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   Table of Contents      
Year : 2012  |  Volume : 2  |  Issue : 1  |  Page : 45-52

Apigenin protects gamma-radiation induced oxidative stress, hematological changes and animal survival in whole body irradiated Swiss albino mice

1 Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, India
2 Division of Radiology, Dr. Kamakshi Memorial Hospital, Chennai, Tamilnadu, India

Date of Submission26-Aug-2011
Date of Web Publication23-Feb-2012

Correspondence Address:
Nagarajan Rajendra Prasad
Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar 608 002, Tamilnadu
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Source of Support: Indian council of Medical Research Ref.No: 3/2/2/3/10-NCDIII, IRIS ID: 2009-08970), Conflict of Interest: None

DOI: 10.4103/2231-0738.93134

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Aim: The present study was undertaken to find out the possible radioprotective efficacy of apigenin against whole body gamma (γ)-irradiation, oxidative damage and hematological alterations in Swiss albino mice. Materials and Methods: The percentage of mice surviving 30 days, of exposure to radiation dose (7-11 Gy) was used to construct survival dose response curves. Apigenin (15 mg/kg body weight) was administered intraperitonially (i.p) for 7 consecutive days, once daily, and then the mice were exposed to single dose of 7 Gy of γ-radiation. Mice were sacrificed at 24 hours post irradiation, and liver and intestine were taken for various biochemical estimations viz. lipid peroxidation (LPO) markers [thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and lipid hydroperoxides (LOOH)], antioxidant status [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH)]. Further blood was collected for the hematological studies [Haemoglobin (Hb) content, red blood cell (RBC) and white blood cell (WBC) count]. Results: Apigenin 15 mg/kg body weight elevated radiation LD 50 from 8.2 to 10 Gy, indicating the dose modifying factor (DMF) of 1.21. It was found that there was an increased LPO level with decreased antioxidant status in 7 Gy irradiated Swiss albino mice. It has been also observed that Hb content, WBC and RBC count was decreased in irradiated Swiss albino mice. Conversely, significant decrease in LPO and restoration of antioxidant status and hematological changes was observed in apigenin pretreated group. Conclusion: Hence, apigenin pretreatment renders protection against 7 Gy radiation-induced biochemical and hematological alterations in Swiss albino mice.

Keywords: Apigenin, gamma-radiation, lipid peroxidation, radioprotection

How to cite this article:
Begum N, Prasad NR, Thayalan K. Apigenin protects gamma-radiation induced oxidative stress, hematological changes and animal survival in whole body irradiated Swiss albino mice. Int J Nutr Pharmacol Neurol Dis 2012;2:45-52

How to cite this URL:
Begum N, Prasad NR, Thayalan K. Apigenin protects gamma-radiation induced oxidative stress, hematological changes and animal survival in whole body irradiated Swiss albino mice. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2022 Dec 2];2:45-52. Available from:

   Introduction Top

Ionizing radiation in interaction with living cells causes a variety of changes depending on absorbed dose, duration of exposure, interval after exposure and susceptibility of tissues. [1] The exposure of mammals to ionizing radiation, such as gamma-radiation, can cause the development of a complex, dose-dependent series of potentially fatal physiologic and morphologic changes, such as nausea, vomiting, loss of appetite, decreased leukocyte count and weakened immunofunction. [2] Oxidative stress contributes to normal tissue damage during tumor therapy with irradiation. One of the major reasons for cellular injury after radiation exposure is the generation of reactive oxygen species (ROS). [3] Radiation attenuates the endogenous antioxidant enzymes, which are considered as the first line defense mechanism in the maintenance of redox balance and normal biochemical processes. [4] One approach to reduce the toxicity of ionizing radiation is the concomitant treatment with a radioprotector, the practical importance of which is undisputed. [5] The currently available one, such as amifostine, have many drawbacks including high cost, side effects and toxicity. [6] In fact, currently no radioprotective agent is available, either alone or in combination, to meet all the requisites of an ideal radioprotector. [7] Several novel approaches are on to locate a potent and non-toxic radioprotector. [8] Use of natural products as possible radioprotectors is gaining momentum in recent years due to lesser toxicity, reduced cost and other associated advantages. [9]

