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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 14  |  Issue : 1  |  Page : 25-32

Protective effect of Hypericum perforatum on dexamethasone-induced diabetic depression in rats


1 Department of Research on Children with Special Needs, National Research Centre, Giza, Egypt
2 Department of Pharmacology, National Research Centre, Giza, Egypt
3 Department of Medical Physiology, National Research Centre, Giza, Egypt
4 Department of Pathology, National Research Centre, Giza, Egypt

Date of Submission27-Feb-2019
Date of Acceptance18-Apr-2019
Date of Web Publication27-Jun-2019

Correspondence Address:
Mohamed E Elhadidy
Department of Research on Children with Special Needs, National Research Centre, El-Bouhouth St., Giza, 12622
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jasmr.jasmr_7_19

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  Abstract 

Background/aim Complex interactions among psychological, social, and biological factors are the reason for diabetic depression. The present study was designed to evaluate the effect of Hypericum perforatum extract on dexamethasone-induced diabetic depression.
Materials and methods A total of 24 adult male Wistar rats were divided into four groups (six rats each): group 1: control; group 2: daily treated with dexamethasone (0.44 mg/kg; intraperitoneally for 28 days); and groups 3 and 4: daily treated with H. perforatum extract (100 and 200 mg/kg; orally) concurrent with dexamethasone injection for 15 consecutive days. Plasma levels of blood glucose, glucose transporter-2, CD4, total antioxidant capacity, malondialdehyde, and nitric oxide were measured. In addition, the brain contents of serotonin, dopamine, cyclooxygenase-2, and transforming growth factor-β1 were determined. Moreover, assessment of histopathological changes of brain tissues and immunohistochemical analysis of caspase-9 were performed.
Results Significant elevations were recorded in blood glucose level and plasma levels of malondialdehyde and nitric oxide. In addition, brain contents of dopamine, transforming growth factor-β1, and cyclooxygenase-2 were increased significantly in dexamethasone-treated group. However, plasma levels of glucose transporter-2, CD4, and total antioxidant capacity and the brain content of serotonin were significantly decreased in comparison with control group. Both doses of H. perforatum significantly ameliorated all biochemical parameters and alleviated histopathological and immunohistochemical apoptotic changes induced by dexamethasone in the rat cortex, striatum, and hippocampus.
Conclusion H. perforatum extract possesses antioxidant, anti-inflammatory, and immunomodulatory effects against dexamethasone-induced diabetic depression.

Keywords: dexamethasone, Hypericum perforatum, inflammation, neurotransmitters


How to cite this article:
Elhadidy ME, Salama AA, El-Kassaby M, Omara EA. Protective effect of Hypericum perforatum on dexamethasone-induced diabetic depression in rats. J Arab Soc Med Res 2019;14:25-32

How to cite this URL:
Elhadidy ME, Salama AA, El-Kassaby M, Omara EA. Protective effect of Hypericum perforatum on dexamethasone-induced diabetic depression in rats. J Arab Soc Med Res [serial online] 2019 [cited 2019 Dec 6];14:25-32. Available from: http://www.new.asmr.eg.net/text.asp?2019/14/1/25/261616


  Introduction Top


Although the pathophysiology of depression still remains elusive, it is a heterogenic disease etiologically and clinically. It is suggested that complex interactions among psychological, social, and biological factors are the reason for this disorder [1]. Approximately 350 million people are affected by depression worldwide [2]. Depression is a serious disease with a lifetime prevalence, extending from ∼11% in low-income countries to 15% in high-income countries [3]. The prevalence of depression among type 2 diabetic patients was 69% [4]. It was estimated that ∼50% of patients have a history of at least one suicide attempt during their lifetime [5]. Clinicians and researchers usually criticize antidepressant drugs, while they showed thousands of clinical trials and will continue to know the effective treatment of antidepressant drugs against depressive disorders [2].

Diabetic peripheral neuropathy is the most common microvascular complication in both type 1 and type 2 diabetes mellitus, and loss of limb sensation followed by lower limb amputation has a significant negative effect on quality of life of patients [6],[7].

