|Year : 2016 | Volume
| Issue : 2 | Page : 217-224
Effect of etidronate on depression paradigms in male Swiss albino mice and Wistar rats: An experimental study
N Amitha, SS Torgal
Department of Pharmacology, Jawaharlal Nehru Medical College, KLE University, Belagavi, Karnataka, India
|Date of Web Publication||29-Sep-2016|
No. 295, Rajaram Marg, 1st Cross, Chidambar Nagar, Belagavi - 590 006, Karnataka
Source of Support: None, Conflict of Interest: None
Objective: Bisphosphonates represent the first choice in the treatment of osteoporosis, and no data are available concerning their effects on comorbid behavior alterations. There are some contradictory reports regarding these drugs with respect to antidepressant activity in humans. Hence, the present study was planned to investigate the effects of etidronate in male Wistar rats and Swiss albino mice using depression paradigms, namely, forced swimming test (FST) and tail suspension test (TST).
Materials and Methods: Eighteen male Wistar rats and 18 male Swiss albino mice were brought and acclimatized 10 days prior to experimentation. Then, they were randomized into three groups: (1) control (distilled water), (2) standard (amitriptyline), and (3) test (etidronate). After treatment, the Wistar rats were subjected to FST while Swiss albino mice were subjected to TST to evaluate the antidepressant activity.
Results: Etidronate showed significant decrease in the immobility time in both FST and TST when compared to that of control group. There was no significant decrease in the immobility time when compared between the standard amitriptyline and etidronate groups. Locomotor performance was tested using actophotometer for all the three groups taken in the study. Effects on locomotor activity showed no significant difference among all three groups.
Conclusion: From the results, it is concluded that etidronate can have antidepressant activity. Based on experimental and observational studies, there appears to be a role of etidronate in depression.
Keywords: Depression, etidronate, forced swimming test, osteoporosis, tail suspension test
|How to cite this article:|
Amitha N, Torgal S S. Effect of etidronate on depression paradigms in male Swiss albino mice and Wistar rats: An experimental study. Indian J Health Sci Biomed Res 2016;9:217-24
|How to cite this URL:|
Amitha N, Torgal S S. Effect of etidronate on depression paradigms in male Swiss albino mice and Wistar rats: An experimental study. Indian J Health Sci Biomed Res [serial online] 2016 [cited 2019 Aug 24];9:217-24. Available from: http://www.ijournalhs.org/text.asp?2016/9/2/217/191278
| Introduction|| |
Mental disorders have always been a huge burden not only on an individual but also to the entire community. The World Health Organization estimates that major depression is the fourth most important cause of loss in disability-adjusted life years (DALYs). It is also estimated that by the year 2020, if the current trends continue, depression will be the second-leading cause of DALYs, accounting for 5.7% of total burden of disease.  In India, many studies have estimated the prevalence of depression in community which varied from 1.7 to 74/1000 population. 
Osteoporosis is a chronic disease of compromised bone strength that affects pre- and post-menopausal women and men. In recent years, a relationship between depression and osteoporosis has become evident.  Decreased bone mineral density (BMD) has been observed in depressed women and men. , Older men appear to be even more susceptible to the effects of depression on bone density than older women.  Depression itself has been associated with fractures. Further, animal studies suggest that depression may predispose to osteoporosis.  Suspected mechanisms include an impaired hypothalamic-pituitary-adrenal system with increased serum cortisol levels, and upregulation of the proinflammatory cytokines interleukin 6 (IL-6), and tumor necrosis factor (TNF). ,
Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been the pharmacological options available for treating osteoporotic patients with depression.  About one-third of these patients do not respond primarily to antidepressant therapy. Those who do respond will progressively become resistant to treatment or show relapse.  They also have slow therapeutic onset, low remission rates as stated by Fava and Davidson.  In addition, a series of study over the last 10-15 years showed that bone loss may be a potential side effect of SSRIs and may even result from physiological effects of depression itself. Moreover, SSRIs and TCAs present with various adverse effects such as anorexia initially followed by weight gain, decreased libido, ejaculatory disturbances, extrapyramidal side effects, and serotonin syndrome. 
