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Impact of gliclazide and selenium co-treatment on depression in a diabetic rat model
*Corresponding author: Musaratafrin Saiyed, Department of Pharmacology, A. R. College of Pharmacy and G. H. Patel Institute of Pharmacy, Anand, Gujarat, India. musaratsaiyed40@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Gupta P, Saiyed M. Impact of gliclazide and selenium co-treatment on depression in a diabetic rat model. Indian J Physiol Pharmacol. doi: 10.25259/IJPP_544_2024
Abstract
Objectives:
Insulin deficiency, insulin resistance, and chronic hyperglycaemia impair neurogenesis and neurotransmitter levels and activate the hypothalamic-pituitary-adrenal axis, leading to oxidative stress and reduced serotonin, resulting in depression. Depression and type 2 diabetes mellitus are comorbid conditions, with each increasing the risk of the other. This study evaluates the effects of gliclazide and its combination with selenium on reserpine-induced depression in diabetic rats.
Materials and Methods:
Using a fructose-fed-alloxan model, diabetes was induced in Wistar rats, followed by reserpine (0.2 mg/kg/day, i.p.) for 14 days to induce depression. The treatment groups received gliclazide (10 mg/kg/day, p.o.) or gliclazide with selenium (0.2 mg/kg, p.o.) along with reserpine. Effectiveness was measured using the open field test (OFT), tail suspension test (TST), sucrose preference test (SPT) and oxidative stress parameters. Statistical significance was analysed using one-way analysis of variance followed by Dunnett’s test.
Results:
Gliclazide and its combination with selenium significantly alleviated reserpine-induced depression by increased rearing and crossing in OFT, decreased immobility time in TST, increased sucrose consumption in SPT and reduced oxidative stress in diabetic rats, decreased malondialdehyde levels and increased superoxide dismutase and glutathione levels.
Conclusion:
The study concludes that the combination of gliclazide with selenium offers protective effects and may benefit patients already using gliclazide as an oral hypoglycaemic agent.
Keywords
Depression
Diabetes mellitus
Hyperglycaemia
Insulin
Reserpine
Serotonin
INTRODUCTION
Depression is a common, primary mood disorder characterised by a persistent depressed mood, anhedonia, feelings of guilt, disturbed sleep, low energy, poor concentration, cognitive dysfunction, negative rumination, decreased appetite and libido and suicidality.[1,2] Depression and type-2 diabetes mellitus (T2DM) are comorbid conditions, with each increasing the risk of the other. Several studies have revealed that additional roles of insulin in the brain, including its involvement in memory enhancement, neuron protection, synaptic plasticity regulation and maintenance of hypothalamic-pituitary-adrenal (HPA) axis homeostasis, elucidate the relationship of insulin with depression.[3,4] Anti-diabetic and anti-depressant treatments have been found to elevate serotonin levels and the brain’s AMP-activated protein kinase activity while reducing plasma cortisol levels. These treatments also increase branched-chain amino acids in plasma and decrease serotonin availability at serotonin receptors, exerting an inhibitory effect on serotonergic receptors.[5,6] Selenium, a trace element with an important role in protecting the brain against oxidative damage, suggests its potential for depression. Observational studies have consistently shown a positive association between selenium status, diabetes, insulin resistance and depression.[6,7] This study aimed to evaluate the effect of gliclazide and its combination with selenium in an experimental rat co-model of depression and diabetes mellitus.
MATERIALS AND METHODS
Study approval and drug procurement
The protocol (CPCSEA/ARCP/2022-23/01) for this study was authenticated and conducted in the Research Laboratory of the Pharmacology Department. Gliclazide was provided as a gift by Indoco Remedies Ltd., Navi Mumbai. Reserpine (Yarrow Chem Products), fructose (Chemdyes), alloxan (Sigma Aldrich) and selenium (Bluebonnet Nutrition Corporation) were purchased for the study.
Animals and experimental design
Wistar rats of either sex weighing 150–200 g were procured from Zydus Health Care, Ahmedabad, and divided into four groups of eight animals each (n = 8). The rats were housed under standard conditions according to the guidelines of the Committee for Control and Supervision of Experiments on Animals.