Apigenin, a common dietary flavone present abundantly in common fruits and vegetables, is a non-toxic and non-mutagenic flavone. [10] Apigenin has long been considered to have various biological activities such as - antioxidant, [11] anti-inflammatory, [12] and anti-tumorigenic, [13] in various cell types. Apigenin caused a significant decrease in lipid peroxidation (LPO) levels and improved the antioxidant status in liver and kidney of male Wister rats induced by DEN (N-nitrosodiethylamine), due to its antioxidant sparing property. [14] Moreover, a recent study highlighted the ability of apigenin to inhibit matrix metalloproteinase activity and cyclooxygenase-2 expression in ultraviolet (UV)-irradiated dermal fibroblast and keratinocytes. [15],[16] Besides, apigenin also has potential to protect hydrogen peroxide-induced Deoxyribonucleic acid (DNA) damage in human peripheral blood lymphocytes. [17] The research of Rithidech et al. [18] highlighted the protective effect of apigenin on radiation-induced chromosomal damage in human lymphocytes. However, the effect of apigenin in averting radiation induced oxidative stress in animal models has not yet been reported. Hence, the present study was undertaken to evaluate the radioprotective effect of apigenin against γ-radiation-induced animal survival ability, oxidative stress and hematological alterations in Swiss albino mice.

   Materials and Methods Top


Apigenin was purchased from Shaanxi Huike Botanical Development Co., LTD., China. Thiobarbituric acid (TBA), phenozine methosulphate (PMS), nitroblue tetrazolium (NBT), 5, 5-dithiobis 2-nitrobenzoic acid (DTNB), nicotinamide adenine dinucleotide (NAD) were purchased from Sigma chemicals Co., St. Louis, USA. All other chemicals were of analytical grade and obtained from SD Fine chemicals, Mumbai, India.

Experimental animals

Male Swiss albino mice, 8-10 weeks old weighing 22-25 gram were obtained from the Central Animal House [Institutional Ethics Committee Number: 160/1999/CPCSEA], Department of Experimental Medicine, Rajah Muthiah Medical College and Hospital, Annamalai University. The animals were fed on the standard pellet diet (Agro Corporation Private Limited, Bangalore, India) and water ad libitum.

The animals were housed in polypropylene cages under controlled conditions of 12 hour light-dark cycle, 50% humidity and at 23 ± 2°C. The animals used in the present study were maintained in accordance with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA). This study was approved by the Animal Ethical Committee of Rajah Muthiah Medical College and Hospital Annamalai University (Reg No.160/1999/CPCSEA proposal number: 749; dated 16.12.2010).

Irradiation of mice

Animals were placed in ventilated perspex containers and subjected to whole-body radiation (via dual energy linear accelerator unit or LINAC) in the department of radiology, Dr. Kamakshi Memorial Hospital, Chennai, Tamil Nadu, India at a dose rate of 1.66 Gy/minute. During all irradiation procedures, the animals were kept under mild anesthesia (ketamine hydrochloride). This study was also approved by the ethical committee of the Dr. Kamakshi Memorial hospital (ref no: EC/2010; dated: 02-10-2010) for whole body irradiation of Swiss albino mice.

Preparation of the apigenin and mode of administration

Apigenin was dissolved in 0.05% dimethyl sulphoxide (DMSO) immediately before use and was administered intraperitoneally (i.p) at different concentrations (3, 5, 7.5, 15 and 30 mg/kg body weight) at a volume of 0.2 ml/kg body weight.

   Experimental Design Top

Experiment 1: Assessment of acute toxicity of apigenin in non-irradiated mice

The acute toxicity of apigenin was determined according to Prieur et al. [19] and Ghosh. [20] Briefly, the animals were allowed to fast by withdrawing the food and water for 18 hours. The fasted animals were divided into several groups of 6 each. Each group of animals were injected i.p with various doses (25, 50, 75, 100, 150, 200, 250, 300 and 350 mg/kg body weight) of freshly prepared apigenin. The animals were provided with food and water immediately after the drug administration. The animals were observed continuously for the first 2 hours followed by every hour up to 6 hours and daily thereafter for 14 days, for any signs of morbidity, mortality and behavioral toxicity.