Bisphosphonates (BPNs) are most commonly used in the treatment of osteoporosis to reduce the risk of fractures. Surprisingly, a study done at Lareb, The Netherlands in 2010, showed reports of depression with the use of alendronate, etidronate, and pamidronate and concluded that it could be a class effect for all the BPNs.  Depression is an inflammatory disorder, wherein there is increase in cytokine levels. A study stated that particularly nitrogenous BPNs are known to induce acute phase responses, increase in IL-6 and IL-8.  Another study showed that high levels of TNF caused upregulation of Ets-2 and Bcl-xl expression which reduced the susceptibility of BPNs-induced apoptosis of osteoclasts. 
BPNs, a class of agents taken up by osteoclasts and macrophages to inhibit the activity of inflammatory cytokines, are thought to inhibit the inflammation induced by these cells. Etidronate is reportedly effective in relieving pain in patients suffering from steroid-induced osteoporosis, postmenopausal osteoporosis, and osteoarthritis. A group of studies determined whether intermittent cyclical etidronate inhibits bone resorption or inflammatory changes over two study periods of 1.5 years and 3 years in osteoporotic patients with rheumatoid arthritis (RA).  They found that etidronate also inhibited the production of mediators related to inflammation, pain, and angiogenesis, namely, IL-6, prostaglandin E2 (PGE 2 ), substance P, and vascular endothelial growth factor, in synovial cells of arthritic models.
From these studies also, it can be hypothesized that BPNs can have antidepressant-like activity since the above-mentioned cytokines play a role in pathophysiology of depression. Hence, in view of controversial reports, the present study is undertaken to explore the effects of etidronate on depression paradigms in male Swiss albino mice and Wistar rats.
| Materials and Methods|| |
Adult male Wistar rats weighing 175 ± 25 g and adult male Swiss albino mice weighing 25 ± 5 g were obtained from the Central Animal House of J. N. Medical College, Belagavi. The animals are delivered to the laboratory at least 10 days before the experiment. They were housed under standard laboratory conditions and acclimatized to 12-12 h light/dark cycle for 10 days prior to the day of experimentation. They were maintained on standard chow pellet (Amrut brand) and water ad libitum. The study was approved by the Institutional Animal Ethics Committee constituted as per the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals.
Experimental protocol and drug administration
Eighteen adult male Wistar rats were divided into three groups with 6 rats in each group (n = 6) and 18 adult male Swiss albino mice were also divided into three groups with 6 mice in each group (n = 6).
Standard antidepressant amitriptyline (tablet tryptomer 10 mg. Merind Ltd. [Wockhardt Ltd.]) was bought from local pharmacy, and etidronate (Arrow - etidronate 200 mg. Vardhaman Health Specialities, Bengaluru) was purchased. Clinical doses for these drugs were converted into rat or mouse equivalent doses with the help of the table devised by Paget and Barnes [Table 1]. 
It is noteworthy that all the three groups, i.e., control, standard, and test groups, were treated per orally. All the drugs were dissolved in distilled water.
The animals were kept on fasting on the day prior to the experimentation. Only water was provided to the animals on the experiment days because etidronate has poor intestinal absorption and food reduces their gastrointestinal absorption by 60%. 
Forced swimming test
Rodents are forced to swim in small enclosures (cylinders) from which there is no escape and rapidly become immobile after an initial period of vigorous activity. Initially, immobility was interpreted as evidence that they had learned that escape was impossible and had given up hope. Immobility was therefore given the name, "behavioral despair." It has subsequently been shown in numerous laboratories that immobility is reduced by a wide range of clinically active antidepressant drugs. As a consequence, this simple test is now widely used to screen novel substances for potential antidepressant activity.
