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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 16  |  Issue : 3  |  Page : 300-308

The effect of diabetes mellitus on the rat ventral prostate and the possible protective role of Ginkgo biloba extracts


1 Department of Histology & Cell Biology, Faculty of Medicine, Al-Azhar University, Assiut Branch, Assiut, Egypt
2 Department of Human Anatomy & Embryology, Faculty of Medicine, Port Said University, Port Said, Egypt

Date of Submission25-Oct-2018
Date of Acceptance27-Jan-2019
Date of Web Publication15-Apr-2019

Correspondence Address:
Esam O Kamel
Department of Histology & Cell Biology, Faculty of Medicine, Al-Azhar University, Assiut, 71622
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_114_18

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  Abstract 


Context Diabetes mellitus (DM) is a worldwide common disease that causes many complications in the male genital system including the prostate gland. Many studies have shown that extracts of Ginkgo biloba have antioxidant and free radical eliminating effects.
Aim The present study aims to explore the histological effects of DM on the ventral prostate gland in rats and the possible protective role of Ginkgo extracts.
Materials and methods Forty-five adult albino male rats were chosen for this study and they were classified into three equal groups. The control group was divided into two subgroups: the subgroup 1 rats received distilled water for 6 weeks; the subgroup 2 rats were injected intraperitoneally by a single dose of 0.15 ml 0.1 mol/l citrate buffer. To induce diabetes rats in the diabetic and protective groups were administered 60 mg/kg streptozotocin intraperitoneally, a week later rats in the protective group received Ginkgo extract orally in a dose of 100 mg/kg/day for 6 weeks. Six weeks after diabetes induction, samples from the ventral prostate from all groups were obtained for histological examination.
Results No structural differences between the two control subgroups were observed. The diabetic group showed focal epithelial stratification with pyknotic nuclei resting on the disrupted basement membrane. By electron microscope (EM) the cells had irregular nuclei, few mitochondria, many cytoplasmic vacuoles, dilated rough endoplasmic reticulum (rER) cisternae, and few apical microvilli. In other areas, the cells were destructed with dissolved cytoplasm; many fragmented rounded bodies were observed in the lumen. The Ginkgo was found to improve most of the prostatic changes associated with DM.
Conclusion Ginkgo extracts improve the prostatic changes produced by DM.

Keywords: diabetes mellitus, Ginkgo biloba, ventral prostate


How to cite this article:
Kamel EO, Abd-Elrhman ASA. The effect of diabetes mellitus on the rat ventral prostate and the possible protective role of Ginkgo biloba extracts. Al-Azhar Assiut Med J 2018;16:300-8

How to cite this URL:
Kamel EO, Abd-Elrhman ASA. The effect of diabetes mellitus on the rat ventral prostate and the possible protective role of Ginkgo biloba extracts. Al-Azhar Assiut Med J [serial online] 2018 [cited 2020 Jul 6];16:300-8. Available from: http://www.azmj.eg.net/text.asp?2018/16/3/300/255851




  Introduction Top


Diabetes mellitus (DM) is a worldwide common disease [1]. Hyperglycemia, the main sign of diabetes, enhances oxidative stress in the association of glucose oxidation in the mitochondria [2], which later acts as one of the important factors causing microvascular and macrovascular complications [3]. Impotency, reduced libido, spermatogenesis impairment, decreased sperm count and motility, decreased semen volume, and decrease serum testosterone have been reported in diabetic people and in experimental diabetic animals [1]. Prostatic complications are commonly reported in patients with DM [4]. Some researchers reported a direct relationship between diabetes and prostate pathologies which may contribute to metabolic aberrations and disturbances in the levels of sex hormone in diabetics [5],[6].

Pathologies of the prostate, triggered by prostate health in diabetic male rats decreased insulin production and secretion or insulin action resistance [7], may lead to a decrease in prostatic secretions [8].