Experiment 2: Survival (LD 50/30 ) assay

Prior to the assessment of radioprotective potential of apigenin, whole body survival study was carried out to fix the optimum dose of apigenin. The whole body survival study was determined according to Satyamitra et al. [21] For this, mice were categorized into 6 groups with 6 animals in each.

The animals were monitored daily for 30 days to fix the effective concentration of apigenin against radiation induced toxicity. Survival curve was drawn by plotting percentage survival as a function of post-irradiation day.

Experiment 3: Dose modifying factor

The Dose modifying factor (DMF) was determined according to Parihar et al. [22] to investigate the radioprotective effect of apigenin; and, the animals were divided in to radiation control and experimental groups. Radiation control (irradiation alone, 7-11 Gy) animals were administered with 0.2 ml (0.05%) of DMSO i.p 1 hour prior to irradiation. Experimental group (apigenin + irradiation) animals were administered with 0.2 ml apigenin i.p (dose selected from experiment: 2 i.e 15 mg/kg body weight) daily for 7 consecutive days (on seventh day 1 hour prior to 7-11 Gy irradiation) served as treated groups.

Animals were monitored daily for the development of radiation sickness symptoms and mortality up to 30 days post-irradiation.

The DMF was calculated as follows:

DMF = LD 50/30 of (apigenin + irradiation)/LD 50/30 of (0.05% DMSO + irradiation)

Experiment 3: Radioprotective effect

To ascertain the radioprotective ability of apigenin, the optimum dose of apigenin (selected from experiment: 2) was administered to mice prior to whole body exposure of 7 Gy radiation. For this, mice were categorized into 4 groups with 6 animals in each. Animals were sacrificed by cervical dislocation at 24 hours post irradiation; and, liver and small intestine were excised for performing various biochemical estimations viz. LPO markers [thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and lipid hydroperoxides (LOOH)], antioxidant status [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH)] and peripheral blood to estimate hematological changes.

  • Group I : Sham control (0.05% DMSO)
  • Group II : Apigenin only (15 mg/kg body weight)
  • Group III : Radiation only (7 Gy)
  • Group IV : Apigenin (15 mg/kg body weight) + Radiation (7 Gy)

Measurements of lipid peroxidative markers and antioxidant status

Animals were sacrificed by cervical dislocation to obtain liver and intestinal tissues. 10% homogenate was prepared in ice-cold phosphate buffered saline (PBS, 0.2 M, pH 7.4) using glass homogenizer. The homogenate was centrifuged at 5000 revolutions per minute (rpm) for 10 minutes at 4°C in cold centrifuge. The supernatant was separated and used for the estimation of LPO markers (TBARS, CD and LOOH), [23] SOD, CAT, GPx activities and GSH level using standard spectrophotometric assays. [24]

Hematological parameters

0.1 ml of blood was collected from the tip of mouse tail and transferred to vials containing ethylenediaminetetraacetic acid (0.5 M) and used for the estimation of haemoglobin (Hb) content, [25] red blood cell count (RBC) and white blood cell count (WBC) by adopting standard procedures.

Statistical analysis

The data were expressed as Mean ± Standard Deviation (SD) (n=6). Statistical analysis of the data was carried out by one-way analysis of variance (ANOVA) followed by Duncan's Multiple Range Test (DMRT) using a statistical package program (Statistical Package for the Social Sciences - SPSS version 11.5 for Windows); and, P<0.05 was considered as statistically significant.

   Results Top

Experiment 1: Acute toxicity of apigenin

The administration of different concentrations of apigenin viz. 25 and 50 mg/kg body weight has not induced mortality during the observation period. However, 16.6% animals died when the drug dose was raised to 75 mg/kg body weight. A further increase in the dose of apigenin at 100 mg/kg body weight resulted in 33.3% mortality and 50% reduction in the survival of mice was observed at 150 mg/kg body weight. 66.6% of the mice died when the drug dose was increased to 200 mg/kg body weight and 83.3% mortality was observed for 250 mg/kg body weight of apigenin. One hundred percent mortality was observed at 300 mg/kg body weight and thereafter up to a dose of 350 mg/kg body weight of apigenin [Table 1].
Table 1: Effect of various concentrations (25-350 mg/kg body weight) of apigenin on the acute toxicity in Swiss albino mice. Different doses of apigenin were administered to mice (i.p). Mortality was observed for 14 consecutive days