In this study, rats in different groups were administered the respective drug three times, i.e., 24, 5, and 1 h prior to experimentation. After that, they are placed in the cylinder filled with water for 6 min and the duration of immobility (in seconds) was recorded. The apparatus used for this test consists of a vertical plexiglass cylinder measuring 40 cm in height and 18 cm in diameter. The apparatus was filled with water up to 15 cm and the temperature was maintained at 25 ± 2°C. ,
Behavioral despair paradigm is the basic principle of this test. When a normal animal is subjected to an aversive situation, it alternates between two kinds of behaviors, namely, agitation and immobility. These can be named as searching behavior (characterized by intense motor activity and expense of energy) and waiting behavior (immobility and energy saving), respectively. It is also called as searching-waiting strategy. Antidepressant drugs modify the balance between these forms of behavior in favor of searching. ,,
When rats are forced to swim in a restricted environment from which there is no escape, they will eventually cease to move altogether and make only those movements necessary for keeping their heads above the water. This characteristic and readily identifiable behavior of immobility indicates a state of despair in which the rat has learned that escape is impossible and resigns itself to the experimental conditions. Such behavior is said to be equivalent to clinical depression. Therefore, the drugs that decrease this immobility would have antidepressant activity. Rats were preferred over mice in this test because the rat version is said to be more selective for this experiment, i.e., fewer false positives. ,,
Forced swimming test (FST) has two swim sessions. The first session is called "pretest" which consists of 15 min session conducted prior to drug administration and without behavioral recording. This prior habituation session ensures a stable and high duration of immobility during the 6 min test session, usually performed 24 h later. Adult male Wistar rats weighing 175 ± 25 g were subjected to swimming for 15 min. After a period of vigorous swimming for 4-5 min, the rats became immobile and remained in this position for about 80% of the time. The immobility time was measured only when the rat ceased to struggle and remained floating motionless in the water making only those movements necessary to keep its head above the water. The rats were removed, dried and the first dose of the drug was given orally simultaneously, and they were returned back to their cages provided with food and water. The water in cylinder was changed for every rat before subjecting it to swim. These rats were subjected to the test session on the next day (at 24 h).
On the next day, the rats were given the second dose of drug orally, 4 h prior to test and the third dose of drug orally, 1 h prior to test. Then, they were subjected to FST and the duration of immobility (in seconds) was recorded for 6 min. ,
The water in the cylinder was changed every time for each animal after the test.
Tail suspension test
This protocol describes a procedure in mice that are conceptually related to the FST, except that immobility is induced by suspending the mice by the tail. After initially trying to escape by engaging in vigorous movements, mice rapidly become immobile. The duration of immobility is reduced by a wide variety of antidepressants. This procedure has several advantages over the FST. No hypothermia is induced, and the animals resume normal spontaneous activity immediately after the test. No special postexperimental treatment (rubbing down, maintenance in a warmed environment) is required.
The apparatus consists of two metallic rods connected with a horizontal rod, 35 cm apart. A nylon thread was suspended from its center, and a hook was attached to the free end of the nylon thread to enable suspension of the mice by their tail. Height of the horizontal rod was adjusted so that the snout of the mice was 58 cm from the base.
Basic principle of this test is the behavioral despair paradigm which was discussed in the earlier test (FST). When mice are hung by their tails, they are subjected to inescapable stress. After an initial bout of vigorous activity, the mice attain immobility. Any drug that decreases the time spent in immobility is said to have antidepressant activity. ,,
A mouse pretreated with a drug or vehicle was suspended from the hook hanging at the center of the horizontal rod by an adhesive tape stuck 1 cm proximal to the tail tip. The mouse was said to be immobile when it stopped moving and hung motionless. Immobility time in seconds was recorded over a period of 6 min. ,
Effect of all the drugs used in the present study on locomotor activity was tested using the actophotometer [Graph 1]. , The apparatus consists of a metal box measuring 68 cm in length, 68 cm in breadth, and 45 cm in height. It is equipped with photocells sensitive to infrared light. 
This test provides simultaneous measures of locomotion, exploratory behavior, and anxiety. This test helps to differentiate between sedative and stimulant drugs. It also helps to rule out any influence of the drugs on locomotor system which in turn may affect immobility (in antidepressant tests).
Pretreated mice were placed in the center of the apparatus for a period of 5 min. The device electronically counts the number of times the infrared beams interrupted by movement of the animal. This actophotometer count is a measure of the locomotor activity.