Herbal medicines have been applied for centuries in the treatment of several diseases. Ginkgo extract is a widely used herbal in the treatment of neurodegenerative diseases such as Alzheimer, memory loss, schizophrenia, mild cognitive impairment, dementia as well as cancer and cardiovascular sicknesses [9],[10],[11].

Many studies have shown that Ginkgo biloba extracts have antioxidant and free radical eliminating effects [12]. G. biloba extract directly attenuates reactive oxygen species and stabilizes the cell redox state by upregulating the activity of antioxidant enzymes [13]. G. biloba extract enhances the activity of gamma-glutamylcysteine synthetase and glutathione reductase, the main enzymes essential for the synthesis and reduction of glutathione [14].


  Aim Top


The current study was designed to evaluate the protective effects of G. biloba extracts on the prostatic complications of diabetes.


  Materials and methods Top


Animals

Our study was carried out on 45 adult albino male albino rats weighing 250–300 g. They were gained from the house of animals of Faculty of Medicine, Assiut University, Egypt. They were kept in suitable conditions for 1 week for adaptation and maintained in clean ventilated stainless steel cages at normal temperature (22±5°C) under a 12 : 12 h light–dark cycle, and they were fed a laboratory diet (bread and water). At the beginning of the experiment, blood sugar levels were measured in all animals using a glucometer to exclude diabetic rats.

Study groups

The animals were randomly divided into three groups, each group included 15 rats.
  • Group I: the control group of nondiabetic rats was further divided into two subgroups. Subgroup 1 included rats that received distilled water only for 6 weeks. Subgroup 2 included rats that received a single dose of intraperitoneal injection of 0.15 ml 0.1 mol/l citrate buffer.
  • Group II: the diabetes group.
  • Group III: the protective group.


For induction of diabetes, the rats in diabetes and protective groups were received 60 mg/kg streptozotocin (STZ) (Sigma Chemical Company, St. Louis, MA, USA) intraperitoneally (prepared by dissolving STZ in citrate buffer just before injection) [15]. After 72 h, blood glucose levels of rats from diabetes and protective groups were measured using Accu-Chek Glucometer (Roche, Manheim, Germany) with compatible glucometer strips. Rats have blood glucose of more than or equal to 250 mg/dl were considered diabetic and chosen for the study [16].

One week after diabetes induction the rats in the protective group received G. biloba leaves extract orally at a dose of 100 mg/kg for 6 weeks [17].

Six weeks after diabetes induction, the animals were killed by decapitation and the ventral prostate lobes were obtained. The samples were taken and divided into two parts; one part was processed for light microscopy and the other part for electron microscopy.

Light microscopic examination

Prostatic specimens were fixed in 10% neutral buffered formaldehyde solution for 48 h and then after being washed briefly in water the specimens were dehydrated with ascending grades of ethyl alcohol (70, 80, 90, 95, and 100%), followed by clearing the samples and were then paraffin embedded. Five-micrometer-thick sections were obtained by rotatory microtome; then the sections were stained with hematoxylin and eosin for general morphological and structural study [18].

Transmission electron microscopic examination

The tissues obtained were fixed in fresh 3% glutaraldehyde for 4 h. Then 1 mm specimens were cut and washed in 0.15 mol/l phosphate buffer, pH 7.4, for 2 h (two changes), and then postfixed in 1% osmium tetroxide for 1 h. The specimens were dehydrated and embedded in epoxy resin. One-millimeter-thick sections were stained with toluidine blue (1%) for examination by light microscopy [18]. For electron microscopy, ultrathin sections (50–70 nm thick) were cut by ultramicrotome and stained using uranyl acetate and lead citrate [19]. The sections were examined by a transmission electron microscope at the unit of electron microscopy, Assiut University.

Drugs

G. biloba leaf extracts (Ginkgo capsules; Arab company for pharmaceutical and medicinal plants, Mepaco-Medifood, Egypt) were used in the current study in doses of 100 mg/kg/day [17].


