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First published online October 26, 2006
British Journal of Radiology (2007) 80, 77-84
© 2007 British Institute of Radiology
doi: 10.1259/bjr/41714035
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Full paper

Protection of Swiss albino mice against whole-body gamma irradiation by diltiazem

V Nunia, MSc, PhD G Sancheti, MSc and P K Goyal, MSc, PhD

Radiation and Cancer Biology Laboratory, Department of Zoology, University of Rajasthan, Jaipur – 302 004, India

Correspondence: Dr P K Goyal, Radiation and Cancer Biology Laboratory, Department of Zoology, University of Rajasthan, Jaipur – 302 004, India. E-mail: pkgoyal202{at}rediffmail.com


   Abstract
Top
 Abstract
Introduction
 Methods and materials
 Results
 Discussion
 References
 
The aim of the present study was to evaluate the radioprotective effect of diltiazem (DTZ) on Swiss albino mice exposed to gamma radiation. In the present study, radioprotective efficacy of DTZ (a calcium channel blocker) was studied against radiation induced haematological and biochemical alterations. Swiss albino mice of 6–8 weeks old were administered diltiazem (100 mg kg–1 by weight) intraperitoneally prior to whole body gamma-irradiation (7.5 Gy). Radiation exposure resulted in a significant decline in different bone marrow cells (pro- and normoblasts) and blood constituents (erythrocytes, leukocytes, differential leukocyte count, haematocrit, haemoglobin and erythrocyte sedimentation rate). Pro- and normoblasts, erythrocytes, leukocytes, haematocrit and haemoglobin values showed a significant (p<0.0051) decline until day 3, following a gradual recovery from day 7, but normal values were not recorded until 28 days post-exposure. In contrast, erythropoietin levels increased significantly and reached a maximum on day 3. In DTZ pre-treated irradiated animals, a significant increase in pro- and normoblasts, erythrocytes, leukocytes, differential leukocyte count, haematocrit and haemoglobin values, and a significant decrease in erythropoietin values, were observed compared with control. A significant elevation above normal in lipid peroxidation level was recorded in gamma irradiated mice, whereas this increase was considerably less in DTZ pre-treated animals. Similarly, pre-treatment of DTZ caused a significant increase in erythropoietin and glutathione levels in serum in comparison with irradiated animals. From our study it is clear that DTZ provides protection against radiation-induced haematological and biochemical alterations in Swiss albino mice.


   Introduction
Top
 Abstract
 Introduction
Methods and materials
 Results
 Discussion
 References
 
Over the past 50 years, radiation research has focused on screening a plethora of chemical as well as biological radioprotectors [1–3]. The research is aimed towards the protection of the human population against natural background radiation, occupational and medical exposures, and nuclear industry as well as nuclear warfare. Several molecular drugs of synthetic and natural origin are being tested in experimental models and human clinical trials to mitigate injury caused by whole exposure, ranging from sublethal to supralethal doses [4–8]. However, severe toxic effects associated with most of these drugs at therapeutic levels have restrained their use. Therefore, a search for newer and more effective agents is taking place to find a potent radioprotector with minimum or no toxicity.

Diltiazem (DTZ), a calcium channel blocker, is used in cardiovascular therapy and acts by inhibiting the influx of Ca2+ through specialized channels into cells, thus influencing numerous cell functions [9]. There are some reports on the protective action of calcium channel blockers in mammals [10–16]. Recently, we have demonstrated the role of DTZ in survival and anaemia following ionizing radiation [17–]. The present study is an attempt to investigate the radioprotective effect of DTZ on bone marrow stem cells, haematological constituents and on some biomarkers with a view to its possible application in the clinical field.


