Evaluation of venlafaxine on glucose homeostasis and oxidative stress in diabetic mice

Abstract

Depression occurs frequently with diabetes affecting the quality of life. All major classes of antidepressants have been shown to have a direct pharmacologic effect on metabolic function, which further worsens glycemic control. There were no reports on the effects of venlafaxine on glucose levels and oxidative stress in diabetic animals. The present study evaluated the effects of venlafaxine (8 and 16 mg/kg per d) on glucose homeostasis along with oxidative stress in brain in diabetic mice (streptozotocin (STZ), 40 mg/kg per d for 5 days). We observed that 21 days of administration of venlafaxine (8 and 16 mg/kg per d) in diabetic mice significantly enhanced swimming in normal and STZ-treated mice with a corresponding reduction in immobility. No significant difference in blood glucose levels was observed in diabetic and normal mice following venlafaxine treatment. Venlafaxine (16 mg/kg) reversed STZ-induced elevated thiobarbituric acid reactive substance (TBARS) levels and also restored the glutathione (GSH) levels in diabetic mice. Venlafaxine (8 and 16 mg/kg) per se does not produce any significant effect in normal animals. The results indicate a dose-dependent antidepressant action of venlafaxine in diabetes-induced depressive mice. Furthermore, the blood glucose levels were not significantly altered in normal and diabetic mice. In addition, venlafaxine exhibited a decrease in TBARS and elevation in GSH levels in mice brain. Venlafaxine drug treatment appears to be safer for depression associated with diabetes.

Keywords

Venlafaxine diabetes depression modified forced swimming test

Introduction

Depression is common among people with diabetes and is associated with worse diabetes outcomes.^1,2 A number of clinical studies suggest that approximately 15–20% of patients with either insulin-dependent diabetes mellitus or noninsulin-dependent diabetes mellitus suffer from clinical depression.^3–5 In addition to the negative psychological and social consequences, depression is also a risk factor for poor metabolic control, decreased physical activity, higher obesity and potential diabetes-related end-organ complications.⁶ Thus, the association between diabetes and depression is complex and requires careful analysis.

Antidepressant use is common in patients with diabetes mellitus. They may also interfere with blood glucose metabolism, paradoxically increasing the risk of both hyper- and hypoglycemia.^7–9 If antidepressants indeed interfere with glucose homeostasis in patients with diabetes mellitus, then this could further complicate glycemic control, which is a limiting factor to prevent or delay microvascular complications in the long term. However, evidence on the association of antidepressant use and impaired glucose homeostasis is scarcer and mainly originates from case reports and short-term trials with selected and small group of patients with comorbid diabetes mellitus. Hence, the prescribing of antidepressants in patients with diabetes requires a careful analysis of the available data. While selective serotonin reuptake inhibitors (SSRIs) appear to be a safer alternative, there is evidence of alteration in blood glucose levels with certain drugs.^10
–13

Venlafaxine, a novel antidepressant, selectively inhibits reuptake of serotonin as well as norepinephrine (NE).^14,15 It exhibits six- to sevenfold selectivity for the inhibition of serotonin reuptake when compared with NE reuptake in rat brain synaptosomal preparations and a 15- to 30-fold higher affinity for serotonin transporter binding sites when compared with those of NE transporter.¹⁶ Because of its dual reuptake inhibiting properties, it may produce a better and complete antidepressant action when compared with SSRIs like fluoxetine.¹⁷ However, the effect of venlafaxine on blood glucose levels in diabetic condition is currently unknown.

Numerous studies indicate that reactive oxygen species (ROS)-induced neuronal damage has an important role in the pathophysiology of depression.^18–20 Although most of the oxygen used in the brain tissue is converted to CO₂ and water, small amounts of oxygen forms ROS. The existences of polyunsaturated fatty acids, which are the targets of the ROS in the brain, make this organ more sensitive to oxidative damage.^21–23 There are various antioxidant mechanisms in the brain that neutralize the harmful effects of ROS; however, with depression, the loss of efficiency of antioxidants mechanisms and the alterations in the proinflammatory cytokine system result in increase in the free radical formation due to the activation of phagocytic cells.²⁴ Psychological stress, which accompanies severe depression, may also increase lipid peroxidation.²⁵

As depression is frequently associated with diabetes and oxidative stress as well, in this study, we wanted to observe the antidepressant effects of venlafaxine and its effect on glucose homeostasis along with oxidative stress in brain in diabetic mice.