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Experiment 2: Survival (LD 50/30 ) assay

The results corresponding to the optimum protective dose of apigenin on the survival rate of mice evaluated after whole-body exposure to a lethal dose of 10 Gy radiation is shown in [Figure 1]. All irradiated animals without apigenin treatment showed 100% mortality within 12 days and exhibited signs of radiation sickness within 2-4 days after exposure to 10 Gy of γ-radiation. The main symptoms included reduction in the food and water intake, irritability, weight loss, emaciation, lethargy, diarrhea and ruffling of hair. Facial edema was also observed in a few animals between 1 and 2 weeks after exposure. The first mortality in 10 Gy exposed group was observed on day 4 and 50% of the animals died within 1 week after irradiation [Figure 1]. The pretreatment of mice with various concentration of apigenin delayed the onset of radiation-induced mortality depending on the drug dose. This delay was longest for 15 mg/kg body weight apigenin, where the first mortality was reported by day 9 post-irradiation. The shortest delay in the mortality was observed for 3 mg/kg body weight, where the first mortality occurred on day 4 post-irradiation. Apigenin 15 mg/kg body weight was found to be the most effective dose maintaining 50% survival up to 30 days. Therefore, the optimum protective dose of apigenin has been considered to be 15 mg/kg body weight, which increased the survival of mice approximately by 50% when compared to the irradiated control.
Figure 1: Dose dependent effect of apigenin on the survival rate of mice observed for an experimental duration of 30 days. Different concentration (3, 5, 7.5, 15, 30 mg/kg body weight) of apigenin were administered to mice (i.p) 1 hour before exposure to 10 Gy gamma (γ) radiation. Whole body survival was observed for 30 days

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Experiment 3: Dose modifying factor

A dose-dependent survival ability of mice has been observed in both the control and the experimental groups [Figure 2]. In the control group, 16.6% of total animals died within 30 days when exposed to 7 Gy gamma radiation and no animal could survive till day 30 after exposure to 8, 9, 10 and 11 Gy gamma radiation. The first death was recorded on days 9, 6, 5 and 4 at 8, 9, 10 and 11 Gy doses, respectively. Exposure to 11 Gy gamma radiation resulted in 100% mortality of mice by day 9. The pre-treatment of apigenin enhanced the survival percentage of mice exposed to different doses of gamma radiation. Apigenin pre-treatment inhibited mortality completely at 7 Gy. However, at 8, 9, 10 and 11 Gy no animal died before days 13, 10, 9 and 7 respectively. Radiation dose-response curves for mice with or without pre-treatment of apigenin are shown in [Figure 2] (Panel A and B). The LD 50/30 for the radiation alone group was 8.2 Gy, which increased to 10 Gy with apigenin pretreatment, thus giving DMF of 1.21 for apigenin treated group [Figure 2], [Panel C].
Figure 2: Survival curves for mice exposed to different doses (7-11 Gy) of whole-body gamma (γ) radiation with and without pretreatment with 15 mg/kg body weight apigenin. Panel (a) Radation alone, (b) Apigenin (15 mg/kg body weight) + Radiation, (c) Radiation dose- response curves for 30-day survival of mice exposed to different doses of Radiation with (▲)/without (■) apigenin. Dose Modifying Factor (DMF) for apigenin = 1.21

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Measurements of lipid peroxidative markers and antioxidant status

The optimal dose 15 mg/kg body weight was selected to assess the changes in radiation-induced liver and intestine LPO markers and antioxidant status. There was a significant increase in the LPO markers in γ-irradiated Swiss albino mice at 24 hours when compared to control. Administration of apigenin, by itself has not elevated LPO at 24 hours. Animals exposed to 7 Gy gamma radiation showed significantly (P<0.05) increased TBARS (13.90 ± 0.31,12.60 ± 0.31), CD (20.58 ± 1.12, 21.28 ± 1.12) and LOOH (25.18 ± 0.80, 23.11 ± 0.70) at 24 hours against the control values of TBARS (4.09 ± 0.13, 4.89 ± 0.13), CD (8.21 ± 0.38, 7.11 ± 0.38) and LOOH (6.28 ± 0.30, 6.88 ± 0.20) in liver and intestine. However, there was a significant inhibition of LPO markers observed in both liver and intestine at 24 hours of post-irradiation when apigenin was administered before 7 Gy of gamma radiation [Table 2].
Table 2: Effect of apigenin on radiation induced lipid peroxidation (LPO) [thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and lipid hydroperoxides (LOOH)] in liver and small intestine of Swiss albino mice