   Methods and materials
Top
 Abstract
 Introduction
 Methods and materials
Results
 Discussion
 References
 
Animal care and handling
Animal care and handling was carried out according to the guidelines set by WHO (World Health Organization; Geneva, Switzerland) and INSA (Indian National Science Academy; New Delhi, India). The departmental animal ethical committee approved this study. Swiss albino mice aged 6–8 weeks and weighing 22±2 g, taken from an inbred colony, were used for this study. The mice were maintained under controlled conditions of temperature and light (light: 10 h; dark: 14 h). Four animals were housed in a polypropylene cage containing sterile paddy husk (procured locally) as bedding throughout the experiment. They were provided standard mouse feed (Hindustan Levers Ltd, India) and water ad libitum. Tetracycline water once a fortnight was given as a preventive measure against infection.

Irradiation
A cobalt teletherapy unit (ATC-C9) at the Cancer Treatment Centre, Radiotherapy Department, SMS Medical College and Hospital, Jaipur, was used for irradiation. Unanaesthetised animals were restrained in well-ventilated Perspex boxes and exposed to gamma radiation at a distance (SSD) of 77.5 cm from the source to deliver the dose-rate of 1.04 Gy min–1.

Drug
DTZ (Dr Reddy's Laboratory; Hyderabad, India) was dissolved in double distilled water and injected into mice intraperitoneally at 100 mg kg–1 body weight of the animal.

Experimental design
Determination of optimum dose of DTZ against radiation
DTZ dose was selected on the basis of our drug tolerance study. Various doses of DTZ (25 mg kg–1, 50 mg kg–1, 100 mg kg–1, 200 mg kg–1 by weight of animal) were tested for their effects on the tolerance to 8.0 Gy gamma radiation in Swiss albino mice and the survival rate (12.5%, 33.3%, 82.5% and 12.5%, respectively) of the animals was observed. The most optimum and tolerable dose of DTZ (100 mg kg–1 body weight of animal) was selected [17] and used in this experiment for further study.

LD50/30 and dose reduction factor (DRF)
In order to establish the survival dose response, a total number of 75 animals were sorted into 5 groups of 15 mice each and exposed to radiation in the presence or absence of DTZ. The dose reduction factor of DTZ against radiation was calculated on the basis of survival experiment and measured as 1.25 (Figure 4Go).


Figure 4
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  		Figure 4. Dose-response curves for the determination of LD50/30 (survival data was collected for four radiation doses and calculated by regression analysis).

 
Modification of radiation response
The mice for this experiment were selected from an inbred colony and divided into four groups. Animals in Group I were injected intraperitoneally with double distilled water (volume equal to DTZ solution) to serve as control, while animals in Group II were administered DTZ intraperitoneally in a dose of 100 mg kg–1 by weight of animal. Mice in Group III received an equal volume of double distilled water (as in Group I) and were exposed to 7.5 Gy {gamma}-rays. Animals in Group IV (experimental) were given DTZ (as were Group II) and exposed to 7.5 Gy gamma radiation.

All animals were observed daily for 28 days for any signs of radiation sickness, morbidity, behavioral toxicity and mortality. The percentage of surviving animals on each day was used for analysis of survival. At least six animals from all the above groups were autopsied at 12 h, 24 h, day 3, day 7, day 14 and day 28 post-irradiation, and the haematological and biochemical parameters were studied.

Bone marrow smear preparation and counting
Femurs from the mice were dissected out and cleaned. The heads were cut off, and bone marrows flushed out and diluted with mice serum, using a syringe. Thin films of the cell suspension were prepared on clean glass slides and stained with Leishman's reagent. A total of 500 cells were counted from each slide and the percentage of pro- and normoblast cells were determined in relation to total cellular count.

Haematological study
Blood was collected from the caudal vein in a vial containing 0.5 M EDTA (ethylenediaminetetraacetic acid). Total number of erythrocytes, leukocytes, differential leukocyte count, haematocrit, haemoglobin and erythrocyte sedimentation rate were estimated by adopting standard procedures.