Group I animals (n = 6) were administered 0.9% saline orally as a vehicle control for 32 days. The treatment regimen lasted for 31 days and was divided into two phases, as illustrated in Figure 1. The first phase involved the induction of diabetes, followed by the second phase as induction of depression. T2DM was induced in rats using the fructose-fed alloxan model, while depression was induced through reserpine administration. The test drugs evaluated in the study were gliclazide and selenium.
- Study timeline.
Diabetes mellitus was induced in all animals except vehicle group. For induction of diabetes, animals received 20% w/v fructose solution in drinking water for 14 days. On day 15, after an overnight fast, alloxan (150 mg/kg, i.p.) was administered. After 48 h, fasting blood glucose levels (BGL) were measured using a digital one-touch glucometer, and animals with BGL ≥200 mg/dL were selected for further study.[8,9] Eighteen diabetic rats were randomly divided into three groups (n = 6) and received reserpine (0.2 mg/kg/day i.p.)[10] for 14 days to induce depression. Group II (Model group) received only reserpine. Group III and Group IV additionally received gliclazide (10 mg/kg/day p.o.)[11] and a combination of gliclazide (10 mg/kg/day p.o.)[11] with selenium (0.2 mg/kg/day p.o.)[12] for the same duration.
Behavioural tests
On day 31, following the last drug administration, behavioural tests were conducted in the following sequence: Open field test (OFT) and tail suspension test (TST). On day 32, the sucrose preference test (SPT) was performed.
OFT
The OFT was used to assess both locomotor and exploratory behaviours. Each rat was individually placed in the centre of a 60 × 60 × 40 cm box divided into nine equal quadrants. For a duration of 5 min, the number of quadrants crossed with all four paws (indicating locomotor activity) and the frequency of rearing on its hind limbs (indicating exploratory activity) were recorded.[13-15]
TST
The antidepressant-like effects of gliclazide and gliclazide with selenium were assessed using the TST. Rats were suspended 60 cm above the floor by adhesive tape about 1 cm from the tip of their tails. Immobility time was recorded over 5 min, with rats considered immobile when they remained motionless and hung passively.[13,14]
SPT
SPT, commonly used to evaluate depressive-like behaviour (anhedonia), was conducted over 24 h. On day 31, after a 23-h fasting period, each rat was presented with two bottles for the final hour, one containing 1% sucrose solution and the other containing simple drinking water. The volume of each solution consumed was recorded, and the percentage preference for sucrose was calculated using the following formula:[10,13,16]
Measurement of brain oxidative stress markers
Oxidative stress markers, including brain superoxide dismutase (SOD),[17] malondialdehyde (MDA)[18] and reduced glutathione (GSH),[19] were measured chemically.
Statistical analysis
Data were expressed as mean ± standard error of the mean and were analysed using one-way analysis of variance, followed by Dunnett’s test. Statistical analysis was performed with GraphPad Prism 9.0 software, with a significance level set at P < 0.05.
RESULTS
Body weight changes
From day 0 to 17, Wistar rats treated with a 20% fructose solution and a single dose of alloxan showed significant increases in body weight across the model control, gliclazide-treated treated and gliclazide with selenium-treated groups. On day 17, body weights increased from initial values to 200 ± 2.58, 203.33 ± 3.33 and 205 ± 4.28 g, respectively. This increase was statistically significant (P < 0.0001) compared to the vehicle control group. From day 17 to 32, the model control group’s body weight decreased significantly, while the other groups showed slight increases. By day 32, body weights in the model control group significantly differed from the vehicle control group (P < 0.0001), with the gliclazide-treated and gliclazide with selenium-treated groups showing significant increases compared to the model control group (P < 0.001) [Figure 2].
- Change in body weight.
Blood glucose level (BGL)
The administration of 20% fructose and alloxan significantly increased fasting BGL in the model control, gliclazide and gliclazide with selenium-treated groups by day 17. These groups showed BGL (mg/dL) of 216.33 ± 2.43, 217.83 ± 3.59 and 218.16 ± 2.82, respectively, which were significantly higher than the vehicle control group (P < 0.0001). By day 32, the model control group had a further significant increase in BGL, while the gliclazide and gliclazide with selenium-treated groups showed significant reductions (P < 0.0001) compared to the model control group [Figure 3].