Materials and methods

Animals

Swiss strain male albino mice (25–35 g) raised at the Central Animal House Facility of Jamia Hamdard University were used (maintained at a temperature of 25 ± 2°C and relative humidity 50 ± 15%). The animals were housed in polypropylene cages (10 mice per cage) with a 12-h light–dark cycle. The mice were fed on a standard pellet diet (Amrut rat and mice feed, Pune, India) and water ad libitum. The project was undertaken with prior approval from the University Animals Ethics Committee (Project number: 584). All experiments were performed during the daytime on healthy animals.

Drugs and treatment

Healthy mice were made diabetic by intraperitoneal injection of streptozotocin (STZ; 40 mg/kg per d for 5 days).²⁶ Serum glucose levels were measured 7 days after the last injection by glucose oxidase peroxidase (GOD/POD) method (Span Diagnostics, INDIA), and mice showing hyperglycemia were selected as diabetic mice. They were randomly distributed into various subgroups and treated with venlafaxine (8 or 16 mg/kg per d, orally) for 21 days.¹⁵ STZ was dissolved in 1:1 normal saline and citrate buffer (pH 4.5) on the day of experiment, whereas venlafaxine was dissolved in normal saline 1 day before dosing. Similar treatments were given to the nondiabetic (normal) animals also. After treatment, the following parameters were assessed.

Forced swimming test

This procedure was carried out following a modified version of the conditions proposed by Cryan et al.²⁷ Each mouse was introduced into inescapable plastic cylinder (40 cm height and 15 cm diameter) containing 30 cm of fresh water at 22 ± 2°C (on 20th day of venlafaxine treatment) and was forced to swim for 15 min. After the swimming session, each mouse was dried, warmed and returned to its home cage. Tank water was changed every two sessions. After 24 h (on 21st day), the animals were again reexposed to the swimming in a similar environment for 6 min. The total duration of climbing, swimming and immobility in the last 5 min of the 6-min test session was recorded for each animal.

Biochemical parameters

After the behavioral testing, the animals were immediately decapitated and the blood was collected. Their brains were removed, weighed and homogenized in ice-cold KCl-phosphate buffer (0.1 M, pH 7.4). First, tissue protein was estimated using 0.1 ml of 10% homogenate, which was diluted with 0.9 ml of distilled water. The resultant mixture was mixed with 5 ml of alkaline solution and allowed to stand at room temperature for 10 min. This was followed by the addition of 0.5 ml Folin–Ciocalteau reagent into each of the test tube. The tubes were shaken immediately for a thorough mixing. After 30 min, the absorbance was read at 750 nm against a reagent blank. The protein content was expressed in milligrams.²⁸

For glutathione (GSH) estimation, 2 ml of 10% homogenate was mixed with 2.5 ml of 0.02 M EDTA. Resultant mixture of 2 ml was further mixed with 4 ml of distilled water and 1 ml of 50% trichloroacetic acid (TCA) solution. The tubes were shaken intermittently for 10–15 min. This was followed by centrifugation at 3000 r/min for 10 min. The supernatant of 2 ml was mixed with 4 ml of tris buffer (0.4 M, pH 8.9) and 0.1 ml of 5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB) solution and shaken. The absorbance was read at 412 nm within 5 min of addition of DTNB solution against a blank with no homogenate. The results were expressed in micromoles of GSH per milligram of protein.²⁹

