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Journal of Diabetes and Metabolic Disorders logoLink to Journal of Diabetes and Metabolic Disorders
. 2019 Dec 2;18(2):543–549. doi: 10.1007/s40200-019-00445-8

Efficacy of melatonin in restoring the antioxidant status in the lens of diabetic rats induced by streptozotocin

Marjan Khorsand 1,2, Masoumeh Akmali 2,✉, Morteza Akhzari 2
PMCID: PMC6914748  PMID: 31890680

Abstract

Background

Melatonin is a well-known free radical scavenger. The present study aimed to investigate the effects of melatonin treatment on the antioxidant status in the lenticular tissue of streptozotocin (STZ)-induced diabetic rats.

Methods

Thirty-four male rats were randomly divided into four groups as follows: healthy control rats (group 1, n = 10); diabetic control rats (group 2, n = 10); melatonin-treated (5 mg/kg·day) diabetic rats (group 3, n = 10) and melatonin-treated (5 mg/kg·day) healthy rats (group 4, n = 4). Diabetes was induced by injection of streptozotocin (50 mg/kg, ip). Following 8-weeks of melatonin treatment, all rats were killed and the blood plasma and their lenses were stored at −70 °C for antioxidant enzyme activities assay and biochemical determination.

Results

The plasma glucose and lens malondialdehyde (MDA) increased significantly in the rats of group 2 as compared to the group 1. Also, a significant decrease in the levels of catalase (CAT) and glutathione reductase (GR) activities in the lenses and plasma reduced glutathione (GSH) was found. However, the levels of lenticular MDA (not significant) and the plasma glucose significantly decreased in the rats of group 3 compared to the group 2. Besides, the levels of CAT, GR in the rats lens and plasma GSH increased significantly.

Conclusion

Diabetes mellitus induced hyperglycemia and oxidative stress, whereas melatonin decreased the blood glucose levels and lipid peroxidation and increased the activities of antioxidant enzymes in diabetic rat lenses.

Keywords: Antioxidant enzymes, Diabetes, Melatonin, Oxidative stress, Streptozotocin

Introduction

Diabetes mellitus is one of the most prevalent metabolic diseases characterized by hyperglycemia, resulting from insulin deficiency or insulin resistance [1–3]. The long-term hyperglycemia in diabetes is associated with some complications and dysfunction of various organs, including the eyes, kidneys, heart and nerves [3]. Oxidative stress, as an important factor in the development of diabetic complications, is described as the imbalance between free radicals formation and antioxidant scavenging systems [4]. It has been shown that auto-oxidation of glucose in hyperglycemic condition produces reactive oxygen species (ROS), such as superoxide radical (O•2−), hydrogen peroxide and hydroxyl radical (OH•) which results in chronic oxidative stress in diabetic rats [5–7]. To protect the cells against serious damaging effects of ROS, organisms have developed enzymatic and non- enzymatic antioxidant defense systems [7, 8].

The lens is one of the tissues which exposed to harmful effects of ROS in diabetes. In hyperglycemic condition, excessive glucose transports into the lens in a non-insulin dependent manner, which leads to activation of the polyol pathway enzymes. Thus, activated enzymes produce the more sorbitol and fructose that are responsible for oxidative stress enhancement and lenticular cataract development [7].

A new hypothesis suggests that during hyperglycemia the elevation of intracellular glucose metabolism causes oxidative stress and increases the generation of ROS at the mitochondrial level. Also, increased O•2− concentration causes an elevation in the levels of the polyol pathway enzymes such as aldose reductase (rate-limiting enzyme) and up-regulation of the related genes expression. This process, coupled with a decrease in the level of reduced glutathione (GSH), enhanced oxidative stress in the lens [9]. Also, previous studies showed that the oxidation of thiol groups of lens proteins in senile cataract is developed as follows; GSH easily being oxidized to GSSG (oxidized form) and is conjugated with the lens proteins then, ultimately protein-GSH mixed disulfide, glutathionylated and aggregated proteins (PSSG) are formed [10]. On the other hand, the accumulation of PSSG directly induces the pigmentation and lens opacity [11].