- Blood Glucose Level (mg/dL) on Day 0, Day 17 and Day 32.
Behavioural tests
Open field test (OFT)
On the 31st day, the model control group showed significantly (P < 0.001) reduced locomotion (133.33 ± 1.81) and rearing frequency (13.16 ± 1.13) compared to the vehicle control group (rearing: 20 ± 2.29, locomotion: 144.16 ± 2.08). The gliclazide-treated (rearing: 25.5 ± 1.54, locomotion: 147.33 ± 2.60) and gliclazide with selenium-treated groups (rearing: 29.66 ± 1.45, locomotion: 150 ± 1.87) showed significant (P < 0.0001) increases in these behaviours compared to the model control group. Although the gliclazide with selenium group showed slightly higher rearing and locomotion than the gliclazide-only group, the difference was not statistically significant [Table 1].
| Groups | Rearing | Locomotion |
|---|---|---|
| (No. of rearing) | (No. of crossing) | |
| Vehicle control | 20±2.29 | 144.16±2.08 |
| Model control | 13.16±1.13* | 133.33±1.81* |
| Gliclazide treated | 25.5±1.54# | 147.33±2.60# |
| Gliclazide with selenium treated | 29.66±1.45# | 150±1.87# |
Data are expressed as mean ± SEM, n=6. *p<0.001 When Model control group compare with Vehicle control group, #p<0.0001 when Gliclazide treated group and Gliclazide with Selenium treated group compare with Model control group using by one way ANOVA followed by Dunnet’s test.
Tail suspension test (TST)
The immobility time in the model control group (175.16 ± 4.20 s) was significantly higher (P < 0.0001) than in the vehicle control group (144.16 ± 1.75 s). The gliclazide-treated (135.66 ± 4.00 s) and gliclazide with selenium-treated groups (134.00 ± 2.76 s) exhibited significantly reduced immobility times compared to the model control group (P < 0.0001). Although the immobility time was lower in the gliclazide with selenium combination group compared to the gliclazide-only group, the difference was not statistically significant [Figure 4].
- Effect of gliclazide and gliclazide with selenium on immobility time using tail suspension test.
Sucrose preference test (SPT)
Reserpine-induced depression resulted in anhedonia, with a sucrose preference of 0.63 ± 0.02, compared to 0.97 ± 0.06 in the vehicle control group, although this difference was not statistically significant. Gliclazide treatment increased sucrose preference to 1.39 ± 0.12, compared to 0.63 ± 0.02 in the model control group, but this difference was also not statistically significant. However, the gliclazide with selenium-treated group showed a significant increase (P < 0.001) in sucrose preference to 2.22 ± 0.50 compared to 0.63 ± 0.02 in the model control group. While the gliclazide with selenium group had a higher sucrose preference (2.22 ± 0.50) compared to the gliclazide-only group (1.39 ± 0.12), this difference was not statistically significant [Table 2].
| Groups | Vehicle control | Model control | Gliclazide treated | Gliclazide with selenium treated |
|---|---|---|---|---|
| Sucrose preference (%) | 0.97±0.06 | 0.63±0.02 | 1.39±0.12 | 2.22±0.50# |
Data are expressed as Mean ± SEM, n=6 #p<0.001 when Gliclazide with Selenium treated group compared with Model control group by one way ANOVA followed by Dunnet’s test.
Oxidative stress markers
SOD activity
The SOD activity was significantly lower in the model control group (0.21 ± 0.049) compared to the vehicle control group (0.47 ± 0.028) (P < 0.0004). Treatment with gliclazide (0.39 ± 0.036) and gliclazide combined with selenium (0.42 ± 0.01) significantly increased SOD levels compared to the model control group (P < 0.001). Although the gliclazide with selenium group showed higher SOD levels than the gliclazide alone group, this difference was not statistically significant [Table 3].