The release of cytokines and the immune response activation play a significant role in the major depression pathophysiology [8]. Long-term immune system imbalance, nutrient excess associated with obesity, or metabolic syndrome may cause type 2 diabetes mellitus, which is viewed as a low-grade inflammatory disease [9]. An imbalance between proinflammatory and anti-inflammatory cytokines in anxiety and depression has been seen, as well as a correlation between psychological symptoms and transforming growth factor-beta (TGF-β) level has been found [10].

Dexamethasone and prednisone as corticosteroids are prescribed medications that decrease inflammation and suppress the immune system. Osteoporosis, weight gain, and diabetes mellitus are considered the common adverse effects of long-term treatment with corticosteroids. However, during acute corticosteroid therapy, the most common mood changes are mania and hypomania, although depression has also been reported. However, during long-term treatment with corticosteroids, mania is reported to be less than depression. The cognitive symptoms and mood changes usually occur during the first few weeks of therapy and also are dose dependent [11].

Hypericum perforatum is a perennial plant known as St John’s wort, and is highly distributed over the world. For centuries, it has been used for treatment of many disorders, such as anxiety, minor burns, and mild to moderate depression in traditional medicine. Scientists have studied its properties as antidepressant in the past years, while finding that several of its major molecular components protect from toxic insults, either through their antioxidant properties or through the mechanisms of neuroprotection directly [12].

Therefore, the present study was conducted to investigate the protective effect of H. perforatum extract against dexamethasone-induced diabetic depression in rats.


  Materials and methods Top


Animals and ethical approval

A total of 24 adult male Wistar albino rats weighing 120–140 g were purchased from the Animal House Colony of the National Research Centre (Dokki, Giza, Egypt) and were acclimatized to laboratory conditions 1 week before beginning the experiment [13]. The Medical Research Ethics Committee of the National Research Centre, Giza, Egypt, had approved the experiments with approval number 18174.

Drugs

Dexamethasone (Fortecortin) tablets were purchased from Merck KGaA (Frankfurter Str., Darmstadt, Germany).

H. perforatum (Safamood) tablets were purchased from Atos for Production of Medicinal Herbs (Atos Pharma, El Salam City, Cairo, Egypt).

Experimental design

Diabetic depression was induced by intraperitoneal injection of dexamethasone (0.44 mg/kg, body weight) [14] for 28 consecutive days.

The rats were divided into four groups (six rats each) as follows:

Group 1: rats received saline and served as normal control.

Group 2: rats were daily treated with dexamethasone (0.44 mg/kg) intraperitoneally for 28 days.

Groups 3–4: rats were treated with H. perforatum extract at a dose of 100 and 200 mg/kg, body weight [15], correspondingly, concurrent with dexamethasone injection for 15 consecutive days.

Sample preparation

At the end of the experimental period, blood samples were collected from the retro-orbital venous plexus by heparinized capillary tubes under diethyl ether anesthesia [16]. Blood samples were centrifuged at 3000 rpm for 10 min. The separated plasma was stored at −20° C till examination. After blood collection, the rats were killed, and the whole brain was rapidly removed, and then dissected out, weighed, and thoroughly washed with isotonic saline. The individual brain of each animal was homogenized immediately to give 10% (w/v) homogenate in ice-cold medium containing 50 mM tris HCl and 300 mM sucrose (pH 7.4). The homogenate was centrifuged at 3000 rpm for 10 min in a cooling centrifuge.

Biochemical analysis

Blood glucose level was determined using Biodiagnostic Kit (El-Bouhouth St., Giza, Egypt). Glucose transporter-2 (GLUT2) and CD4 plasma levels were determined using kit Bioneovan Co. Ltd (Keyuan Road Daxing Industry Zone Beijing, China) and SinoGeneclon Co, Ltd (North Dakota, Japan), ELISA kits. Serotonin and dopamine brain contents were also determined according to Kema [17] and Miagkova et al. [18] using Biosource EIA kit (Rue De L’ industrie, Nivelles, Belgium), ELISA kit. Plasma total antioxidant capacity (TAC), malondialdehyde (MDA), and nitric oxide (NO) levels were determined according to Koracevic et al. [19], Ohkawa et al. [20], and Montgomery and Dymock [21] using commercially available kits (Biodiagnostic Kit). Brain contents of cyclooxygenase-2 (COX2) and TGF-β were determined using kit Bioneovan Co Ltd, and SinoGeneclon Co. Ltd, ELISA kits.