Melatonin, as an endogenous hormone secreted by the pineal gland, is a well- known and effective antioxidant [12]. Several studies revealed the protective effect of melatonin against oxidative stress resulting from hyperglycemia in experimental diabetic models [1]. Melatonin exerts this beneficial effect directly as a free radical scavenger [13]. Also, melatonin indirectly improves the activity and gene expression of antioxidant enzymes in various tissues, thus reducing the oxidative damages [14–16].

Melatonin has antioxidant effects on diabetic rat lenses through the following mechanisms: first, melatonin can reach all cells and subcellular compartments, considering its lipophilic and hydrophilic properties. Thus, it is likely that the exogenous administration of melatonin probably enters the lens. Second, melatonin directly scavenges free radicals as well as inhibits their generation and third, melatonin exerts indirect antioxidant properties by stimulating the activity of antioxidant enzymes including CAT, GR, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and inhibiting the pro-oxidative enzymes [14]. Some studies have reported the protective role of melatonin in diminishing of lens opacity and peroxide levels and enhancing the antioxidant enzyme activities in the gamma-ray induced cataract in the rat lenses. Naturally, there are many antioxidants in the lens, such as ascorbic acid, GSH and superoxide dismutase. Therefore, melatonin administration has a synergistic and protective role with these antioxidants to neutralize the free radicals and other oxidants [11].

The protective effects of melatonin administration against ultraviolet-B (UVB) and gamma radiation-induced oxidative stress in the lenses of experimental rats were shown by earlier researchers [8, 14]. But there is no report yet showing the effect of melatonin on changes in the activities of antioxidant enzymes under the diabetic condition in rat lenses. Therefore, this study was designed to evaluate the potential protective effects of melatonin against diabetes-induced antioxidant status changes in the rat lenses.

Materials and methods

Materials

β-Nicotinamide adenine dinucleotide phosphate-reduced form(NADPH), 2-thiobarbituric acid (TBA), 1, 1, 3, 3-tetra ethoxy propane (TEP), reduced glutathione (GSH), 5, 5′-dithiobis-(2-nitrobenzoic acid) (DTNB), oxidized glutathione (GSSG), hydrogen peroxide (H2O2), ethylenediaminetetraacetic acid (EDTA), bovine serum albumin (BSA), and melatonin were obtained from Sigma-Aldrich (St. Louis, MO). Streptozotocin (STZ) was purchased from Upjohn Company (Kalamazoo, MI, USA). Enzymatic kit used for determination of glucose was prepared from Pars Azmun Company (Tehran, Iran). All other reagents were obtained from other commercial sources.

Animals and experimental design

Thirty-four adult male Sprague Dawley rats, weighing 250–300 g, were obtained from the animal house of Shiraz University of Medical Sciences. The animals were kept at temperature of 22-28 °C with controlled photoperiod (12 h of light and 12 h of dark) and fed with standard diet and free access to water.

Four experimental groups were used as follows: healthy control rats (group 1, n = 10); diabetic control rats (group 2, n = 10); melatonin-treated diabetic rats (group 3, n = 10); and melatonin- treated healthy rats (group 4, n = 4). Diabetes was induced in the rats of groups 2 and 3, by injection of a single dose of streptozotocin (50 mg/kg body weight/ip), which was freshly prepared with 0.9% NaCl and 5% dextrose according to the manufacturer’s instructions whereas the rats of groups 1 and 4 received only the vehicle (ip). Ten days after STZ injection, diabetes was confirmed in rats with fasting blood glucose levels of 300 mg/dl or above in the rat tail vein. Then, the rats in groups 3 and 4 received gavage by melatonin (5 mg/kg body weight) once a day for 8 weeks. In this period, the rats in groups 1 and 2 received vehicle (1/500 v/v % ethanol / D.W.). At the end of the treatment time, all of the animals were killed under ether anesthesia, the lenses dissected, and blood was drawn from the heart. The lenses and plasma of each animal were stored at −70 °C for further determination.