| Groups | Vehicle control | Model control | Gliclazide treated | Gliclazide with selenium treated |
|---|---|---|---|---|
| Superoxide dismutase (UI/g) | 0.47±0.03 | 0.21±0.05* | 0.39±0.04# | 0.42±0.01# |
| Glutathione (mM) | 0.432±0.01 | 0.009±0.0001* | 0.177±0.002# | 0.408±0.002#$ |
| Malondialdehyde (µmol/g) | 0.077±0.05 | 0.181±0.10 | 0.046±0.00 | 0.043±0.00 |
Data are expressed as mean ± SEM, n=6. *p<0.0001 when Model Control group compared to Vehicle control group. #p<0.001 when Gliclazide treated group and Gliclazide with Selenium treated group compared with Model control group, $p<0.0001 when Gliclazide with Selenium treated group compare with Gliclazide treated group by using one way ANOVA followed by Dunnet’s test.
Reduced GSH activity
GSH levels were significantly lower in the model control group (0.009 ± 0.0001) than in the vehicle control group (0.432 ± 0.01) (P < 0.0001). Both the gliclazide (0.177 ± 0.002) and gliclazide with selenium groups (0.408 ± 0.002) exhibited significantly higher GSH levels compared to the model control group (P < 0.0001). The gliclazide with selenium group also had significantly higher GSH levels than the gliclazide group (P < 0.0001) [Table 3].
MDA levels
MDA levels were higher in the model control group (0.181 ± 0.103) compared to the vehicle control group (0.077 ± 0.047). Treatment with gliclazide (0.046 ± 0.0035) and gliclazide with selenium (0.043 ± 0.0033) reduced MDA levels compared to the model control group, with the gliclazide and selenium combination showing a more pronounced reduction, though the difference was not statistically significant [Table 3].
DISCUSSION
T2DM is a long-term endocrine and metabolic condition marked by elevated BGL.[20,21] Depression is recognised as the most prevalent psychiatric mood disorder associated with diabetes mellitus as a comorbidity, with its incidence being twice as high in diabetic patients compared to non-diabetic individuals.[10,14,22-24] Insulin insufficiency or deficiency, insulin resistance-induced hyperglycaemia and reduced availability of serotonin 5-hydroxytryptamine (5-HT) in the brain are key features of both T2DM and depression, respectively.[10,14] Hyperglycaemia is also considered a primary metabolic cause in the development of depression, as it is associated with increased oxidative stress due to the overproduction of reactive oxygen species (ROS), which in turn reduces serotonin availability.[10,25] In addition, oxidative stress impairs glucocorticosteroid release and receptor function, dysregulates the polyol and glycolytic pathways, disrupts the HPA axis, overexpresses advanced glycation end-products and reduces levels of brain-derived neurotrophic factor.[10,25] These mechanisms collectively decrease serotonin synthesis and increase its reuptake, resulting in low serotonin availability in the brain and the development of depression.[10,25] The co-occurrence of depression and T2DM negatively impacts patients’ health and quality of life.[10]
In the present study, a co-model of diabetes mellitus and depression in Wistar rats was utilised to evaluate the effectiveness of gliclazide and its combination with selenium. Diabetes was induced in the model control group, the gliclazide-treated group and the gliclazide-with-selenium-treated group by the fructose-fed-alloxan model.[8,9] Excessive fructose intake induces insulin resistance, obesity and compensatory hyperinsulinaemia in experimental animals, leading to β-cell exhaustion and impaired β-cell function.[8,24] Alloxan exerts its diabetogenic effect by selectively destroying pancreatic β-cells through ROS generation.[9] These mechanisms were evident in the model control, gliclazide-treated and gliclazide-with-selenium-treated groups, as indicated by significantly higher body weight and fasting BGL on day 17, consistent with other research findings.[8,26]
In diabetic animals, chronic administration of reserpine for 14 days depletes brain monoamine (serotonin) levels, leading to depression.[22] The model control group exhibited significant decreases in rearing and locomotion in the OFT, significant increases in immobility time in the TST on day 31, reduced sucrose preference in the SPT on day 32 and increased oxidative stress, all of which demonstrated reserpine-induced depression in diabetic animals. These results align with those of other studies.[10,22]
