|Year : 2018 | Volume
| Issue : 55 | Page : 65-71
Ameliorative effect of quercetin and rutin via modulation of hypothalamic–Pituitary–Adrenal axis and regulation of fasting glucose in chronic stress-induced prediabetes
Mustajab Quraishi, Santosh N Mokale, Nikhil S Sakle
Department of Pharmacology, Y. B. Chavan College of Pharmacy, Aurangabad, Maharashtra, India
|Date of Submission||20-Jul-2017|
|Date of Acceptance||29-Aug-2017|
|Date of Web Publication||28-Jun-2018|
Nikhil S Sakle
Y. B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Aurangabad - 431 001, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Quercetin (QUE) and Rutin (RUT) have nutritive and medicinal values. On the other hand, there are no reports of scientific assessment of its hypothalamo–pituitary–adrenal (HPA) axis modulation in the treatment of prediabetes (DM). Aim: The current study was designed to investigate the modulatory effects of QUE, RUT, and escitalopram (ESC) as antidepressants on HPA axis in chronic stress-induced pre-DM in rats. Materials and Methods: The experimental protocol was of 5 weeks. Chronic unpredictable mild stress (CUMS) was used as a model of depression to induce pre-DM in rats. The treatment was started at the end of 4th week. After 5th week, the plasma adrenocorticotropic hormone (ACTH), serum corticosterone (CORT), fasting blood glucose (FBG), and behavioral parameters were evaluated. Results: Oral administration of QUE (50 mg/kg), RUT (50 mg/kg), and ESC (2.5 mg/kg) to stressed control alleviated HPA axis-associated parameters (ACTH and CORT) and significantly decreased the FBG. Besides this, the depressive effects induced by CUMS were significantly improved as evident from results indicating a promising antidepressant activity. Moreover, submaximal dose of QUE (25 mg/kg) and RUT (25 mg/kg) enhanced the antidepressant activity of ESC (1 mg/kg, p.o.), which suggests that they may act through the HPA axis. Conclusion: Current results suggest that chronic stress in rats causes dysregulation of the HPA axis which leads to diabetic-like condition, i.e., “pre-DM.” It is possible that QUE, RUT, and ESC may be able to suppress the HPA axis response which could be beneficial for the treatment of stressed diabetic patients.
Abbreviations used: QUE: Quercetin; RUT: Rutin; HPA: Hypothalamic–Pituitary–Adrenal Axis; CUMS: Chronic unpredictable mild stress; ACTH: Adrenocorticotropic hormone; CORT: Corticosterone; FBG: Fasting Blood Glucose; ESC: Escitalopram; FST: Fasting Blood Glucose.
Keywords: Antidepressants, chronic unpredictable mild stress, depression, diabetes, hypothalamo–pituitary–adrenal axis
|How to cite this article:|
Quraishi M, Mokale SN, Sakle NS. Ameliorative effect of quercetin and rutin via modulation of hypothalamic–Pituitary–Adrenal axis and regulation of fasting glucose in chronic stress-induced prediabetes. Phcog Mag 2018;14, Suppl S1:65-71
|How to cite this URL:|
Quraishi M, Mokale SN, Sakle NS. Ameliorative effect of quercetin and rutin via modulation of hypothalamic–Pituitary–Adrenal axis and regulation of fasting glucose in chronic stress-induced prediabetes. Phcog Mag [serial online] 2018 [cited 2019 Nov 20];14, Suppl S1:65-71. Available from: http://www.phcog.com/text.asp?2018/14/55/65/235260
- The present study aims to reveal and establish the modulatory effects of quercetin, rutin, and escitalopram as antidepressants on hypothalamo–pituitary–adrenal axis in chronic stress-induced prediabetes in rats.
| Introduction|| |
Stress is a term used in behavioral research that indicates “a physical, chemical, or emotional factor to which an individual fails to make a satisfactory adaptation” and it varies from person to person. When the hypothalamus senses stimuli, produces general adaptation syndrome and stimuli are called stressors. It has been well established that stress gives rise to the pathogenesis of a variety of diseases, including psychiatric disorders, endocrine disorders, immune suppression, sexual and cognitive dysfunctions, peptic ulcer, hypertension and heart diseases, ulcerative colitis, anxiety, and depression.,
A number of clinical studies have given evidence that depression is associated with hyperactivity of the hypothalamo–pituitary–adrenal (HPA) axis. Antidepressant drug treatment normalizes the hyperactivity of the HPA axis with clinical recovery on or after depression.