Preparation of lens homogenates

First, a lens of each rat was weighed and homogenized in normal saline and then it was centrifuged in Eppendorf tubes at 10000×g for 30 min at 4 °C. The clear supernatant was used for antioxidant enzymes and MDA assays [17].

Enzymes assays

GR (EC 1.8.1.7) activity in the rat lenses was assayed to the method suggested by Racker [18]. The decrease in absorbance at 340 nm due to the oxidation of NADPH was recorded and enzymatic activity measured.

Briefly, the reaction mixture contained phosphate buffer (90 mM, pH = 7.6), GSSG (48.96 mM), EDTA (4.5 mM), BSA (30 mg/ml), and lens supernatant. The enzymatic reaction started by the addition of NADPH (1.5 mM), and the decrease in absorbance at 340 nm was recorded for 5 min.

Enzyme activity in the lens supernatants was expressed as milli unit (mU) per mg protein using a molar extinction coefficient of 6.22 × 103 L/mol per cm for NADPH. One unit of the enzyme corresponded to the amount of enzyme which oxidizes one μmol NADPH /min per mg protein under assay conditions at 25 °C.

CAT (EC 1.11.1.6) activity in the rat lenses was determined according to the method proposed by Aebi [19]. The enzyme was assayed spectrophotometrically. Briefly, the reaction mixture contained phosphate buffer (66.7 mM, pH = 7.0), lens supernatant and H2O2 (120 mM). The decomposition of H2O2 was monitored at 240 nm by the use of the molar absorption coefficient of 43.6 L. M−1 cm−1 at 25 °C for 3 min. Enzyme activity was expressed as unit (U) per mg protein. One unit of the enzyme corresponded to the amount of enzyme which decomposes one μmol H2O2 /min per mg protein under assay conditions at 25 °C.

Biochemical measurements

Lipid peroxidation in the lens was determined by the measurement of MDA as a thiobarbituric acid reactive substance using the method published by Paulo et al [20]. For determination of MDA, sample was added to trichloroacetic acid (20% (w/v)) and TBA (0.86%(w/v)); the mixture was heated in 100 °C for 20 min, after cooling and centrifugation at 5000 g for 15 min, the absorbance of the supernatant was measured at 532 nm against blank. The quantity of MDA was calculated in terms of nmole per mg protein using TEP as a standard.

Also, GSH level in the plasma was assayed using Ellman’s reagent [21]. The reaction mixture contained phosphate buffer (100 mM, pH =7.4), EDTA (1 mM), DTNB (1.5 mg/ml), and 0.1 ml of the deproteinized sample. The absorbance was measured at 412 nm against the blank. The GSH concentration was calculated in terms of μM using GSH as standard. The lens protein content was determined by the Bradford method using BSA as a standard [22]. Blood glucose concentrations were monitored with a glucometer every 2 weeks and using a commercial diagnostic kit by the glucose oxidase method at the end of the experiment [23]. Body weights of all rats were monitored weekly. All tests were performed triplicate.

Statistical analysis

All data were presented as mean ± SD. One-way analysis of variance (ANOVA), using SPSS software version 12.0, followed by the Least Significant Difference (LSD) posttest were used for the differences among the groups except for weight differences. For analysis of the time duration of changes in the weight of the experimental groups, ANOVA and Tukey’s post hoc test for multiple comparisons was used and, p value ≤0.05 was considered significant.

Results

Effects of melatonin on lens antioxidant enzymes and biochemical parameters

The effects of melatonin gavage on GR and CAT activities at the end of the eighth week in the experimental rats are shown in Table 1. As seen, induction of diabetes decreased the GR and CAT specific activities significantly (p ≤ 0.05) in the rats’ lenses in group 2 in comparison with the healthy control rats, but in the melatonin treated diabetic rats (group 3) specific activities of GR and CAT activities increased significantly when compared to the diabetic control ones (p ≤ 0.05).

Table 1.