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In control mice, liver and intestine SOD activity was 13.50 ± 0.63 and 8.80 ± 0.63, CAT activity was 12.09 ± 0.40 and 10.89 ± 0.40 whereas Gpx 11.04 ± 0.53 and 9.02 ± 0.53 at 24 hours respectively; and, apigenin treatment by itself has not altered the baseline SOD, CAT and Gpx activities. Whole body irradiation of mice to 7 Gy resulted in declined SOD (7.21 ± 0.29, 3.29 ± 0.29), CAT (4.13 ± 0.19, 3.15 ± 0.19) and Gpx (4.54 ± 0.26, 3.84 ± 0.26) activities. Whereas, apigenin administration 1 hour prior to 7 Gy gamma radiation resulted in a significant (P<0.05) increase in SOD, CAT and Gpx activities both in liver and intestine at 24 hours post-treatment [Table 3].
Table 3: Effect of apigenin pretreatment on the radiation-induced alteration in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities and glutathione (GSH) levels in liver and small intestine of Swiss albino mice

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The GSH levels in the liver and intestine for the control animals at 24 hours were 12.35 ± 0.55 and 11.65 ± 0.55, respectively. Apigenin treatment alone has not altered the GSH level when compared with the untreated control. However, a significant decrease in GSH (5.95 ± 0.15, 3.65 ± 0.15) content was observed in irradiated animals. Treatment of mice with 15 mg/kg body weight with apigenin 1 hour before exposure to 7 Gy of gamma radiation resulted in a significant (P<0.05) increase in GSH content both in liver and intestine at 24 hours compared with respective irradiated groups [Table 3].

Hematological changes

[Table 4] shows the Hb, WBC and RBC levels in the control and experimental mice. WBC and RBC counts were observed to be decreased in the radiation group; whereas administration of apigenin prior to the exposure of radiation significantly improved the counts of WBC and RBC in mice when compared to the corresponding radiation group. Further, results of Hb content showed that there was a decrease in the level of Hb in radiation group when compared to the control group. But i.p administration of apigenin at a dose of 15 mg/kg body weight significantly improved the Hb levels in mice when compared to the radiation group. Thus the reversal of WBC, RBC and Hb content to near normal by apigenin administration suggests that apigenin possesses protective action on the haemopoitic system.
Table 4: Effect of apigenin on hematological changes in gamma (γ )-irradiated peripheral blood of Swiss albino mice

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   Discussion Top

In the present study, significant radioprotection was achieved when apigenin at the dose of 15 mg/kg body weight was given i.p for 7 consecutive days before irradiation. Its radioprotecctive effect was calculated by determining LD 50/30 (DMF = 1.21). A dose dependent mortality was observed on exposure to 7-11 Gy in the 30 day survival assay. Irradiation of animals to 7-11 Gy gamma rays resulted in radiation sickness within 3-5 days of exposure. The symptoms included reduction in the food and water intake, weight loss, diarrhea, ruffling of hairs and irritability. A number of reports indicated that radiation induced sickness and mortality was mainly attributed to gastrointestinal and hematopoietic syndromes. [26],[27],[28] Both cell linings, of the alimentary tract and circulatory leucocytes, are relatively short lived and their orderly renewal depends on a population of constantly dividing stem cells. Therefore, any damage to these cells impairs normal physiological host defense processes drastically, causing an adverse impact on survival. [29] In this study, apigenin pretreatment significantly reduced mortality induced by gamma irradiation. This may be due to the protection of intestinal epithelium, which would have allowed proper absorption of the nutrients. The protection of circulating leucocytes may boost up the immune response against irradiation induced damage. [30]

