cyclophosphamide (10 + 10 mg/ml) treated. A. cepa bulbs of all groups were pregerminated in tap water for 72 h then, transferred to the respective test solutions containing drugs for 48 h. After the defined period of treatment, A. cepa bulb roots were harvested, root numbers and length were determined. The root tips, approximately 1 cm were hydrolyzed in 1N HCl at 60°C for 5 min. Aceto-carmine squash technique was applied for preparation of the root tip for cytological examination fixed in aceto-alcohol (1:3) to determine mitotic indices and chromosomal aberrations.
Scoring of mitotic index and chromosome aberration
The mitotic index (MI) of A. cepa root meristem treated cells was determined by scoring approximately 900–1000 cells, and observing the cells in dividing (interphase) and nondividing (prophase, metaphase, anaphase, and telophase). Anaphase and telophase cells were examined for aberrations, that is, chromosome fragments, bridge, vagrant chromosomes, C-anaphase, multipolar anaphases, and telophase sticking chromosomes, and scored. The MI of Group I was considered as 100% and percentage MI of the treated groups was calculated. The concentration of treatment media showing percentage MI <50% was regarded as toxic.
Results were expressed as mean ± scanning electron microscope and were analyzed using one-way ANOVA, followed by Tukey's Kramer multiple comparison test using Graph pad prism software version 5.04 (San Diego, California, USA).
| Results|| |
HPLC analysis of isolated picroliv was performed following the method of Rajpal (2002). The spectrum showed two peaks at the retention time 2.916 min (kutkoside) and 3.831 min (picroside), respectively, as previously reported [Figure 1].
|Figure 1: High-performance liquid chromatography spectrum of isolated picroliv|
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Protection against 4 Gy-γ radiation exposure
Radiation showed a significant decrease (P < 0.01) in body weight, whereas tocopheryl acetate and picroliv showed a moderate decrease (P < 0.05) in body weight compared to 0th-day value [Figure 2]. Radiation exposure caused a decrease in RBC, WBC, and hemoglobin of mice (P < 0.05–0.01). Tocopheryl acetate showed a significant increase in WBC, RBC, and hemoglobin (P < 0.05–0.01) after 15 days of treatment. Picroliv treatment at 30 mg/kg dose also improved WBC, RBC, and hemoglobin content (P < 0.05) following 15 days of the treatment. Tocopheryl acetate and picroliv at 30 mg/kg dose showed a statistically significant (P < 0.05–0.01) increase in CFU count. Radiation exposed animals showed 66% survival compared to 100% of tocopheryl acetate and picroliv (30 mg/kg). Picroliv 20 mg/kg though showed 83% survival, increase in RBC, WBC, hemoglobin and CFU counts were nonsignificant [Table 1]. Tocopheryl acetate and picroliv at 30 mg/kg showed (P < 0.01–0.001) a significant decrease in micronucleated PCEs and PCE/NCE ratio compared to radiation exposure group [Figure 3].
|Figure 2: Effects of picroliv on body weight of 4Gy-γ radiation exposed mice|
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|Table 1: Effect of picroliv on hematological parameters of 4Gy-γ radiation exposed mice|
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|Figure 3: Effects of picroliv on frequency of micronucleated polychromatic erythrocytes expression on bone marrow of 4Gy-γ radiation exposed mice. All data are presented as M ± scanning electron microscope of six animals per group. ***P < 0.001, **P < 0.01, and *P < 0.05 compared to radiation control group. MNPCE: Micronucleated polychromatic erythrocytes, PCE: Polychromatic erythrocytes, and NCE: Normochromatic erythrocytes|
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Cytoprotective activity on Allium cepa root tip
Cytoprotective activity was investigated on A. cepa root meristem at three (1, 5, and 10 mg/ml) concentrations of picroliv alone and in combination with cyclophosphamide (10 mg/ml). Cyclophosphamide showed statistically significant (P < 0.01) cytotoxicity as evident by the decrease in root length and root number of on A. cepa. Picroliv itself is devoid of cytotoxic potential as the groups showed normal root length and root number. Picroliv, when exposed in combination with cyclophosphamide, was able to reverse the cytotoxic potential of cyclophosphamide by significant (P < 0.05–0.01) increase in root length and root number compared to cyclophosphamide alone [Table 2]. The MI study suggests that cyclophosphamide at 10 mg/ml is toxic with MI of 28.04, whereas picroliv at 5 and 10 mg/ml given along with cyclophosphamide reversed the MI to nontoxic level. Picroliv alone at all three concentrations has nontoxic effect with MI ≥50% [Table 3]. Cyclophosphamide at 10 mg/ml concentration had 100% chromosomal aberration which was reduced to 45.45% and 36.36% by picroliv at 5 and 10 mg/ml concentration on concomitant treatment with 10 mg/ml cyclophosphamide [Table 4].