The Effects of melatonin on lens antioxidant enzymes in experimental rats

Experimental groups Lens GR (mU/mg protein) Lens CAT (U/mg protein)
Healthy control rats 0.60 ± 0.14 0.241 ± 0.074
Diabetic control rats 0.30 ± 0.11* 0.095 ± 0.026*
Melatonin treated diabetic rats 0.82 ± 0.5† 0.360 ± 0.34†
Melatonin treated Healthy rats 0.55 ± 0.26† 0.280 ± 0.13†
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Glutathione reductase (GR), catalase (CAT). Each experiment was performed triplicate. Data are presented as the mean ± SD. * significant difference from Healthy control group, † significant difference from diabetic control group (p ≤ 0.05; one-way ANOVA and LSD posttests)

Table 2 demonstrates the effects of melatonin on the lens MDA and plasma GSH levels in the experimental groups. A reduction was observed in the plasma GSH contents in the diabetic animals compared with the healthy control group (p < 0.01), whereas at the end of the experiment, GSH concentration highly elevated in the plasma of the melatonin-treated diabetic ones significantly (p < 0.05). The STZ-induced diabetic group showed a significant 3-fold increase in lens malondialdehyde level compared to the group 1 (P < 0.05); melatonin treatment caused a reduction of about 2- folds in the lens MDA of the diabetic rats which was not surprisingly significant (p > 0.05).

Table 2.

The Effect of melatonin on biochemical parameters in experimental rats

Experimental groups Glucose (mg/dl) Lens MDA (nmol/mg protein) Plasma GSH (μM)
Healthy control rats 126.9 ± 23.56 0.11 ± 0.05 46.15 ± 10.2
Diabetic control rats 446.5 ± 82.91* 0.36 ± 0.48* 25.18 ± 10.4*
Melatonin treated diabetic rats 141.5 ± 29.36† 0.17 ± 0.12 40.70 ± 15.3†
Melatonin treated Healthy rats 160.4 ± 9.63† 0.10 ± 0.021† 44.10 ± 16.8†
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Malondialdehyde (MDA), reduced glutathione (GSH). Each experiment was performed triplicate. Data are presented as the mean ± SD. * significant difference from Healthy control group, † significant difference from diabetic control group (p ≤ 0.05; one-way ANOVA and LSD posttests)

The levels of biochemical parameters in the lens or plasma did not significantly change in the melatonin treated healthy rats (group 4) compared to the healthy control rats as well as enzyme activities (P = 0.08) in the lens.

Changes in blood glucose level and body weight

The effects of melatonin administration on blood glucose and body weight in the rats are shown in Table 2 and Fig. 1.

Fig. 1.

Fig. 1

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The effect of melatonin on body weight rats in experimental groups. The weights of the Healthy control rats were significantly different from the diabetic control group since the second week (p < 0.001). There was a significant difference in body weight between the untreated diabetic rats and the diabetic rats treated with melatonin since the fourth week (p < 0.01). Data show the average of results in all the animals in each group. Each experiment was performed triplicate. #shows the significant difference from the Healthy control group; *shows the significant difference from diabetic control group

The blood glucose level of the STZ-treated group at the end of 8 weeks was elevated significantly compared with the healthy control rats (P < 0.05). As seen, melatonin gavage (5 mg/kg, daily) caused a significant change in the blood glucose concentration significantly (P < 0.05).

The body weight of the diabetic control animals significantly decreased from the second week in comparison with those in the healthy control rats (p < 0.001). The diabetic rats that received melatonin have higher body weight than the diabetic control ones; these changes were statistically significant (p < 0. 01).

Discussion

Diabetes as a chronic metabolic disorder that is associated with hyperglycemia and oxidative stress, which causes several serious complications such as cataract development [12]. A Cataract is deterioration of the transparency of the eye lens, which may cause blindness in developed and developing countries [24, 25]. Oxidative stress has a basic role in the development of dangerous diabetic consequences. Human antioxidant defense systems consist of antioxidative enzymes including SOD, GSH-Px, GR and CAT and no enzymatic ones which convert ROS and reactive nitrogen species (RNS) to non-radical products [8]. Preventive effect of melatonin administration on oxidative stress complications in diabetes mellitus was shown in previous studies [4, 7, 16].