  Results Top


Light microscopic examination

There were no apparent differences in the structure of the ventral prostate glands in the two control subgroups where sections stained with hematoxylin and eosin showed that the ventral prostate gland was composed of acini of variable sizes. These acini were lined with columnar epithelium and had luminal secretions of variable densities but mostly dark. The acini showed many luminal epithelial folds ([Figure 1]). The acinar epithelium was simple columnar having basophilic cytoplasm and basally located rounded vesicular nuclei. The cells were resting on a regular basement membrane and the lumen showed few acidophilic secretions ([Figure 2]). In diabetic rats, the gland was composed of acini of variable sizes and shapes; they revealed few luminal epithelial folds and pale luminal secretions. Collagen fibers are abundant in between the acini ([Figure 3]). Some acini were lined with low cubical cells and others were lined with columnar cells ([Figure 4]). In some areas ([Figure 4]), the lining of the epithelium showed focal stratification resting on a disrupted basement membrane. The cells had pale basophilic cytoplasm and pale staining irregular nuclei, the apical cells were destructed and were devoid of nuclei. The stroma shows many congested blood vessels and infiltrating inflammatory cells ([Figure 4]). In other areas ([Figure 5]), the epithelial cells lost their normal structural architecture where some cells were vacuolated and had pyknotic dense nuclei and other cells had dense cytoplasm with irregular dark nuclei. The basement membrane was irregular and few pale acidophilic secretions were found.
Figure 1 A photomicrograph of the control ventral prostate of albino rats showing acini of variable sizes having luminal secretions of variable densities, mostly dark. The acinar epithelial folds are numerous (arrow). Hematoxylin and eosin, ×100).

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Figure 2 A photomicrograph of the control ventral prostate of albino rats showing a part of the lining epithelium of an acinus. The cells are columnar resting on regular basement membrane (arrowhead); they have basophilic cytoplasm and basally located rounded vesicular nuclei (arrow). The lumen shows acidophilic secretions (star). Hematoxylin and eosin, ×1000.

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Figure 3 A photomicrograph of the ventral prostate of diabetic rats showing acini of variable sizes and shapes with surrounding interacinar stroma. Few epithelial folds are noticed (arrow) and luminal secretions mostly pale could be noticed. The interacinar area shows many collagen bundles (star). Hematoxylin and eosin, ×100.

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Figure 4 A photomicrograph of the ventral prostate of diabetic rats showing lining epithelium of many acini and stroma. The lining epithelium shows focal epithelial stratification (arrowhead) where the cells have pale basophilic cytoplasm and pale staining irregular nuclei (thin arrow). The apical cells are destructed and anucleated (curved arrow), the basal cells rest on irregular basement membrane (spiral arrow). In other acini, some cells are low cubical (short arrow) and others are columnar (white arrow). The stroma shows congested red blood vessels (star). Hematoxylin and eosin, ×400.

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Figure 5 A photomicrograph of the ventral prostate of diabetic rats showing part of the lining epithelium of an acinus. The apparent normal architecture of the epithelium is lost. One cell is vacuolated and having a pyknotic dense nucleus (arrowhead). Other cells have dense cytoplasm (thick arrows) with irregular dark nuclei (thin arrow). The basal lamina is irregular (curved arrow). Pale acidophilic secretions are found. Hematoxylin and eosin, ×1000.

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In diabetic rats treated with G. biloba, the gland was formed of acini of regular shapes and variable sizes. The acini showed few epithelial folds. Dark luminal secretions were observed in some acini ([Figure 6]). The epithelial cells were columnar with basophilic cytoplasm and rounded vesicular nuclei ([Figure 7]). In other areas ([Figure 7]), the acini had a less high epithelium with basophilic cytoplasm and slightly flat nuclei. The epithelium was resting on a regular basement membrane and dark luminal acidophilic secretions were found.
Figure 6 A photomicrograph of the ventral prostate of a rat from the protective group showing acini of regular shapes and variable sizes. Few acini show few epithelial folds (arrow). Dark luminal secretions are observed in some acini (star). Hematoxylin and eosin, ×100.