|Table 2: Effect of different concentration of picroliv and cyclophosphamide on growth of Allium cepa root|
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|Table 3: Effect of different concentration of picroliv and cyclophosphamide on mitotic index of Allium cepa root meristems|
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|Table 4: Effect of different concentration of picroliv and cyclophosphamide on chromosomal aberrations in Allium cepa root meristematic cell|
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Control group and all thee picroliv-alone treated group, A. cepa roots showed normal meristematic cells. Cyclophosphamide at 10 mg/ml showed severe cytotoxicity with chromosome fragmentation, along with vagrant, sticky, and C-anaphase chromosomes. Picroliv at 1 mg/ml concentration also showed all types of chromosomal aberration. Picroliv at 5 mg/ml concentration had the normal dividing cell with C-anaphase, multipolarity, and sticky chromosomes, whereas at 10 mg/ml concentration showed mostly normal dividing cells with few fragments and sticky chromosome [Figure 4].
|Figure 4: Effect of picroliv on Allium cepa root meristem cells (100Ũ) (a) Control group showin normal dividing cell, (b) Cyclophosphamide (10 mg/ml) showed fragment, vagrant, C-anaphase and sticky chromosome, (c) Picroliv (10 mg/ml) showing normal dividing cell, (d) Picroliv + cyclophosphamide (1 + 10 mg/ml) showed prophase arrest with extensive chromosomal aberration (e) Picroliv + cyclophosphamide (5 + 10 mg/ml) showed C-anaphase, multipolarity and sticky chromosomes, (f) Picroliv + cyclophosphamide (10 + 10 mg/ml) showed cells in interphase and prophase with few fragments and sticky chromosome|
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| Discussion|| |
Cancer is the leading cause of mortality in the world. Several therapies are there to combat cancer mainly chemotherapy and radiation therapy but are associated with severe side effects. The world is modernizing but solutions are in our past, as there are many herbs having numerous pharmacological properties. We aimed to investigate the radioprotective and cytoprotective potential of picroliv on A. cepa root meristem against cyclophosphamide. P. kurroa is an important herb in the traditional Chinese and Ayurvedic systems of medicine, used to treat the liver and upper respiratory conditions. Its traditional uses include treatment of a wide range of conditions, including fevers, chronic diarrhea, constipation, dyspepsia, and jaundice.
Exposures of 4 Gy-γ radiation cause break in DNA and generate free radicals that can damage cell membranes, proteins, and organelles, and consequently, the majority of fast-dividing cells such as RBCs and WBCs get affected, and level gets a decline. Lowering of RBCs further causes low hemoglobin percentage, along with a decrease in the spleen CFUs and formation of MN. The results of this study showed that picroliv at 30 mg/kg dose given i.p, for up to 15 days can effectively protect against gamma radiation-induced clastogenecity. Whole body irradiation of a moderate dose range (5–10 Gy) led to a decreased concentration of all the cellular elements in the blood due to the destruction of mature circulating cells, leakage through capillary wall, and reduced of production of cells. Picroliv showed a significant increase in WBC and RBC count as well as in hemoglobin content signifying its beneficial effect on radiation damage to hemopoietic effect. The hemoglobin content was observed to improve in picroliv treated irradiated animals. Irradiation has damage to the RBCs, which are sequestrated by the liver and spleen, resulting in a decrease of hemoglobin. P. kurroa and its active constituent picroliv is a well-known hepatoprotective that possibly acts by stimulating liver and spleen, which remove defective and damaged RBCs from peripheral blood circulation.,, The feedback mechanism, however, stimulated hemopoiesis in the bone marrow, and therefore, higher hemoglobin levels were observed on the 15th posttreatment days of picroliv.
Picroliv treatment-related enhancement of CFU counts in the spleen of irradiated mice indicates its protective role on the stem cells and/or stimulating the proliferation of the surviving cells. The increase in CFU counts in the spleen is associated with an increase in WBC in picroliv treated irradiated animals. Damage of the hematopoietic system is a major factor contributing to mortality following acute radiation exposure. Hematopoietic, as well as gastrointestinal damage, mostly contribute to mortality. Internal infection due to immunosuppression also contributes to the death of irradiated mice. Picroliv at 30 mg/kg dose showed 0% mortality compared to 34% in the radiation control group along with moderate protection against severe loss in the body weight.
Measurement of micronuclei in bone marrow erythrocytes is a marker of genotoxic effect indicating in vivo cytogenetic chromosomal damage related to exposures to radiation and chemotherapeutic drugs., MN frequency depends on the proportion of cells which have divided following the induction of DNA damage and the fate of micronuclei in cells which have divided more than once. Protective effect of picroliv against radiation-induced genotoxicity is obvious from its ability to reduce MN frequency observed with 30 mg/kg dose. Picroliv has efficiently reduced the MN frequency may be protected from DNA damage due to chromosomal breakage and loss along with protective effect on the spleen. Under normal conditions, the spleen removes MN-containing erythrocytes from the peripheral blood. Hepatoprotective and antileishmanial efficacy of picroliv supports its protective effect on the liver and spleen. Picroliv has also reduced the PCE ratio which is used as an index of cytotoxicity, as the radiation control group has high PCE.