Histopathological examination

The brain tissue was fixed in 10% formalin for 24 h and dehydrated in ascending series of ethanol (50–90%), followed by absolute alcohol then cleared in xylene and immersed in paraffin. The paraffin blocks were sectioned at 5 µm and stained with hematoxylin and eosin [22].

Immunohistochemistry for caspase-9

The brain sections were cut in 5-μm thickness, deparaffinized, and hydrated. Immunohistochemistry was performed with mouse monoclonal antibodies against caspase-9 expression in the nuclei (brown) for detection of the caspase cleavage activity which indicated positive apoptotic neuron. The paraffin sections were heated in a microwave oven (25 min at 720 W) and incubated with anti-caspase antibodies (1 : 50 dilution) overnight at 4°C. After washing with PBS and streptavidin/alkaline phosphatase complex (1 : 200 dilution; Dako) for 30 min at room temperature, the binding sites of anti-body were visualized with 3,3′-diaminobenzidine (Sigma-Aldrich, , St. Louis, Missouri, USA). After washing with PBS, the samples were counterstained with hematoxylin for 2–3 min and dehydrated in ethanol solutions, and then in xylene and mounted, examined, and evaluated by a high-power light microscope.

Statistical analysis

All the values were presented as mean±SE. Comparisons between different groups were carried out using one-way analysis of variance followed by Tukey’s HSD test for multiple comparisons. Difference was considered significant when P value less than 0.05. Graph Pad prism software (version 5, GraphPad Software Inc., San Diego, California, USA) was used to carry out these statistical tests.


  Results Top


Biochemical results

The daily treatment with dexamethasone resulted in a significant increase in blood glucose level by 1.8 fold and decrease in plasma levels of GLUT2 by 83.46% and CD4 by 57.1% compared with the control group, and also the brain contents of serotonin were decreased by 28.8% and dopamine brain levels were increased by 36.975% in comparison with the normal control group. The treatment of rats with H. perforatum with low and high doses significantly reduced blood glucose level by 51.87 and 62.37%, respectively, and increased plasma levels of GLUT2 by 196.8 and 231.75%, respectively, and CD4 by 93.4 and 119.81%, respectively, in comparison with dexamethasone-treated group. However, H. perforatum increased the brain serotonin levels by 15 and 17.1% (low and high doses, respectively) and decreased the brain contents of dopamine by 18.5 and 16.4% (low and high doses, respectively) in comparison with the dexamethasone group ([Table 1]).
Table 1 Effects of treatment with Hypericum perforatum on plasma levels of glucose, glucose transporter-2, CD4, and on brain contents of serotonin and dopamine

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Dexamethasone treatment increased significantly the plasma contents of MDA and NO by 52.73 and 91.42%, respectively, and decreased the serum contents of TAC by 53.57% compared with the normal control group, and also significantly increased the brain contents of COX2 and TGF-β1 by 119.5 and 36%, respectively, compared with the control group. The treatment of rats with H. perforatum at low and high doses significantly ameliorated the increases in the plasma contents of MDA by 33.72 and 34.4%, respectively, and NO by 24.75 and 41% respectively; moreover, a decrease in the plasma contents of TAC 46.15 for both low and high doses in comparison with the dexamethasone group was found. However, H. perforatum (low and high doses) decreased significantly the brain contents of COX2 by 50 and 31.5%, respectively, and also significantly decreased the brain contents of TGF-β by 20 and 30.5% for low and high doses, respectively, in comparison with the dexamethasone-treated group ([Table 2]).
Table 2 Effects of treatment with Hypericum perforatum on plasma levels of total antioxidant capacity, lipid peroxidation (malondialdehyde), and nitric oxide, and on brain contents of cyclooxygenase-2 and transforming growth factor-β1