For thiobarbituric acid reactive substance (TBARS), 0.2 ml brain homogenate was diluted to 4 ml of 0.15 M KCl solution. Then the resultant solution was mixed with 1 ml of 30% TCA and 1 ml of 0.8% thiobarbituric acid. All tubes were then covered with aluminum foils and placed on a shaking water bath maintained at 80°C for 30 min. The tubes were then shifted to crushed ice bath. This was followed by centrifugation at 3000 r/min for 10 min. The amount of malondialdehyde (MDA) formed in each of the samples was assessed by measuring the absorbance of supernatant at 535 nm using spectrophotometer against a reagent blank. Results were measured in nanomoles of MDA per milligram of protein.³⁰

Statistical analysis

The data were expressed as mean ± SEM, and the results were analyzed by the analysis of variance. Pair wise follow-up comparisons of individual treatment groups were conducted using Dunnett’s multiple comparison tests. p < 0.05 were considered significant.

Results

Effect of venlafaxine on modified forced swimming test (FST) in diabetic and normal mice

The results are summarized in Table 1. STZ significantly decreased swimming behavior (p < 0.01, F _5,30 = 7.53), whereas venlafaxine (8 and 16 mg/kg) enhanced swimming in normal and STZ-treated mice significantly. On the other hand, immobility was found to be significantly reduced by venlafaxine (16 mg/kg; p < 0.05) in diabetic mice and with venlafaxine (8 and 16 mg/kg) per se (p < 0.01, F _5,30 = 2.99). No significant change in climbing behavior was observed with any of the treatments.

Table 1.

Effect of venlafaxine on modified FST in diabetic and normal mice^a

Group no.	Treatment	Dose (mg/kg)	Swimming	Climbing	Immobility
1	Control	10 ml/kg, orally	54.83 ± 12.08^b	62.6 ± 24.46	184.83 ± 29.47
2	STZ	40	17.16 ± 2.65^c	34.5 ± 5.73	248.33 ± 4.03
3	STZ + Ven	40 + 8	43.5 ± 2.39^d	88 ± 29.96	169.5 ± 31.41
4	STZ + Ven	40 + 16	46.66 ± 7.91^b	93.16 ± 18.45	159.16 ± 18.08^d
5	Ven I per se	8	50.66 ± 1.66^b	96.16 ± 20.48	157.16 ± 21.68^b
6	Ven II per se	16	68 ± 1.41^b	91.66 ± 15.26	141.33 ± 14.71^b

STZ: streptozotocin; Ven: venlafaxine; FST: forced swimming test.

^aValues are mean ± SEM, number of animals = 6, swimming F _5,30 = 7.53, climbing F _5,30 = 1.41, immobility F _5,30 = 2.99.

^b p < 0.01 versus STZ.

^c p < 0.01 versus control.

^d p < 0.05 versus STZ.

Effect of venlafaxine on blood glucose level in diabetic and normal mice

The effect of venlafaxine on blood glucose levels in diabetic and normal mice are presented in Table 2. STZ was found to increase glucose levels in mice (p < 0.01, F _5,30 = 26.123). No significant difference was observed in diabetic mice following venlafaxine treatment (8 and 16 mg/kg), when compared with STZ control (group 2). Similarly, venlafaxine (8 and 16 mg/kg) did not produced any change in blood glucose levels of normal mice, when compare with control (group 1).

Table 2.

Effect of venlafaxine on blood glucose level in diabetic and normal mice^a

Group no.	Treatment	Dose (mg/kg)	Glucose level (mg%)
1	Control	10 ml/kg, orally	102.8 ± 2.38^b
2	STZ	40	175.1 ± 7.56^c
3	STZ + Ven	40 + 8	154.5 ±6.52^c
4	STZ + Ven	40 + 16	163.33 ± 7.33^c
5	Ven I per se	8	94.66 ± 5.89^b
6	Ven II per se	16	104.16 ± 5.87^b

STZ: streptozotocin; Ven: venlafaxine.

^aValues are mean ± SEM, number of animals = 6, F _5,30 = 26.123.

^b p < 0.01 versus STZ.

^c p < 0.01 versus control.