The present study aimed to evaluate the effects of melatonin on antioxidant content and enzymes in diabetic rat lenses. The current research was conducted to indicate the potential antioxidant properties of melatonin concerning STZ-induced diabetes. This is the first study about the effects of melatonin on oxidative stress in the lens of diabetic rats.

As compared to the healthy controls, the rats’ body weight diminished in the diabetic control group (p < 0.05) whereas the body weight of the melatonin-treated diabetic ones was significantly higher than that of diabetic control animals after 8 weeks (p < 0.05). Abdulla et al. demonstrated no significant differences in body weight of the diabetic control rats and the melatonin-treated diabetic rats after using melatonin (10 mg/kg. day ip) for 8 weeks [26]. The difference among our data and those of Abdulla et al. may be due to the time, dose and the procedure of melatonin administration. Previous researchers reported that administration of melatonin to pinealectomized rats caused to elevation in insulin secretion from pancreatic β-cells and reduction in plasma glucose level. Besides, another investigation demonstrated that the number of insulin receptors increased in hepatocyte membranes in experimental animals significantly [16]. In diabetic rats that received melatonin, the pancreas β-cells were regenerated and insulin secreted that resulted in an increasing in body weight significantly [27].

We showed that the administration of melatonin caused a reduction in the glucose concentration in diabetic animals. Abdel-Wahab et al. and Anwar et al. demonstrated that melatonin (10 mg/kg ip and 200 μg/kg ip) decreased the plasma glucose concentration in the diabetic rats [16, 28]. Other researchers reported that treatment with melatonin (10 mg/kg) reduced blood glucose in alloxan-induced diabetic rats after 45 days [29]. Akmali et al. showed that pre- and post-feeding of diabetic rats with melatonin increased the specific activities of carbohydrate metabolizing key enzymes in the liver, such as glucokinase, hexokinase and glucose-6-phosphate dehydrogenase, which can lead to a decrease in the plasma glucose levels [30, 31]. However, Huseyin Vural et al. reported that administration of melatonin (10 mg/kg ip. per day, 6 weeks) could not diminish the plasma glucose in the diabetic rats [4]. According to previous studies and our research melatonin at low doses and different time intervals can reduce glucose concentration in diabetic animals, which is probably due to the regeneration of β-cells by melatonin treatment.

Our results indicated the effect of melatonin on enhancement of antioxidant enzymes and reduction of lipid peroxidation end product in terms of MDA in the lens of animal models of diabetes whereas previous researchers focused mainly on the changes in the antioxidant status in other tissues by melatonin treatment [26, 32]. We demonstrated that the specific activities of CAT and GR in the lens of diabetic rats decreased at the end of the experiment (p < 0.05) and elevated the MDA level while administration of melatonin corrected these changes. These results are in agreement with those of other investigations on the effect of melatonin on CAT and GR activities in the kidney, liver and plasma of the diabetic rats [7, 26–28]. Ozlem et al. reported that administration of melatonin (200 μg/kg ip) decreased the MDA level in the renal homogenate in diabetic rats after 4 weeks [27]. Some studies have reported that STZ-induced diabetes increases the MDA formation and melatonin consumption (10 mg/kg) decreases MDA in the RBC, liver and sciatic nerve [29, 33]. Shirazi et al. reported that gamma irradiation (5 Gy) of rats’ cranium increased the MDA levels in the lens when compared to the control group while melatonin treatment reversed this change [14]. Therefore, melatonin elevated not only antioxidant power in diabetic rat lenses but also enhanced the antioxidant potential in different tissues by the unclear process.