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Histopathological results

Microscopic examination of hematoxylin and eosin-stained sections of the cerebral cortex and striatum from control group showed the normal structures of neuronal cells of all these areas contain rounded nuclei with prominent nucleoli surrounded by basophilic cytoplasm ([Figure 1]a and [Figure 2]a).
Figure 1 Photomicrographs of cerebral cortex sections stained by hematoxylin–eosin stain (a). Control group showing normal neuronal cells with prominent nuclei (N). (b) Dexamethasone group showing necrosis of neurons, vacuoles (V), and apoptotic (arrowhead) and pyknotic nuclei (P). Focal gliosis (arrow) and red neurons (R). (c) Dexamethasone and Hypericum perforatum (100 mg/kg) group showing vacuoles (V), apoptotic (arrowhead) and pyknotic nuclei (P), and red neurons (R). (d) Dexamethasone and H. perforatum (200 mg/kg) group showing some apoptotic (arrowhead) and pyknotic nuclei (P) and red neurons (hematoxylin–eosin stain, ×400).

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Figure 2 Photomicrographs of striatum sections stained by hematoxylin–eosin stain. (a) Control group shows normal neuronal cells with prominent nuclei (N). (b) Dexamethasone group shows degenerated, necrosis of neurons, vacuoles (V), apoptotic (arrowhead) and pyknotic nuclei (P), and dilated blood vessel (thin arrow). (c) Dexamethasone and Hypericum perforatum (100 mg/kg) group shows necrosis of some neurons, vacuoles (V), apoptotic (arrowhead) and pyknotic nuclei (P), and red neurons. (d) Dexamethasone and H. perforatum (200 mg/kg) group shows some apoptotic (arrowhead) and pyknotic nuclei (P) and red neurons (hematoxylin–eosin stain, ×400).

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The histopathological alterations in different brain region (cortex and striatum) of rats after given dexamethasone showed degenerated, vacuolated, necrosis of neurons, and cerebral hemorrhage. Focal gliosis, congestion of blood vessel, and dystrophic changes in the form of shrunken, apoptotic, and pyknotic nuclei were also observed ([Figure 1]b and [Figure 2]b).

Moderate neuronal degeneration and pyknosis were detected in the group treated with dexamethasone and H. perforatum (100 mg/kg) ([Figure 1]c and [Figure 2]c). In rats treated with dexamethasone and H. perforatum (200 mg/kg), the cerebral cortex and striatum of rats showed considerable improvement in neurons, and most of them appeared normal with large vesicular nuclei containing one or more nucleoli. Few apoptotic and pyknotic nuclei were also noticed ([Figure 1]d and [Figure 2]d).

In addition, the hippocampus of control rat revealed normal-appearance pyramidal cells with nuclei ([Figure 3]a). However, the hippocampus of rat treated with dexamethasone showed decreased thickness of pyramidal layer, necrosis of pyramidal cells, and apoptotic with pyknotic nucleoli ([Figure 3]b). Light microscopic examination of the dexamethasone and H. perforatum (100 and 200 mg/kg) region of the hippocampus showed thick pyramidal layer of near-normal appearance in dose-dependent manner. Some pyramidal cells showed apoptotic and pyknotic nucleoli ([Figure 3]c, d).
Figure 3 Photomicrographs of hippocampus sections stained by hematoxylin–eosin stain. (a) Control group showing pyramidal layer of normal neuronal cells with prominent nuclei (N). (b) Dexamethasone group showing decrease of thickness and necrosis of pyramidal layer and apoptotic (arrowhead) with pyknotic nucleoli (P). (c and d) Dexamethasone and Hypericum perforatum (100 and 200 mg/kg, respectively) group showing thick pyramidal layer of near-normal appearance, moderate apoptotic (arrowhead), and pyknotic nucleoli (P) (hematoxylin–eosin stain, ×400).