Effect of venlafaxine on biochemical parameters of oxidative stress in diabetic and normal mice

The effect of STZ and venlafaxine on TBARS and GSH are mentioned in Table 3. A significant increase in TBARS and reduction in GSH were observed in diabetic mice treated with STZ. Venlafaxine (16 mg/kg) reversed STZ-induced elevated TBARS levels in diabetic mice (p < 0.001, F _5,30 = 4.518). Venlafaxine (16 mg/kg) also restored the GSH levels of diabetic mice (p < 0.05, F _5,30 = 5.547). Venlafaxine (8 and 16 mg/kg) per se does not produced any significant effect in normal animals.

Table 3.

Effect of venlafaxine on biochemical parameters of oxidative stress^a

Group no.	Treatment	Dose (mg/kg)	TBARS (nm/mg protein)	GSH (µm/mg protein)
1	Control	10 ml/kg, orally	5.82 ± 0.07^b	1.97 ± 0.34^c
2	STZ	40	9.39 ± 0.06^d	0.80 ± 0.33^e
3	STZ + Ven	40 + 8	6.69 ± 1.11	1.39 ± 0.41
4	STZ + Ven	40 + 16	5.42 ± 0.93^b	1.91 ± 0.07^c
5	Ven I per se	8	6.01 ± 0.88^c	2.23 ± 0.21^b
6	Ven II per se	16	5.02 ± 0.63^b	2.77 ± 0.25^b

STZ: streptozotocin; Ven: venlafaxine; TBARS: thiobarbituric acid reactive substances; GSH: glutathione

^aValues are mean ± SEM, number of animals = 6; TBARS: F _5,30 = 4.51; GSH: F _5,30 = 5.54.

^b p < 0.01 versus STZ.

^c p < 0.05 versus STZ.

^d p < 0.01 versus control.

^e p < 0.05 versus control.

Discussion

The present study characterizes the effects of venlafaxine on modified FST, blood glucose levels and oxidative stress parameters in diabetic mice. We report that venlafaxine reduced immobility with a subsequent enhancement in swimming per se and in STZ-induced diabetic mice in modified FST.²⁷ These results are in agreement with various other reports depicting antidepressant actions of venlafaxine in various other models.^31,32 The pattern of effects that were observed for venlafaxine (8 and 16 mg/kg) in the modified FST is qualitatively similar to that described previously for 5-hydroxytryptamine (5-HT) related drugs.²⁷ This suggests that antidepressant action of venlafaxine (at these doses) in diabetic mice could be due to the involvement of serotonergic system. There are reports of dose-dependent involvement of serotonin and NE reuptake blockade in animal models of depression with venlafaxine.¹⁵ Literature shows that venlafaxine at lower dose inhibits only serotonin reuptake, while inhibition of serotonin and NE occurred at higher doses. In our study, we have observed an increase in swimming behavior at a dose of 8 and 16 mg/kg in normal and diabetic mice. Our results are in agreement with the earlier investigations showing an involvement of serotonin system (at lower dose) in producing antidepressant action in diabetes-induced depressive mice.^15,31,32

In many previous studies, administration of antidepressants has been reported to cause significant changes in the levels of blood glucose and insulin levels, both experimentally and clinically.^10,31,33,34 In our study, STZ treatment rendered the mice diabetic, and after 7 days of STZ treatment, the glucose levels were elevated significantly. Venlafaxine treatment for 21 days did not alter the glucose levels in normal or diabetic mice. Some serotonergic antidepressants (e.g. fluoxetine, sertraline, etc.) reduce hyperglycemia, normalize glucose homeostasis and increase insulin sensitivity, whereas some noradrenergic antidepressants (e.g. desipramine, imipramine, etc.) exert opposite effects.³⁵ Our results are in agreement with the reports indicating the drugs like venlafaxine, duloxetine, and so on, that exert dual mechanism, which do not appear to disrupt glucose homeostatic dynamics.^31,36 Although severe hypoglycemia following venlafaxine intoxication has been reported,³⁷ we found the lack of hyper- or hypoglycemic activity of venlafaxine in diabetic and normal mice. The inhibition of serotonin reuptake selectively, at low doses by venlafaxine could be responsible for its lack of hyper- or hypoglycemic effects in diabetic mice. Improved insulin sensitivity in nondiabetic depressed inpatients remitting during venlafaxine treatment has also been reported.³⁶ Our study confirms that venlafaxine do not disrupt glucose homeostatic dynamics in diabetic animals.