In the present study, we observed that induction of diabetes decreased the plasma GSH concentration in the rats and administration of melatonin increased the GSH levels significantly near to healthy control rats. Sekkin et al. demonstrated that induction of diabetes caused depletion in GSH in the pancreas tissue and treatment with melatonin for 6 weeks elevated the GSH levels significantly [34]. Klepac et al. also, reported that melatonin (20 mg/kg, ip) increased the plasma GSH concentration in diabetic rats by 9% after a single injection [7]. The GSH concentration, as a critical component of the antioxidant defense system, exists in high levels in the lens that is necessary for maintaining the transparency of this tissue. It was documented that in the many cataractous lenses, depletion of GSH can damage the cytoskeletal proteins, which may result in the membrane dysfunction [31, 35]. Hyperglycemia would lead to enhanced oxidative stress such as ROS in the lens. Also, protective enzymes against oxidation may be inactivated or ineffective by glycation [35].

In a parallel study, we showed that melatonin has the beneficial effects on the progression of cataract (data not shown) [31].

Some studies have performed on the effect of melatonin on human antioxidant capacity, including: Kozirog et al, reported that administration of melatonin (5 mg/day) for 2 months for patients with metabolic syndrome significantly increased CAT activity and decreased TBARS level, low-density lipoprotein cholesterol (LDL-C) and blood pressure [36]. Kornelia et al. reported that melatonin administration (5 mg/day, 4 weeks) improved antioxidant capacity (a significant increase in the SOD activity and reduction in the MDA level in the non-insulin-dependent diabetes mellitus (NIDDM) patients. These results indicate the antioxidant role of melatonin in the NIDDM and metabolic syndrome patients; therefore, melatonin can be used as an additional treatment to reduce diabetes and metabolic syndrome complications [37]. But the effect of melatonin on the antioxidant system in lens and prevention of diabetic cataracts in humans has not been investigated. Therefore, further studies are needed to obtain effective doses for human.

In conclusion, melatonin reduces hyperglycemia and also restores the antioxidant status in the lens of diabetic rats induced by streptozotocin. Actually, hyperglycemia and oxidative stress represent two main factors in the pathogenesis of diabetic complications.

Acknowledgements

The authors thank from the biochemistry department of Shiraz University of Medical Sciences for technical assistance in this work.

Abbreviations

ROS

Reactive oxygen species

UVB

Ultraviolet-B

NADPH

β-Nicotinamide adenine dinucleotide phosphate-reduced form

TBA

2-thiobarbituric acid

TEP

1, 1, 3, 3-tetra ethoxy propane

GSH

Reduced glutathione

DTNB

5, 5′-dithiobis-(2-nitrobenzoic acid)

GSSG

Oxidized glutathione

STZ

Streptozotocin

MDA

Malondialdehyde

GR

Glutathione reductase

NADPH

Reduced nicotinamide adenine dinucleotide phosphate

CAT

Catalase

GSH

Reduced glutathione

SOD

Superoxide dismutase

GSH-Px

Glutathione peroxidase

RNS

Reactive nitrogen species

EDTA

Ethylenediaminetetraacetic acid

BSA

Bovine serum albumin, Non-insulin-dependent diabetes mellitus (NIDDM)

Authors’ contributions

Masoumeh Akmali contributed to the design the study, and drafted the manuscript, Masoumeh Akmali, Marjan Khorsand and Morteza Akhzari conducted the analysis, wrote and revised manuscript, Marjan Khorsand performed the biochemical analysis and animal treatment.

Funding

The Shahid Sadoughi University of Medical Sciences (Yazd, Iran) and Shiraz University of Medical Sciences (Shiraz, Iran) funded this study, which is derived from the student thesis of Marjan Khorsand by grant number 1083.

Compliance with ethical standards

Ethics approval and consent to participate

All experiments in this study performed according to the guidelines of “Animal Care Ethics Committee” of Shiraz University of Medical Sciences, Shiraz, Iran (IR.SUMS.REC).

Conflict of interest

There is no financial or personal conflict of interest.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Marjan Khorsand, Email: ma.kh58@yahoo.com.

Masoumeh Akmali, Email: akmali34@yahoo.com.

Morteza Akhzari, Email: maratez2009@yahoo.com.

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