Chronic stress in animals results in elevated adrenocorticotropic hormone (ACTH) and glucocorticoid levels in plasma and elevated production of corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus. The increased CRH secretion due to impaired negative feedback to the increment of cortisol is associated with depression. A clear relationship of stress has been established for depression and DM. It may lead to deterioration of glycemic control through the neuroendocrine system in which the stressors lead to the activation of the HPA axis, leading to various endocrine abnormalities, such as higher corticosterone (CORT) levels, which antagonize the actions of insulin. At the same time, an increase in visceral adiposity is observed, which plays an important role in DM by means of contributing to insulin resistance.
Diabetes is a chronic disease and for the most part a still hidden disease. All diabetic patients go through a process called “pre-DM” or “impaired fasting glucose.” It is a condition in which the blood glucose is lower than the DM, but higher than normal fasting blood glucose (FBG) between 100 and 125 mg/dl. It is estimated that up to 70% of people with pre-DM may develop type 2 DM during their lifetime.,
| Materials and Methods|| |
Quercetin (QUE) and rutin (RUT) were purchased from Sigma-Aldrich Chemicals Private Ltd (MO, USA). Escitalopram oxalate (ESC) was purchased from Abbott Healthcare Pvt. Ltd., India. All the chemicals were extra pure and of analytical grade.
Male Wistar rats (body weight 180–220 g) were obtained from Wockhardt Research Centre Pvt., Ltd, Aurangabad, India, and housed in standard conditions (12 h light/dark cycle, 20 ± 2°C; 65% ± 15% relative humidity) with free access to water ad libitum. Behavioral experiments were performed between 8.00 and 10.00 am. All the experimental procedures were carried out according to the Institutional Animal Ethics Committee and the efforts were made to minimize animal suffering and to reduce the number of animals used.
After acclimatization to laboratory conditions for a period of 1 week, the rats were randomly divided into seven groups, each containing six animals and maintained as follows:
Rats subjected to the chronic unpredictable mild stress (CUMS) procedure were called as stress rats. Unstressed rats were exposed to behavioral tests and not subjected to the CUMS. Group I: Unstressed control rats receive normal saline orally. Group II: Stress control rats receive normal saline orally. Group III: Stress rats receive QUE (50 mg/kg, p.o.). Group IV: Stress rats receive RUT (50 mg/kg, p.o.). Group V: Stress rats receive ESC (2.5 mg/kg, p.o.). Group VI: Stress rats receive QUE (25 mg/kg, p.o.) and ESC (1 mg/kg, p.o.). Group VII: Stress rats receive RUT (25 mg/kg, p.o.) and ESC (1 mg/kg, p.o.).
Chronic unpredictable mild stress procedure
This model intends to use chronic stress in rats, which develops depressive state. Rats were subjected to different kinds of stressors such as cage tilt of 45°, changes in temperature, tail squeezing, change in the light/dark cycle, wet bedding, and others are summarized in [Table 1]. In general, stressors were applied at different times each day following a semi-random 2-week schedule. The stress procedure lasted for 4 weeks prior to the behavioral testing. Furthermore, bedding was changed every 3 days and animals were exposed to fresh environment. At the beginning of week 5, the stressed rats received the treatment with QUE, RUT, and ESC. Stressors continued to be applied during the testing phase, except on testing days to avoid the effects of acute stress. At least 12 h of rest was provided between a stressor and a test.
Adrenocorticotropic hormone and corticosterone measurement
A volume of 2 ml of blood sample was collected (8:00–10:00 am) by retro-orbital puncture with all aseptic precautions in a plain and EDTA vacutainer. It was allowed to clot for 30 min at room temperature for serum. Serum and plasma were separated by centrifugation at 2500 rpm for 5 min and subsequently stored at −20°C for ACTH and CORT determination. ACTH was determined by the chemiluminescent method using an IMMULITE automatic analyzer (DPC, Los Angeles, CA). The CORT was estimated by automated chemiluminescence immunoassay system (Alpha Prime LS, France) by using Cortisol ELISA kit (DRG, USA).
Fasting blood glucose
FBG was measured after 12 h fasting period with a glucometer (Accu-check Go; Roche Diagnostics, Germany). For the determination, blood samples were collected from the tail vein.
Open field test
The arena was used to assess the exploratory activity of the animal over a 5-min period after drug administration. Apparatus was made up of Plexiglass (80 cm × 80 cm × 50 cm) with transparent walls and a black floor, divided into 16 squares of equal area. The following parameters were analyzed using the ANYMAZETM software (Stoelting Co., USA): the number of lines crossed, total distance traveled, the number of entries and time in the center zone, and the number of entries and time in the peripheral zone.