Gliclazide, a sulfonylurea class oral hypoglycaemic agent, demonstrated antidepressant effects in animals by significantly increasing rearing and locomotion in the OFT, significantly reducing immobility time in the TST on day 31, improving sucrose preference in the SPT on day 32 and reducing oxidative stress, indicating its effectiveness against reserpine-induced depression in diabetic animals.[27] Selenium, a trace element with antioxidant properties and neuromodulatory effects, plays a vital role in the proper functioning of selenoproteins such as GSH peroxidase, thioredoxin reductase and selenoprotein-P, which protect the brain against lipid peroxidation and oxidative cellular damage.[7,28,29] The combination of gliclazide and selenium produced a synergistic effect against depression, as evidenced by significant increases in rearing and locomotion in the OFT, significant reductions in immobility time in the TST on day 31, improved sucrose preference in the SPT on day 32 and reduced oxidative stress. These results are consistent with those of other studies.[10,13,14]
In this study, reserpine was observed to increase MDA levels and significantly reduce SOD and GSH levels in the model control group. This is likely due to the overproduction of ROS, which causes oxidative stress and contributes to depression. Co-administration of gliclazide and selenium with reserpine confirmed their effectiveness against depression compared to the model control group. Gliclazide and selenium exerted their antioxidant effects primarily by reducing systemic oxidative stress through the azabicyclo-octyl ring and selenoproteins, respectively,[7,27,29] as demonstrated by diminished MDA levels and improved SOD and GSH levels. Extensive ROS causes lipid peroxidation and increases the levels of lipid peroxides such as MDA. The elevated MDA levels, a marker of lipid peroxidation, confirmed the role of free radicals in reserpine-induced depression. Treatment with gliclazide and selenium-attenuated brain MDA levels is consistent with findings reported by other researchers.[10] SOD is a key antioxidant enzyme that effectively scavenges oxygen-free radicals and inhibits lipid peroxidation in brain tissue.[10,29] Treatment with gliclazide and selenium significantly restored brain SOD levels and provided protection against reserpine-induced oxidative stress. GSH plays a vital role in suppressing oxidative stress by removing reactive species through its xenobiotic electrophiles. Gliclazide and selenium significantly alleviated oxidative stress by improving brain GSH levels. These results are consistent with other studies.[10,29-31]
Moreover, the combination of gliclazide with selenium was found to prevent weight gain in animals, as indicated by only a slight increase in body weight. This suggests that selenium provides a protective effect against the weight gain commonly associated with gliclazide use. These findings may be attributed to selenium’s impact on thyroid function. This combination also demonstrated better glycaemic control in animals compared to the gliclazide-alone group, suggesting that further research could be conducted to explore its potential in diabetes mellitus management. These effects may be due to improved insulin levels, which positively influence the serotonergic pathway and its levels. Therefore, studying this interaction could provide a deeper understanding of the mechanisms involved in depression and diabetes mellitus.
For a healthy society, preventing, identifying and treating health problems are crucial. In diabetic patients, depression often remains underdiagnosed, and diabetes specialists should be aware of this common comorbidity.
CONCLUSION
Study findings confirm the role of gliclazide and selenium in diabetes. The restorative effect of gliclazide and gliclazide with selenium on BGL and oxidative stress acts reserpine-induced depression and fructose-fed alloxan-induced DM. Considering these results, it can be concluded that gliclazide with selenium appears to be protective. Patients who are already taking gliclazide as an oral hypoglycaemic agent can combine selenomethionine as a selenium supplement, and it can give a promising protective effect against depression in diabetes mellitus.
Acknowledgement:
The authors would like to thank Indoco Remedies and Yarrow Chem Products.
Ethical approval:
The research/study was approved by the Institutional Animal Ethics Committee (IAEC) at A. R. College of Pharmacy and G. H. Patel Institute of Pharmacy, number CPCSEA/ARCP/2022-23/01, dated 29th December 2022.
Declaration of patient consent:
Patient’s consent is not required as there are no patients in this study.
Conflicts of Interest:
There are no conflicts of interest.
Use of Artificial Intelligence (AI)-Assisted Technology for Manuscript Preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial Support and Sponsorship: A. R. College of Pharmacy and G. H. Patel Institute of Pharmacy.
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