Biochemical study
Erythropoietin estimation:
Erythropoietin level was measured by SRL (SRL Ranbaxy Ltd; Mumbai, India). This test was performed using an immulite analyser kit (Catalog No. LKEPZ; manufactured by Diagnostic Products Corporation, Los Angeles, CA).

Lipid peroxidation assay:
The lipid peroxidation level in liver and serum was measured by the assay of thiobarbituric acid reactive substances (TBARS) using the method of Ohkhawa et al [19]. Briefly, homogenate was mixed with sodium dodecyl sulphate (SDS), pH 3.5, 20% trichloroacetic acid (TCA). To the same, aqueous thiobarbituric acid (TBA), double distilled water was added and heated at 95° C for 60 min. The mixture was cooled and added to n-butanol and pyrimidine (15:1 weight by volume). The absorbance was read at 532 nm using a UV-VIS Systronic.

Glutathione assay:
The hepatic level of glutathione was determined by the method of Moron et al [20]. Briefly, liver homogenate was added to 20% TCA, centrifuged, and the supernatant was collected. The supernatant was mixed with 0.3 M Na2HPO4 and 5-5, dithiobis-2-nitrobenzoic acid (DTNB) reagent, and allowed to stand for 10 min at room temperature. The absorbance was read at 412 nm using a UV-VIS systronics spectrophotometer.

The glutathione content in blood was measured spectrophotometrically using DTNB as a coloring reagent, according to the method of Beutler et al [21]. Briefly, 0.2 ml of blood was mixed in 1.8 ml of double distilled water and added to the precipitating solution, centrifuged and supernatant was collected. This supernatant was mixed with 0.3 M disodium hydrogen sulphate and DTNB reagent, and allowed to stand for 2 min at room temperature. The absorbance was read at 412 nm.

Statistical analysis
The results obtained in the present experiment were expressed as mean±S.E. The Student's t-test was used to make a statistical comparison between groups – Group I and Group III; and Group III and Group IV. The significance level was set at p<0.005.


   Results
Top
 Abstract
 Introduction
 Methods and materials
 Results
Discussion
 References
 
Sickness and mortality
No toxic effects in terms of sickness were observed in the animals treated with double distilled water (Group I) and DTZ (Group II). All animals exhibited signs of radiation sickness within 2 days following exposure to 7.5 Gy with double distilled water (Group III). These symptoms included anorexia, lethargy, diarrhoea, slow gait, body weight-loss and ruffled fur. The animals started dying from the day 7 and 100% mortality was observed within 30 days post-irradiation. In animals pre-treated with DTZ prior to irradiation (Group IV), 87.5% survived until day 28 following irradiation.

Pro- and normoblast cell counting
Animals treated with DTZ alone (Group II) did not show any significant change in the number of pro- and normoblasts, and their values were found to be close to normal at all autopsy intervals. At 7.5 Gy, elevation in counts started from day 7 (10.54 days±0.73) with a gradual decline at day 14 (10.26 days±0.53). The pro- and normoblast numbers were found to be significantly reduced (p<0.005) at all intervals in this group. In the DTZ pre-treated irradiated Group IV, a significant increase in the counts of pro- and normoblasts was observed as compared with their respective control group, Group III, at each autopsy interval. Such cells increased from day 7; however, values were not found to be near to normal even by 28 days post-irradiation (Table 1Go).


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  		Table 1. Survival rate of Swiss albino mice irradiated with 8.0 Gy gamma rays in the presence (experimental) or absence (control) of various doses of diltiazem (DTZ)

 
Haematological studies
Animals treated with DTZ alone (Group II) did not show any significant change in various haematological constituents (erythrocytes, leukocytes, differential leukocyte count, haemoglobin, haematocrit and erythrocyte sedimentation rate) in comparison with control.