Forced swim test
On the 1st day of the forced swim test (FST) (pretest), the rats were placed individually in a cylinder (50 cm × 23 cm) filled with a 30-cm depth with water (25°C ± 1°C) for 15 min and then were removed from the water, dried with towels, placed in a warmer enclosure for 15 min, and then returned to their home cages. The cylinders were emptied and cleaned between rats. Twenty-four hours after the first exposure to FST, the rats were retested for 5 min under identical conditions. Retest sessions were evaluated by ANYMAZE software (Stoelting Co, USA), which measured the average speed, maximum speed, total distance traveled, total mobility and immobility time, and total immobile and mobile episodes. A rat was rated to be immobile if it was making only movements necessary to keep its head above water.
Fluid consumption test
Rats had access to water and 1% sucrose solution both in their home cages for 48 h prior to start of the experiment. Over the next 23 h, the animals were food and water deprived for 23 h. Fluid consumption was recorded by reweighing preweighed bottles of test solution. Bottles were counterbalanced across the left and right sides of the cages throughout the experiment. The percentage preference for sucrose was calculated by determining the percentage of total fluid consumption accounted for by ingestion of the 1% sucrose solution. Sucrose preference was calculated using the following formula: sucrose preference (%) = sucrose intake/(sucrose intake + water intake) × 100.,
Data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey's test and results were expressed as mean ± standard error of the mean (n = 6),aP< 0.001,bP< 0.01, and cP< 0.05,d nonsignificant.
| Results|| |
Effect of treatment on adrenocorticotropic hormone and corticosterone measurement
Hyperactivity of the HPA axis by stressor increases ACTH (69.80%) and CORT (76.31%) level in the stressed rats compared to normal rats as shown in [Figure 1]a and [Figure 1]b. Reversal effects of treatment with QUE (50 mg/kg), RUT (50 mg/kg), and ESC (2.5 mg/kg) have been checked in the present study. In stressed rats, ACTH and CORT levels were significantly decreased by 36.87% and 45.71% (P< 0.001) in QUE (50 mg/kg), 49.80% and 57.87% (P< 0.001) in ESC (2.5 mg/kg), and 43.96% and 52.11% (P< 0.001) in QUE (25 mg/kg) + ESC (1 mg/kg) co-treatment, respectively. On the other hand, RUT (50 mg/kg) 18.55% and 27.27% (P< 0.001) and RUT (25 mg/kg) +ESC (1 mg/kg) co-treatment 8.96% and 14.85% (P< 0.001) decreased ACTH and CORT levels, respectively. The co-treatment of submaximal doses of QUE (25 mg/kg) with ESC (1 mg/kg) demonstrated a synergistic inhibitory effect on the HPA axis. These results indicated that the administration of QUE, RUT, and ESC co-treatment for 7 days effectively prevented CUMS-induced changes in plasma ACTH and serum CORT levels.
|Figure 1: Effect of treatment on (a) Plasma adrenocorticotropic hormone levels (pg/ml), (b) Serum corticosterone levels (ng/ml), and (c) Fasting blood glucose level (mg/dl) in normal and stress rats|
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Effect of treatment on fasting blood glucose
We further investigated the role of treatment with QUE, RUT, and ESC on FBG level. [Figure 1]c indicates that QUE, ESC, and QUE + ESC co-treatment decreases FBG significantly. FBG levels were significantly decreased by 17.81% (P< 0.001) in QUE (50 mg/kg), 17.39% (P< 0.01) in ESC (2.5 mg/kg), and 15.28% (P< 0.01) in QUE (25 mg/kg) +ESC (1 mg/kg) co-treatment compared to RUT (50 mg/kg) 13.59% (P< 0.05) and co-treatment with RUT (25 mg/kg) + ESC (1 mg/kg) 15.42% (P< 0.05). This significant decrease in FBG is through normalization of dysregulated ACTH and CORT levels.