Radiation-induced reactive oxygen/nitrogen species (ROS/RNS) like nitric oxide and superoxide radicals react to produce reactive peroxynitrite, which is known to induce cytotoxicity by interacting with biomolecules like protein, lipids and nucleic acids. [31],[32] To cope with ROS damage organisms possess comprehensive and integrated endogenous enzymatic, non-enzymatic antioxidants and repair systems. [33] ROS affects the antioxidant defense mechanisms by reducing the intracellular concentration of GSH as well as SOD, CAT and Gpx activity. Under normal conditions, the inherent defense system, including glutathione and the antioxidant enzymes, protects against oxidative damage. GSH offers protection against oxygen-derived free radicals and cellular lethality following exposure to ionizing radiation. [34] The present study denotes a significant reduction in liver and intestinal GSH due to radiation. This could be due to an enhanced utilization of the antioxidant system during detoxification of the free radicals generated by radiation. Apigenin administration prior to irradiation inhibited the decline in the intracellular antioxidant enzyme activities viz. SOD, CAT, Gpx and GSH. The increased activity of SOD in apigenin treated plus irradiated mice may be attributed to either SOD-mimetic activity, thus facilitating the replacement of lost SOD activity in irradiated tissue, or by enhancing a de novo synthesis of essential repair enzymes. [35] Thus, maintaining the balance between the rate of generation of radicals and scavenging of free radicals is an essential part of biological homeostasis.

It is commonly accepted that SOD protects against the free radical injury by converting superoxide anion (O 2- ) to hydrogen peroxide (H 2 O 2 ) and thus prevents the formation of hydroxyl radical (OH ), and the H 2 O 2 can be removed by catalase or GPx. Due to the inhibition of SOD, superoxide anion radicals are left to combine with nitric oxide to form peroxynitrite anion (ONOO ) which initiates LPO. The decrease in activities of antioxidant enzymes is in close relationship with the induction of LPO [Table 2], where the activities of SOD, CAT and GPx decline with the increase in LPO. [36] An increase in the GSH level by apigenin may be responsible for the scavenging of radiation-induced free-radicals including LPO, thereby protecting against radiation-induced mortality. It has been reported that LPO starts to increase as soon as the endogenous GSH is exhausted, and the addition of GSH promptly stops further peroxidation. [37] Our present study shows that apigenin pretreatment provides a significant protection against radiation-induced biochemical alterations in liver and intestinal tissues.

Hematopoietic stem cells are highly sensitive to ionizing radiation. [38] Hematopoietic recovery depends on the percentage of residual hematopoietic stem cells. In the present study, there was a considerable decrease in the hematological constituents (Hb, WBC and RBC count) of peripheral blood in the irradiated animals. Similar findings were demonstrated earlier by Benkovic et al. who found noticeable depletion in Hb concentration in Swiss albino mice exposed to 9 Gy gamma radiation. [39] The decrease in the values of hematological parameters following radiation exposure may be assigned to direct damage caused by a lethal dose of radiation. [40] This can be due to direct destruction of mature circulating cells, loss of cells from the circulation by hemorrhage, or leakage through capillary walls and reduced cell production. [41] However, a significant rise in these parameters was evident in apigenin pre-treated animals. This suggested a significant protection of hematopoietic system by apigenin.

   Conclusion Top

In conclusion, our findings demonstrate the potential of apigenin in mitigating radiation-induced hematological and biochemical alterations and mortality of Swiss albino mice. These effects may be due to immunostimulation by increasing hematological constituents in the peripheral blood and due to its ability to trigger the endogenous antioxidant status and suppress LPO in the liver and intestine. Optimum protective dose of 15 mg/kg body weight used in this study is far lower than the LD50 (150 mg/kg body weight) dose. However, further studies are needed before its implementation in human protection against ionizing radiation, especially in the treatment of cancer patients exposed to radiotherapy.

   Acknowledgments Top

The authors gratefully acknowledge the Dr. Kamakshi Memorial Hospital, Chennai, Tamil Nadu, India for providing radiation facility. Naziya Begum gratefully acknowledges the financial assistance awarded by Indian council of Medical Research (ICMR) (Ref.No: 3/2/2/3/10-NCDIII, IRIS ID: 2009-08970), New Delhi, India in the form of Senior Research Fellowship.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]

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