Total erythrocyte count decreased at day 3 autopsy interval (4.25 days±0.16x106 mm–3) following 7.5 Gy gamma irradiation in Group III, but later the number of such cells increased on day 7 (5.73 days±0.06x106 mm–3) with a subsequent decline by day 14 (5.32 days±0.24x106 mm–3). Red cell count showed a significant decrease (p<0.005) as compared to Group I throughout the experiment. In the animals of Group IV, a significant (p<0.005) increase in red cell count with respect to control was noticed during the entire period of study by restoring almost a normal value on the last autopsy interval (i.e. day 28). Haemoglobin concentration in irradiated mice (Group III) showed the maximum decrease on day 3 (9.48 days±0.34). Animals irradiated with DTZ pre-treatment (Group IV) exhibited a higher haemoglobin concentration than Group III, and values were found to be near normal by the end of the experiment. Haematocrit percentage was found to be significantly lower (p<0.005) in irradiated Group III, with a maximum decline on day 3 (26.48 days ±0.16). In Group IV, haematocrit values were higher than control with a recovery from day 7 (35.34 days±0.34) and reached near normal (40.88 days±0.30) by day 28 post-treatment (Table 2Go).


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  		Table 2. Variations in haematological parameters of mice after 7.5 Gy of gamma irradiation with (experimental) or without (control) diltiazem

 
In Group III, the erythrocyte sedimentation rate exhibited a significant rise above normal and reached a maximum on day 3 (7.84 days±0.08). Later, a gradual decrease started from day 7, without attaining a normal value at any time. In DTZ pre-treated animals (Group IV), the increase in the erythrocyte sedimentation rate was significantly less than in Group III and values did not rise much higher than normal, even at the last autopsy interval (3.34 days ±0.32).

A marked decline in total leukocyte count was also observed at 12 h (2913±61.83) which fell further by day 3 (1984±42.84) in irradiated Group III. In DTZ pre-treated irradiated Group IV animals, cells scored significantly higher (p<0.005) than the corresponding control Group III throughout the study. However, an initial depression in counts was observed at 12 h (4693±54.83), but from day 3 the numbers increased gradually; normal counts could not be regained even on the last autopsy (i.e. 28 days) (Table 2Go).

In differential leukocyte counts, the maximum decrease of monocytes and lymphocyte was observed at 24 h (0.94±0.13 and 31.63±0.32, respectively) in Group III. Gradual reparation started from day 3, but normal counts were not evident even by the end of the experiment. In animals pre-treated with DTZ, this decrease was less pronounced in comparison with Group III. Neutrophil percentage showed a significant elevation (p<0.005) in Group III animals and was the highest at 24 h (44.16±0.32), but began to decline at subsequent intervals. In Group IV, such increase in neutrophilic counts above normal (Group I) was significantly less in comparison with control and values were slightly higher than normal on day 28 (26.63±0.72). Non-neutrophilic granulocytes showed a significant decline following radiation exposure, which was found maximal on day 3 (0.64±0.32). Thereafter, gradual reparation started and counts elevated to 37.33% of the normal value. In DTZ pre-treated animals, such a decrease was less in comparison with the control group during the entire period of study (Table 3Go).


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  		Table 3. Variation in differential leucocytes counts in mice after 7.5 Gy of gamma irradiation with (experimental) or without (control) diltiazem (DTZ)

 
Erythropoietin estimation
No significant variation in serum erythropoietin level was observed in DTZ-treated animals (Group II) as compared to normal (Group I). In Group III, there was a significant decrease (p<0.005) in the erythropoietin level on day 3 (1.54±0.22) following 7.5 Gy gamma irradiation, but this elevated on day 7 (1.68±0.18) and showed a subsequent decline on day 14 (1.59±0.08) as compared with Group I (normal). In Group IV, the erythropoietin level was insignificantly higher in comparison with radiation alone treated mice (Group III) at all the autopsy intervals (Figure 1Go).


Figure 1
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  		Figure 1. Variations in the erythropoetin(EPO) level after 7.5 Gy of gamma irradiation with (experimental) or without (control) diltiazem (DTZ).