Effect of antidepressant treatment on open field test
Compared to unstressed control rats, administration of QUE (50 mg/kg), RUT (50 mg/kg), ESC (2.5 mg/kg) as well as co-treatment with QUE (25 mg/kg) + ESC (1 mg/kg) and RUT (25 mg/kg) + ESC (1 mg/kg) to stress rats augmented the number of line crossings (F [6, 35] = 8.526, P = 0.0030), total distance traveled (F [6, 35] = 8.408, P = 0.0031), the number of entries in center zone (F [6, 35] = 6.583, P = 0.8465), and time in the center zone (F [6, 35] = 68.962, P < 0.0001) of the apparatus as demonstrated in [Figure 2]a,[Figure 2]b,[Figure 2]c,[Figure 2]d. In addition, at the same doses, it decreased the number of entries in the peripheral zone (F [6, 35] = 40.517, P = 0.3661) and time in the peripheral zone (F [6, 35] = 275.73, P = 0.1178) significantly shown in [Figure 2]e and [Figure 2]f. Group mean heat maps of the rats' center position for all tests are represented in [Figure 3]. Heat map indicates cumulative time spent in the center and peripheral zones of the apparatus.
|Figure 2: Behavioral data obtained with open field test in various groups. (a) Number of line crossings (b) Total distance traveled (m) (c) Number of entries in center zone (d) Time in center zone (s) (e) Number of entries in corner zone (f) Time in corner zone (s)|
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|Figure 3: Group mean heat map of the animals' center position for all tests. (a) Unstressed control rats receive normal saline orally (b) stress control rats receive normal saline orally (c) Stress rats receive quercetin (50 mg/kg, p.o.) (d) Stress rats receive rutin (50 mg/kg, p.o.) (e) Stress rats receive escitalopram (2.5 mg/kg, p.o.) (f) Stress rats receive quercetin (25 mg/kg, p.o.) and escitalopram (1 mg/kg, p.o.) (g) Stress rats receive rutin (25 mg/kg, p.o.) and escitalopram (1 mg/kg, p.o.)|
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Effect of treatment on immobility in forced swim test
The effects of QUE (50 mg/kg), RUT (50 mg/kg), and ESC (2.5 mg/kg) alone and co-treatment, on the average speed, maximum speed, total distance traveled, total mobility and immobility time, and total immobile and mobile episodes in the FST are shown in [Figure 4]a,[Figure 4]b,[Figure 4]c,[Figure 4]d,[Figure 4]e,[Figure 4]f,[Figure 4]g. One-way ANOVA revealed that the average speed (F [6, 35] = 8.565, P = 0.0140), maximum speed (F [6, 35] = 10.242, P = 0.0266), total distance traveled (F [6, 35] = 9.447, P = 0.1232), and total mobility time (F [6, 35] = 17.763, P = 0.0458) increased significantly. Treatment to CUMS-exposed rats significantly reduced total immobile episodes (F [6, 35] = 24.457, P = 0.9800) and mobile episodes (F [6, 35] = 24.457, P = 0.9800) with total immobility time (F [6, 35] = 17.763, P = 0.0458). Combined submaximal dose of QUE (25 mg/kg) with ESC (1 mg/kg) potentiated antidepressant-like activity significantly by increasing mobility and decreasing immobility time, whereas RUT (25 mg/kg) with ESC (1 mg/kg) showed nonsignificant effect.
|Figure 4: Parameters observed in forced swim test (a) average speed (m/s) (b) maximum speed (m/s) (c) total distance traveled (m) (d) total immobile episodes (e) total mobile episodes (f) total time immobile (s) (g) total time mobile (s)|
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Effect of antidepressant treatment on fluid consumption tests
No differences were observed between unstressed control and stressed rats in total fluid consumption test (water and 1% sucrose solution) over the period of 5 weeks of the study (F [6, 35] = 2.965, P = 0.4935) [Figure 5]a. In contrast, the stressed rats consumed significantly less sucrose solution by the end of the 5th week (F [6, 35] = 252.02, P = 0.1355) [Figure 5]b. Drinking of the sucrose solution accounted for a total fluid consumption in the stressed and in the control rats (F [6, 35] = 69.834, P = 0.4526) [Figure 5]c.
|Figure 5: Effect of treatment on fluid consumption test (a) total fluid consumption (g) (b) Sucrose consumption (g) (c) percentage sucrose preference in normal and stressed rats|
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| Discussion|| |
The HPA axis is an important system activated in response to stress. Chronic stress causes a series of physiological changes in body and increases sympathetic and HPA tone and the sympathetic and HPA systems greatly influence energy metabolism, suggesting that they are possible mediators of the metabolic changes that occur following chronic stress. Hyperactivation of HPA axis in chronic stress impairs negative feedback mechanism which leads to the elevated production of ACTH and glucocorticoids (cortisol in humans and CORT in rodents) from the pituitary gland and adrenal cortex, respectively., Previous studies have clearly shown that 3–4 weeks' exposure to stressors causes increased level of corticosteroids. The occurrence of type 2 DM and pre-DM increased sharply in the recent years.