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Immunohistochemical results

In the cortex, striatum, and hippocampus of control group, sections stained for caspase-9 immunoreactivity showed negligible or weak caspase-9-positive cells ([Figure 4]a, [Figure 5]a, and [Figure 6]a). Dexamethasone groups exhibited higher expression of caspase-9 in the cortex, striatum, and hippocampus) as brown colored neuronal cells that are considered as positive cells in the brain indicating increased apoptosis ([Figure 4]a, [Figure 5]b, and [Figure 6]b). Many neurons exhibited decrease in caspase-9 immunoreactivity in the group treated with dexamethasone and H. perforatum (100 and 200 mg/kg) in a dose-dependent manner ([Figure 4]c and d, [Figure 5]c and d, and [Figure 6]c and d).
Figure 4 Photomicrographs of cerebral cortex sections stained by caspase-9. (a) Control group showing negative immunoreactivity of neurons. (b) Dexamethasone group showing strong brown positively immunoreactive neuron nuclei, with marked expression of positively immunoreactive apoptotic cells. (c and d) Dexamethasone and Hypericum perforatum (100 and 200 mg/kg, respectively) group showing moderate and weak immunoreactivity of neurons (immunohistochemistry of caspase-9, ×400).

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Figure 5 Photomicrographs of striatum sections stained by caspase-9. (a) Control group showing negative immunoreactivity of neurons. (b) Dexamethasone group showing brown positively immunoreactive neuron nuclei. (c and d) Dexamethasone and Hypericum perforatum (100 and 200 mg/kg, respectively) group showing moderate and weak immunoreactivity of neurons (immunohistochemistry of caspase-9, ×400).

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Figure 6 Photomicrographs of hippocampus sections stained by caspase-9 stain. (a) Control group showing negative immunoreactivity of neurons. (b) Dexamethasone group showing brown positively immunoreactive neuron nuclei. (c and d) Dexamethasone and Hypericum perforatum (100 and 200 mg/kg, respectively) group showing moderate and weak immunoreactivity of neurons (immunohistochemistry of caspase-9, ×400).

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  Discussion Top


One of the serious conditions that affect human in the world is diabetes linked with depression, which aggravate the symptoms of one another. The incidence of depression is elevated two to three times higher in diabetic population than in the nondiabetic [23]. The chronic diabetic state performs complications in the behavior and mood resulting in depletion of the activity of brain monoamine specifically serotonin, and worsening of the life quality. Moreover, persisting hyperglycemia produced a reduction of synaptic plasticity, the neurotransmitter activity, and neurogenesis [24].

Our results showed that the dexamethasone increased blood glucose level and decreased plasma level of GLUT2. This result is in agreement with Shurmann who reported that the key for glucose sensing of the pancreatic cell is the glucokinase (glucose phosphorylating enzyme) and GLUT2, which are the initial event in the glucose-stimulated insulin secretion pathway [25]. On the contrary, it was found that dexamethasone decreased plasma level of CD4 T cells compared with the normal control group. Previous results showed that STZ diabetic model induced inflammation as it increased levels of tumor necrosis factor-α which changed immune cell function as it decreased liver CD4 contents as compared with normal rats. Type 2 diabetes inflammation is correlated with T-cell subset imbalance [26]. Because the brain has high oxygen consumption, high level of lipid peroxidation, high content of unsaturated fatty acids, and the activity of antioxidant systems are very low, it is susceptible to reactive nitrogen species and reactive oxygen species [27],[28].

The present data showed that dexamethasone decreased significantly plasma level of TAC. Moreover, NO and lipid peroxidation were significantly increased by dexamethasone compared with the normal control group. Fengy and Tangi [29] suggested that abnormal TAC was exhibited by dexamethasone; in addition, De et al. [30] found that increase in MDA level was associated with a decreased level of reduced glutathione by dexamethasone, whereas Kimura et al. [31] suggested that dexamethasone activated the NO synthase in the inducible form.

Glucocorticoids such as dexamethasone and prednisone have a potent ability to induce apoptosis, suppress the immune system, and decrease inflammation [32]. Not the natural glucocorticoid, but dexamethasone can induce apoptosis in the hippocampus, specifically the dentate gyrus in the brain of rat [33]. Chronic high corticosterone has an effect to suppress neurogenesis in the hippocampus in rats, a mechanism that may be involved in depression [34].