 
Lipid peroxidation assay
No significant difference in blood as well as liver lipid peroxidation levels was observed in animals treated with DTZ alone (Group II) as compared to normal (Group I). A significant increase (p<0.005) in blood and hepatic lipid peroxidation levels was noted in gamma irradiated animals (Group III) as compared to normal. However, levels declined in the DTZ pre-treated irradiated (Group IV) animals (Figure 2Go).


Figure 2
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  		Figure 2. Variation in lipid peroxidation level in the blood and liver after 7.5 Gy of gamma irradiation with (experimental) or without (control) diltiazem. DDW, double distilled water; DTZ, diltiazem; TBARS, thiobarbituric acid reactive substances.

 
Glutathione (GSH) estimation
No significant alterations in the glutathione content of the liver and blood were observed between normal and DTZ- treated animals. However, a statistically significant (p<0.005) decrease in glutathione was noted in Group II as compared with Group I. DTZ pre-treated irradiated (Group IV) animals exhibited a significant elevation (p<0.005) in glutathione (blood and liver) as compared with Group III, but the values remained below normal (Figure 3Go).


Figure 3
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  		Figure 3. Variation in reduced glutathione(GSH) levels in the blood and liver after 7.5 Gy of gamma irradiation with (experimental) or without (control) diltiazem (DTZ).

 

   Discussion
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
References
 
In the present study, it was observed that irradiated mice pre-treated with DTZ (Group IV) did not show any radiation sickness and that the mortality rate was only 12.5% within 28 days. On the other hand, the irradiated animals (Group III) had a mortality rate of 81.25% within 28 days. This indicates an enhanced survival of mice pre-treated with DTZ (Table 1Go).

Exposure of animals to ionizing radiation causes a series of physiological changes known as acute radiation syndrome, which is dependent on the exposure dose and may lead to death. The damage to the haematopoietic system is a major factor in the mortality following an acute radiation exposure [22]. In the present radiation dose, haematopoietic as well as gastrointestinal damage may contribute to mortality. Endogenous infections may also be responsible for the death of irradiated mice. Bacteraemia may be a cause of mortality secondary to haematopoietic and gastrointestinal radiation damage as antibiotic treatment has been shown to increase survival of mice irradiated in the LD50/30 range [23–24]. In Group IV, 87.5% survival of mice was observed within 30 days, which demonstrates a significant protection offered by DTZ.

In the present study, there was a considerable decrease in the haematological values (erythrocytes, leukocytes, differential leukocyte count, haematocrit and haemoglobin) post-irradiation as compared to normal. However, a significant rise in these parameters was evident in DTZ pre-treated animals. In Group III, animals could not survive until day 28. Maximum decline in pro- and normoblasts, erythrocytes, leukocytes, haematocrit, haemoglobin and non-neutrophilic granules was observed on day 3 following irradiation. Micke et al [25] reported a significant decrease of human neutrophilic granulocyte function at 3.5 Gy and 4.0 Gy sublethal radiation dose.

The decrease in the values of haematological parameters following radiation exposure may be assigned to direct damage caused by a lethal dose of radiation [26]. Whole-body irradiation of moderate dose-range (5–10 Gy) leads to a decreased concentration of all cellular elements in the blood. This can be due to direct destruction of mature circulating cells, loss of cells from the circulation by haemorrhage, or leakage through capillary walls and reduced cell production [22].

In the present study, a significant decline in pro- and normoblast counts was observed which is due to the decrease in erythropoietin level produced by the kidneys. The kidney, in particular the peritubular interstitial cells, is the main production site of erythropoietin [27]. Kidneys are probably less sensitive to ionizing radiation, but at higher doses (6–8 Gy) they show serious damage [28] which is further responsible for a decrease in erythropoietin production. In the present study, a significant decrease in serum erythropoietin level was observed in irradiated animals. This decrease was lower in DTZ pre-treated animals, due to the drug having specific effects on kidneys. Renal protective effects of DTZ on the kidneys have been observed by Bakris and Shaikh [29] and Schulman [30]. These effects have been divided into those primarily mediated by changes in renal blood flow [31–32] and those secondarily mediated by electrolyte handling [33]; whereas some may be renal specific, others may result from the systemic hypotensive effects that are produced by DTZ [34]. DTZ may also protect against tubular necrosis of kidneys through its calcium channel-blocking action [35] and maintain the normal level of erythropoietin in kidneys, and further in bone marrow, as well as blood which is subsequently responsible for increased erythropoietic progenitor cells in bone marrow and red blood cells in blood.