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Figure 7 A photomicrograph of the ventral prostate of a rat from the protective group showing parts of the lining epithelium of two acini which have regular basement membrane (curved arrow). The cells of one acinus are tall with basophilic cytoplasm and rounded vesicular nuclei (arrow head). Another acinus has a less high epithelium with a slightly flat nuclei (arrow). Luminal dark acidophilic secretions are found (star). Hematoxylin and eosin, ×1000.

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In toluidine blue-stained sections, the prostatic acinar epithelium of control rats was cuboidal with rounded vesicular nuclei that had prominent nucleoli ([Figure 8]). In diabetic rats ([Figure 9]), the acinar cells were detached from the irregular basement membrane. The detached cells had irregular nuclei. Many rounded detached cytoplasmic bodies are observed in the acinar lumen. In diabetic rats treated with G. biloba ([Figure 10]), the lining epithelium was intact and are formed of cuboidal to columnar cells that had vesicular rounded nuclei with prominent nucleoli. One mast cell was observed in the periacinar computed tomography.
Figure 8 A photomicrograph of the control dorsolateral prostate of albino rats showing parts of the lining epithelium of two acini. One acinus is lined by columnar cells (arrowhead) and the other acinus is lined by cuboidal cells (curved arrow), in both types of cells the nuclei are rounded and vesicular with prominent nucleoli (arrow). Toluidine blue, ×1000.

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Figure 9 A photomicrograph of the ventral prostate of diabetic rats showing a part of the lining epithelium of an acinus. Most of the cells are detached from the irregular basement membrane (thin arrow). The detached cells have irregular nuclei (thick arrow). Many rounded detached cytoplasmic bodies are observed in the acinar lumen (arrowhead). Toluidine blue, ×1000).

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Figure 10 A photomicrograph of the ventral prostate of a rat from the protective group showing a part of the lining epithelium of an acinus with interacinar CT. The epithelial cells are cuboidal to columnar (arrowhead) having vesicular, rounded nuclei with prominent nucleoli (arrow). One mast cell could be observed in the periacinar CT (spiral arrow). Toluidine blue, ×1000.

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Electron microscopic examination

Ultrastructure of the prostate gland in control rats ([Figure 11]) showed that the acinar epithelium was resting on regular basal lamina. The cells were tall columnar having basal euchromatic nuclei. The cytoplasm contained many rough endoplasmic reticulum (rER), abundant mitochondria, and many secretory vesicles. Many apical microvilli were observed. Basal cells with large flat nucleus and scanty electron-lucent cytoplasm were found. In diabetic rats ([Figure 12]), the acini showed epithelial stratification in which most of cells were electron dense and had variable sized, mostly regular outlined nuclei but some cells were electron lucent and had irregular nuclei. Many cytoplasmic vacuoles and few secretory vesicles were noticed. The cells had few mitochondria and dilated cisternae of rER. In other areas in the prostate of diabetic rats ([Figure 13]), the acinar epithelium lost its normal structural architecture. The cells were destructed with dissolved cytoplasm. Many fragmented, rounded bodies were noticed in the lumen, some of these bodies were dense and others are pale. Dense, detached cytoplasmic and nuclear parts were noticed. Some cells were still intact, but they had dense flattened nuclei with irregular outlines. In diabetic rats treated with G. biloba ([Figure 14]), the lining epithelium restored its structural organization. The cells were columnar having basally located euchromatic nuclei. The cytoplasm had large Golgi body, abundant rER, abundant secretory vesicles, and few mitochondria. Few microvilli were observed.
Figure 11 An electron micrograph of control ventral prostate of albino rats showing a part of the lining epithelium of an acinus. The cells are resting on regular basal lamina (arrowhead). The cells are tall, columnar having basal euchromatic nuclei (N). The cytoplasm contains many rER (arrow), abundant mitochondria (m), and many secretory vesicles (spiral arrow). Many apical microvilli are observed (curved arrow). ×3600.