Several clinical studies linked that the hyperactivation of the HPA axis associated with depression leads to various endocrine abnormalities. Depression is the most common form of mental illness and is supposed to contribute in the development or progression of DM. The link between depression and DM might be bidirectional and there might exist a few common physiological and etiological factors. Activation of the HPA axis with elevated cortisol was noticed in both DM and depression.,
It is hypothesized that chronically high cortisol level (as reported in about 50% of patients with depression) might result in obesity, insulin resistance, and type 2 DM. If depression is an underlying cause for the development of type 2 DM, people with depression would be at an increased risk of Pre-DM.
The HPA axis directs the body's neuroendocrine response to stressors through influence and feedback between the hypothalamus, the anterior pituitary, and the cortex of the adrenal glands. The selective serotonin re-uptake inhibitors (SSRIs) are the most commonly prescribed antidepressants because of their safety profile and efficacy., They have been suggested in the treatment of depressed patients with DM, as they may cause hypoglycemia and weight loss in addition to their antidepressant properties.
SSRIs such as citalopram and ESC are considered as drugs of choice in depression. Initial hyperactivation of HPA system is downregulated to normal levels by citalopram and ESC in depressed patients., This normalization is linked with improved clinical outcome. Population uses some phytochemical preparations, alternative to synthetic antidepressant drugs, with relative success.
Based on the hypothesis, in our present study, the CUMS caused hyperactivity of the HPA axis in rats, as indicated by the increased level of ACTH and CORT. This neuroendocrine response leads to increase in FBG, resulting in prediabetic-like condition in rats. Treatment with antidepressant drugs, such as QUE, RUT, and ESC, attenuated the stress-induced increased level of ACTH, CORT, and FBG. Moreover, co-treatment of QUE (25 mg/kg) and RUT (25 mg/kg) with ESC (1 mg/kg) showed synergistic effect in reducing ACTH, CORT, and FBG levels. This indicates that the antidiabetic effects of QUE, RUT, ESC, and their combination are due to suppression of the HPA axis.
Open field test (OFT), FST, and fluid consumption tests are used to access the depressive behavior of rats. Reduced exploration in OFT is suggested as an assessment indicator of depression-like behaviors in the stressed rats, which might be due to lethargy, apathy, and bodily neglect. Our results indicated that treatment with QUE, RUT, and ESC produced significant antidepressant-like effects, when assessed in OFT. What is noteworthy is that, the combination of QUE (25 mg/kg) and RUT (25 mg/kg) with ESC (1 mg/kg) produces synergistic effect and is supposed to be mediated via hyperactivated HPA axis to normal levels in CUMS depressed rats. The red area shown in heat maps denotes maximum occupancy and is the maximum value calculated across all tests in the experiment.
Four weeks of CUMS exposure led to increased depression-like symptoms in stress rats when compared to unstressed control rats as evident from increased immobility in FST. This model is apt for a broad spectrum of antidepressants, which significantly decrease the immobility time. The results of the present study showed that treatment with QUE, RUT, and ESC evoked antidepressant-like effects in the FST by increasing mobility and decreasing immobility time.
The percentage preference for sucrose consumption was thus significantly reduced in the stressed rats. Anhedonia in CUMS-exposed rats decreased self-stimulation of reward pathways in the brain and in decreased preference for a dilute sucrose solution as confirmed in the study., QUE, RUT, and ESC treatment alleviated the depression-like behavior caused by CUMS, as indicated by an increased sucrose preference in rats.
In summary, the results obtained here suggest that the involvement of chronic stress in rats is through dysregulation of the HPA axis which leads to diabetic-like condition. It is possible that change in FBG level by normalization of HPA axis and associated parameters (ACTH and CORT) is through QUE, RUT, and ESC treatment. It is possible that QUE, RUT, and ESC may be able to suppress the HPA axis response which could be beneficial for the treatment of stress diabetic patients.
| Conclusion|| |
The present study showed that CUMS induces prediabetes in rat through the downregulation of HPA Axis. Thus, QUE, RUT and ESC are able to suppress HPA mediated response and effective in stress diabetic condition.
The authors are thankful to Mrs. Fatima Rafiq Zakaria, Chairman, Maulana Azad Educational Trust, Dr. Rafiq Zakaria Campus, Aurangabad 431001 (MS), India, for providing the laboratory facility.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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