The pathophysiology of major depression may be explained by the release of inflammatory cytokines. The glucocorticoid receptor is one of the main mechanisms by which cytokines may contribute to depression, inducing neuroendocrine challenge [8]. In major depression, the two most consistent biological findings are the increase in hyperactivity of the hypothalamic–pituitary adrenal axis and inflammation, but the clinical and molecular mechanisms underlying these abnormalities are still unclear [35].

In the brain and periphery, increased inflammation biomarkers have been indicated in patients with major depression [36]. In CSF and/or peripheral blood in patients with depression, tumor necrosis factor-α, interleukin-1, and interleukin-6 as well as their soluble receptors have been increased [37]. Moreover, the primary precursor of serotonin (tryptophan) was decreased in the peripheral blood of depressed patients administered the innate immune cytokine [38].

The present data revealed that diabetic depression induced elevations in brain contents of COX2 and TGF-β, corresponding to the normal control group. Sun et al. [39] found that the expression of COX2 was elevated in adult mice by dexamethasone administration. TGF-β level was increased in animal model of depression [40] and was explained by Haczku and Panettieri [41], who suggested that depression symptoms or psychological stress are effective on secretion of neurotransmitters and neuroendocrine hormones, and they can change immune cells function and cytokines produced by TGF-β and immune cells, supporting our results, which showed that dexamethasone-induced depression through increasing the dopamine level and decreasing serotonin level as compared with normal control, upregulating TGF-β in the brain. These results are confirmed by our histopathological results that exhibited marked neurologic function. Sze et al. [42] showed histologic damage with administration of dexamethasone. In addition, it has been reported that administration of 3.0 mg/kg dexamethasone to P7 mice increases the apoptosis of cerebellar progenitor cells and reduces the number of cerebellar neurons [43],[44] and can induce programmed cell death. However, it is important that all steroids having glucocorticoid properties do not have the ability to perform the induction of the DNA fragmentation in apoptosis characteristic way [45].

In the present study, pretreatment with H. perforatum reduced blood glucose level, while increased the blood levels of GLUT2 and CD4 in comparison with dexamethasone-treated group. Arokiyaaraj et al. [46] reported that H. perforatum significantly reduced fasting blood glucose in dose-dependent manner compared with diabetic control. H. perforatum contains several phytochemical constituents such as rutin and flavonoids including quercetin and isoquercetin [47]. For example, rutin has been reported to decrease blood glucose level and enhance insulin release in diabetic animals [48].

The current results revealed that pretreatment with H. perforatum ameliorated the changes in brain serotonin and dopamine levels resulting from dexamethasone. H. perforatum is considered as an antidepressant and anti-anxiety agent, and it affects multiple neurotransmitters [49]. Our data were supported by the current histopathological and immunohistochemical studies that showed considerable improvement in neurons in rats treated with H. perforatum (200 mg/kg).

Our results showed that H. perforatum ameliorated the reduction in TAC plasma level and the increase in plasma levels of MDA and NO, which are elevated by daily treatment of dexamethasone. In agreement with our data, H. perforatum protects against lipid peroxidation, through scavenging NADPH-dependent lipid peroxidation and suppressing non-enzymatic Fe2+/ascorbate-dependent lipid peroxidation in cerebral cortex mitochondria. Benedi et al. [50] and El-Sherbiny et al. [51] stated that H. perforatum attenuated brain MDA formation and also elevated glutathione peroxidase and GSH activities.

Pretreatment with H. perforatum, in the present study, decreased COX2 and TGF-β brain contents. Moreover, the decrease in COX2 expression was upregulated by NO and this may be owing to the presence of hyperforin, an active constituent of H. perforatum. This result is confirmed by the study of Kaplan and Doran [52] who showed that H. perforatum reduced inflammation. Moreover, Raso et al. [53] exhibited the effects of H. perforatum on inhibition of lipopolysaccharides leading to induction of COX2 and inducible-NO synthase. These effects may be via hyperforin, which unregulated COX2 [54].


  Conclusion Top


H. perforatum has ameliorating effect on dexamethasone-induced diabetic depression in rats via its antioxidant, anti-inflammatory, and immunomodulatory effects. H. perforatum can be used in alleviating diabetic depression through modulating blood glucose, GLUT2, CD4, and neurotransmitter and downregulating COX2 and TGF-β.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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