Data are expressed as mean ± standard deviation. Data were analyzed using one-way analysis of variance (ANOVA) followed by Bonferroni's multiple comparison test.  P 0≤ 0.05 was considered to be statistically significant.  GraphPad Prism 4.0 software (San Diego, California, USA), a statistical analysis tool, was utilized for all the analyses.
| Results|| |
In the present study, etidronate was investigated for its possible antidepressant activity using animal models of depression.
FST in male Wistar rats and tail suspension test (TST) in male Swiss albino mice were used to evaluate antidepressant activity of etidronate. Amitriptyline was taken as standard antidepressant drug for comparison.
Forced swimming test in male Wistar rats
The duration of immobility in seconds in different groups was noted over a period of 6 min. The mean duration of immobility in the control group was 108.2 ± 14.8 while in amitriptyline was 70.17 ± 7.13 and etidronate was 52.67 ± 27.00. Duration of immobility was significantly (P < 0.001) decreased in amitriptyline and etidronate groups when compared to that of control group. It was also found that etidronate group was comparable to that of amitriptyline-treated group [P > 0.05, [Table 2]].
Tail suspension test in male Swiss albino mice
The duration of immobility time in seconds was noted over a period of 6 min. The mean duration of immobility in the vehicle-treated (control) group was 129.20 ± 20.20, whereas it was 71.00 ± 8.462 (amitriptyline) and 75.00 ± 27.99 (etidronate). Duration of immobility was significantly (P < 0.01) decreased in amitriptyline and etidronate groups when compared to that of control group [Graph 2]. It was also found that etidronate group was comparable to that of amitriptyline-treated group [P > 0.05, [Table 3].
Mean of the locomotor activity in amitriptyline- and etidronate-treated groups was 412.8 ± 73.02 and 396.0 ± 107.4, respectively, and these values failed to show significant (P > 0.05) difference when compared to that of control group, i.e., 438.2 ± 166.5 [Table 4] and Graph 3]. This suggests that there was homogeneity among the three groups compared. No multiple comparison tests were required.
| Discussion|| |
In the present study, evaluation of etidronate for its antidepressant activity using experimental models of depression was carried out along with its effects on locomotor performance. FST in adult male Wistar rats and TST in adult male Swiss albino mice were performed to evaluate antidepressant activity of etidronate. Results of the present study showed that etidronate significantly decreased the immobility time in both the tests when compared to that of control suggesting that it can have antidepressant-like activity. There was no significant decrease in the immobility time when compared between the standard amitriptyline and etidronate groups in both the tests. Locomotor performance was tested using actophotometer for all the three groups taken in the study. Effects on locomotor activity showed no significant difference among all the three groups, suggesting that there was no influence of the drugs on locomotor system.
FST and TST were used to study the antidepressant activity because both these tests are easy to perform, rapid and require a minimum of apparatus.  Actophotometer test provides simultaneous measures of locomotion, exploratory behavior, and anxiety. This test helps to differentiate between sedative and stimulant drugs. It also helps to rule out any influence of the drugs on locomotor system which in turn may affect immobility (in antidepressant tests).
BPNs are potent inhibitors of osteoclast-mediated bone resorption that suppress bone turnover through their ability to prevent the initiation of new erosion sites and to reduce ongoing excavation. Hence, they are the first-line drugs used in the treatment of osteoporosis in pre- and post-menopausal women and elderly men.
It is evident that reduced levels of estrogen can lead to the development of osteoporosis in postmenopausal women. In an experimental model using ovariectomized female rats, it has been documented that estrogen was able to both improve cognitive performance and reduce anxiety and depressed behavior.  However, in clinical practice, the use of estrogen is related to the development of severe adverse drug reactions.  Therefore, the most widely used drugs in the prevention of fractures in postmenopausal osteoporotic women are BPNs.
Another study suggested that a chronic hypoestrogenic state may reduce the response to antidepressant drugs.  Menopausal status and old age are predictors of a poor response to antidepressant treatment. Furthermore, the follicular stimulating hormone may interfere with the mechanism of action of the antidepressant agents.  Thus, BPNs have been evaluated for additional antidepressant property to minimize the side effects and improve quality of life in such patients.