We also investigated the effects of venlafaxine treatment on the levels of ROS in the brains of diabetic mice. We found that lipid peroxidation products were increased and GSH levels were decreased significantly in the brain of diabetic mice. Treatment with venlafaxine (dual serotonin/NE reuptake inhibitor) was effectual in enhancing the GSH levels, which was concomitant to marked reductions in lipid peroxidation events. The present finding shows that chronically administered venlafaxine is capable of alleviating oxidative damage induced by STZ in diabetic mice.

Oxidative stress is primarily or secondarily involved in the pathogenesis of diabetes as well as depression. Increased oxidative stress is a widely accepted participant in the development and progression of diabetes and its complications.³⁸ Similarly, multiple lines of evidences suggest the coexistence of oxidative stress with symptoms the of depression in patients as evidenced by defective plasma antioxidant defenses in association with enhanced susceptibility to lipid peroxidation.^39,40 Significant correlations were found between the severity of depression as well as the length of index episode and duration of illness and alteration on superoxide dismutase (SOD) activity and MDA levels.^25,41 There are four major sources of ROS: (i) oxidative burst (e.g. as encountered during immune cell activation), (ii) oxidative processes (e.g. electron transport chain, cytochrome P₄₅₀ activation and increased monoamine oxidation), (iii) lipid peroxidation and (iv) oxidative stress (e.g. trauma or ischemia).

Our findings demonstrated an increased lipid peroxidation and decreased GSH levels in the brains of diabetic mice when compared with controls, which are in agreement with many studies. Venlafaxine reversed STZ-induced elevated TBARS levels and also restored the GSH levels in diabetic mice. Eren et al. have reported beneficial effects of venlafaxine in the brain of depression-induced rats on the antioxidant defenses in the rat model, and a role of venlafaxine treatment in preventing oxidative stress has also been suggested in depression.²⁴ In a similar study, Zafir et al. have reported a significant recovery in the activities of SOD, catalase (CAT), glutathione-S-transferase (GST), GSH, and so on, by venlafaxine (10 mg/kg per d) treatment following a restraint stress-induced decline of these parameters.³⁹ A role of nitric oxide mechanism has also been implicated in the protective effects of venlafaxine in sleep deprivation in mice⁴⁰ It has also been reported to reverse chronic fatigue-induced behavioral, biochemical and neurochemical alterations in mice.¹⁴

There is a report that shows serotonin may work as an innate antioxidant defense mechanism in the central nervous system.⁴² It is known to exert a protective effect in the hippocampus and attenuate the behavioral consequences of stress by activating 5-HT_1A serotonin receptors. These effects may mediate the therapeutic actions of several antidepressants⁴³ including venlafaxine. NE is also known to protect cortical neurons against microglial-induced cell death.⁴⁴ In a recent study, it has been shown that NE can protect neurons from Aβ-induced damage and causes an increase in GSH production.⁴⁵ These results indicate that the neurotransmitter (5-HT and NE) itself acted as antioxidant. Venlafaxine having dual action on 5-HT, NE and also on DA; hence, it could reverse the oxidative stress in diabetic mice. Study further explains that beneficial effect of venlafaxine in depression associated with diabetes may partially be due to its antioxidant effect.

To conclude, our study indicates dose-dependent antidepressant action of venlafaxine in diabetes-induced depressive mice. The treatment does not interfere with the blood glucose levels and also reversed STZ-induced oxidative stress in mice brain as evident by decrease in TBARS and elevation in GSH levels. The inhibition of 5-HT reuptake at low doses might be responsible for the lack of effects on glucose levels; however, further studies are warranted to explore the possible role of 5-HT and NE reuptake in glycemic alterations.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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