The basic mechanism of radiation damage is free-radical production leading to the formation of peroxides that through lipid peroxidation damage the cell membrane. Tocopheryl acetate is a valued radical scavenging antioxidant that interrupts the chain reaction of lipid peroxidation by reacting with lipid peroxy radicals. P. kurroa is reported with an ability to scavenge free radicals and prevent radiation damage.,, Picroliv restores catalase and superoxide dismutase levels and reduced lipid peroxidation in the liver, kidney, and serum of rat exposed with carcinogen 1,2-dimethylhydrazine. Picroliv has shown the most significant radioprotection at 30 mg/kg dose, as the free radicals are short-lived, it is necessary for the radioprotective molecule to be present in the cellular milieu in sufficient concentrations for optimum activity. Picroliv has lowered the effect of irradiation may be due to collective results of several factors such as efficient scavenging of free radicals, repair of DNA, cell membrane, and other damaged target molecules, and the replenishment of severally damaged cells. Picroliv protects cells and regulates the gene expression during hypoxia/reoxygenation by reduction of lactate dehydrogenase release and modulation of vascular endothelial growth factor and hypoxia-inducible factor expression. Picroliv protects from hepatic ischemia-reperfusion injury through hepatocyte glycogen preservation and reduced apoptosis related to a decrease in mRNA expression of caspase-3 and Fas. An increased level of intracellular antioxidant enzyme superoxide dismutase has possibly contributed to the reduction in tissue lipid peroxidation and inflammatory cytokines level of interleukin by picroliv. These studies strongly suggest picroliv to be a promising agent for ameliorating injury following ischemia-reperfusion. Reduction in apoptotic cell death following radiation exposure could also add to enhanced survival shown by picroliv with a significant contribution toward recovery of bone marrow and gastrointestinal tract damage.
Anticancer drug cyclophosphamide is a well-known cytotoxic drug that acts by intercalating with the DNA of cell retarding growth. Cyclophosphamide produces highly reactive carbonium intermediates which transfer alkyl groups to cellular macromolecules by forming covalent bonds. At higher and continuously administered dosage, cyclophosphamide causes cytotoxicity. Cyclophosphamide has been used as a cytotoxic media for growing A. cepa at 10 mg/ml concentration as standardized in our previous report. In this study, cytotoxic effect of cyclophosphamide was reinforced in the form of shortening and decaying of roots, toxic MI, and 100% chromosome aberrations (CA). MI is used as a biomonitor to assess the mutagenicity of chemicals. Cyclophosphamide treatment at 10 mg/ml concentration drastic reduction was observed in the number of cells entering the mitotic cell division causing prophase accumulation as a common feature. Prophase accumulation is attributed to a delay in the breakdown of the nuclear membrane due to “carry over” inhibitory effects of treatment from the interphase stage or disturbance/breakdown in spindle apparatus. Picroliv at all the tested doses showed nontoxic MI suggesting the absence of any sublethal effect. Picroliv effectively reversed the cytotoxicity of cyclophosphamide with nontoxic MI and minimum CA. This was also confirmed by the appreciable number and length of A. cepa roots grown in the copresence of picroliv and cyclophosphamide. Picroliv itself up to the tested highest 10 mg/ml concentration was potentially nontoxic and promoted cell division protecting from the antiproliferative effect of cyclophosphamide. Picroliv has restored cell division as evident from less aberration in cyclophosphamide intoxicated medium.
| Conclusion|| |
Chromosome fragmentations are mutation causing irreversible changes that result in the creation of micronuclei. Picroliv has shown significantly reduced the expression of micronucleated PCE on radiation-exposed mice. The deformations of chromosomes together with sticking inhibit the normal progress of mitotic division even long after removal of the causative factor. Cyclophosphamide treatment induced fragmentation and occurrence of vagrant and c-anaphase chromosome which has been effectively reversed by the picroliv cotreatment that encouraged normal dividing cell with few fragments and vagrant chromosome. The picroliv restricts the chromosomal aberration with a nonlethal MI, indicating its cytoprotective capability alone as well as in the presence of cyclophosphamide. Iridoid glycosides are known to be hydrolyzed in the intestines forming aglycones, leading to poor oral bioavailability. Isolated picroliv also has poor bioavailability compared than the plant extract itself may be due to some synergism between components of the plant. Maximum plasma concentration of picrosides I and II was detected to be 206.10 and 152.62 ng/ml with a dose of 100 mg/kg picroliv after 1 h, and the half-life was approximately 35 min following oral ingestion.
Looking into these pharmacokinetic profile, picroliv was administered intraperitoneally at 20 and 30 mg/kg dose, as previously optimized by our group for hepatoprotective potential. From the results of the current investigation, it can be concluded that picroliv, the most important bioactive and highly investigated constituent of P. kurroa rhizome has cyto- and radioprotective activity at 30 mg/kg, i.p. dose. Strong hepatoprotective and immune-modulatory properties of picroliv are indicative of its apparent ability to emerge also as a cyto- and radioprotective. Detailed exploration of picroliv for its chemoprotective potential along with its safety profile should be done for further progress in proving its clinical efficacy.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]