Etidronate produces a sustained reduction in the levels of biochemical markers of bone remodeling, returning them to the premenopausal range.  It also increases BMD and decreases the risk of osteoporotic fracture in postmenopausal women and in men. Long-term intervention studies have shown that continuous etidronate therapy is associated with a sustained therapeutic effect on bone density and remodeling. ,,
Antidepressants such as SSRIs and TCAs are the choice of drugs for osteoporosis with depression. Several studies come with the evidence that these antidepressants in turn cause fracture risks and bone loss in such patients. 
BPNs, although indicated for the treatment and prevention of bone health disturbances such as osteoporosis, are the possible mechanisms that indicate their role in osteoporotic patients with depression. They could have central-behavioral effects through a modulation of neurosteroid synthesis. Neurosteroids are potent and effective neuromodulators that are synthesized from cholesterol in the brain. Increasing evidence indicates that dysregulation of neurosteroids production plays a role in the pathophysiology of stress and stress-related psychiatric disorders, including mood and anxiety disorders. ,
These drugs can cross the blood-brain barrier; in fact, they were found to be potent inhibitors of cholesterol biosynthesis from mevalonate mimicking the action of lipophilic statins. The levels of total brain cholesterol were shown to correlate positively with the amount of amyloid beta, which is characteristic for Alzheimer disease (AD). Therefore, BPNs were also indicated as a possible treatment for AD prevention and/or treatment. 
Furthermore, BPNs have a central antinociceptive effect connected with the Ca 2+ mechanism. Ca influx releases substances involved in nociception and inflammation, such as substance P, vasoactive intestinal peptide, neuropeptide Y, prostaglandin, serotonin, and kinins.
Certain studies have investigated that acid sphingomyelinase-ceramide system is one of the newer potential targets for antidepressive drugs.  Roth et al. quoted that BPNs reduced the levels of acid sphingomyelinase proving that they can have antidepressant activity. 
BPNs, a class of agents taken up by osteoclasts and macrophages to inhibit the activity of inflammatory cytokines, are thought to inhibit the inflammation induced by these cells. Etidronate is reportedly effective in relieving pain in patients suffering from steroid-induced osteoporosis, postmenopausal osteoporosis, and osteoarthritis. A group of studies determined whether intermittent cyclical etidronate inhibits bone resorption or inflammatory changes over two study periods of 1.5 and 3 years, in osteoporotic patients with RA.  They found that etidronate also inhibited the production of mediators related to inflammation, pain, and angiogenesis, namely IL-6, PGE 2 , substance P, and vascular endothelial growth factor, in synovial cells of arthritic models. Thus, by reducing the mediators of inflammation, these drugs can have antidepressant activity. 
With the above evidence in support of this study, it can be stated that etidronate can have antidepressant property.
Limitations of this study
Further animal research has to be carried out to substantiate the above results. In future, proper validation by clinical trials on other BPNs with antidepressant activity is required for assessment of biomarkers of depression and gene expression to confirm or give strong evidence in support of antidepressant activity of other BPNs.
- Parameters assessed were only of subjective origin
- Blinding was not followed.
| Conclusion|| |
BPNs being antiresorptive drugs represent the first choice in the prevention of fractures in patients with osteoporosis. In this study, etidronate decreased the immobility time when compared to that of control suggesting they can have additional antidepressant activity and no significant difference between this drug and standard antidepressant amitriptyline, suggesting that they are not better antidepressants than the standard ones. Furthermore, there was no significant difference in locomotor activity when compared to both control and standard interpreting no influence on locomotor system. However, clinical trials may be performed in order to validate these observations. It can actually be concluded that class of BPNs might have positive effects on depressive disorders indirectly improving/maintaining physical abilities and therefore quality of life.
The KLE University, J.N.Medical College, and all the teaching and nonteaching staffs of the Department of Pharmacology are greatly acknowledged for permitting me to conduct this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]