In the present study, an increase in pro- and normoblasts as well as in erythrocytes was observed in DTZ pre-treated animals, thus demonstrating that the drug maintains a higher erythropoietin level, which is in turn responsible for an increase in the number of these cells. Haematocrit is the percentage of whole blood that is made up of cells and a decrease to below normal in its value indicates anaemia. Another measure of anaemia is a decrease in the haemoglobin percentage [36]. In the present investigation, it was observed that haemoglobin levels declined significantly following radiation exposure. These observations are in accordance with the findings of others [37–38]. The decrease in haemoglobin content is attributed to the decline in the number of red blood cells. In DTZ pre-treated animals, haemoglobin values were higher at all radiation doses, which shows a significant protection of erythrocytes by DTZ. An increase in erythropoietin level by DTZ is also directly responsible for an increase in haemoglobin content. The synthesis of haemoglobin begins at 12 h after binding of erythropoietin to its receptor [39] due to an increased iron pool by erythropoietin [40]. A decrease in haematocrit was also observed in the present study that can be attributed to the failure of erythropoiesis, destruction of mature cells, or increased plasma volume [41]. The decline in haematocrit values is due to decreased erythropoiesis and increased plasma volume. The decrease in the number of pro-and normoblasts as well as erythrocytes in the present study also supports the view of decreased erythropoiesis as the cause of a decline in haematocrit. DTZ protects bone marrow and blood erythropoietic cells, and maintains normal haematocrit levels.

One of the basic mechanisms of radiation damage is the production of free radicals, leading to the formation of peroxides and oxidative reactive species. These peroxides, via lipid peroxidation, damage the cell membrane and other cell components. Free radicals such as superoxide anion (O2–), the hydroxyl radical (OH–), and hydrogen peroxide (H2O2) are typically triggered by the exposure of living tissue to ionizing radiation. Membrane damage caused by these reactive oxygen species may allow the entry of excess calcium into cells with sequential biochemical and micro anatomical cellular degranulation and necrosis. By reducing this influx, the calcium channel-blocker DTZ, used in the present study, might prevent cellular injury due to membrane impairment caused by the inhibition of perfusion injury [42] and by direct inactivation of free radicals [14, 43]. The increased glutathione levels caused by DTZ pre-treatment may facilitate the reduction of oxidative free radicals by H+ donation. This allows the restoration of glutathione by glutathione reductase activity. The lower depletion of liver and blood glutathione in the DTZ pre-treated and irradiated animals could be due to the higher availability of glutathione, which increases the ability to cope with free radicals generated by radiation.

The results of the present investigation demonstrate that DTZ pre-treatment protects the haematopoietic system of mice against radiation-induced damage by inhibiting glutathione depletion, decreasing lipid peroxidation and increasing the erythropoietin level, which is subsequently responsible for maintaining haematological constituents in peripheral blood.


   Acknowledgments
 
The authors would like to thank Dr Gajendra Gupta, SDM Hospital, Jaipur, who helped with the identification of bone marrow and blood cells. The authors would also like to thank Prof. DP Agarwal, Dr KS Jheeta and Dr AA Chougle, Radiotherapy Department, SMS Medical College and Hospital, Jaipur, for providing us with irradiation facilities and help in radiation dosimetry.

Received for publication February 16, 2006. Revision received July 12, 2006. Accepted for publication July 26, 2006.


   References
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 References
 

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