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Figure 12 An electron micrograph of the ventral prostate of diabetic rats showing an area of epithelial stratification. Most of the cells are electron dense and have variable sized mostly regular nuclei (N). Some cells are electron lucent and have irregular nuclei (IN). Many cytoplasmic vacuoles (arrow) and few secretory vesicles (arrowhead), few mitochondria (m), and dilated rER cisternae (spiral arrow) are noticed. ×3600.

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Figure 13 An electron micrograph of the ventral prostate of the diabetic rat showing a part of acinar epithelium that lost its normal structural architecture. The cells are destructed with a dissolved cytoplasm (L). Many fragmented rounded bodies are noticed in the lumen; some are dense (arrow head) and others are pale (P). Dense detached cytoplasmic and nuclear parts are noticed (arrow). Some cells are still intact (star) but they have dense irregular flattened nuclei (N). ×3600.

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Figure 14 An electron micrograph of the ventral prostate of a rat from the protective group showing a part of the lining epithelium of an acinus which restored its structural organization. The cells are columnar having basally located euchromatic nuclei (N). The cytoplasm has large Golgi body (G), abundant rER (spiral arrow), abundant secretory vesicles (arrow), and few mitochondria (m). Few microvilli are observed (arrow head). ×3600.

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  Discussion Top


The current study showed that the ventral prostate of control rats was composed of acini of variable sizes. These acini were lined with a columnar epithelium having basophilic cytoplasm and basally located rounded vesicular nuclei. The acini showed many luminal epithelial folds and dark secretions. The cells were resting on a regular basement membrane. In the present study, the prostatic acini of diabetic rats showed wide structural variations. Most of the acini were dilated and were lined by a single layer of flat to cubical cells with few luminal papillary projections. Few acini showed cellular detachment and apoptosis and some acini showed focal areas of epithelial stratification. But still few acini were lined by a single layer of columnar cells having basal nuclei. These results were in accordance with previous studies [20],[21],[22]. The acinar cells were resting on an irregular basement membrane which was disrupted in the areas of epithelial stratifications. The cells had irregular nuclei, dilated rough endoplasmic reticulum, few mitochondria, few secretory granules, and many electron-lucent vacuoles, some of them might have an electron dense core. Similar results were obtained by Hussein [20] who reported that changes in the secretory epithelium of diabetic rats mainly affected the organelles concerned in the secretory process, in addition to the extracellular matrix. Some areas of the acinar epithelium showed marked apoptotic changes that were in agreement with the results obtained in previously documented studies [23],[24],[25]. Denis et al. [26] confirmed that diabetes stimulates apoptosis in different body organs including the prostate gland. English et al. [27] claimed that the atrophy and apoptosis of the prostatic epithelium in diabetes is similar to atrophy of the prostatic gland after castration, which is contributed to the loss of the androgen-dependent acinar cells. These events can be alleviated by the administration of androgens that prove the anabolic effect of testosterone on acinar epithelial growth and proliferation [28]. In diabetes, insulin depletion causes decreased production of testosterone as insulin has a stimulating effect on androgen production by affecting the hypothalamic–hypophyseal–testis axis as well as its local effects through insulin receptors [29]. The diabetic rats that received treatment with insulin and testosterone showed a significant increase in androgen receptor expression [24],[30]. Vikran et al. [31] recorded that preventing insulin production during sexual maturation retards prostate growth.

Many researchers stated that diabetes may depress the activity of Leydig cells leading to decreased testosterone levels [32]. Decreased testosterone production may inhibit the development of male sex glands and accessories, including the prostate gland [33]. The imbalance between the oxidation and the antioxidant state has been shown to play a critical role in mediating diabetic complications in different body organs [34]. The increased oxidative stress condition with reduced levels of the antioxidant enzymes in diabetes directly cause apoptosis by damaging the DNA [35]. Popoola et al. [25] supposed that low levels of LH in diabetic rats, changes in the prostatic fluid phosphorus, and zinc accumulation may cause marked inhibition of cell growth and proliferation and increased prostatic acinar apoptosis [23].

In the present study, epithelial hyperplasia found in some regions was associated with the deposition of many collagen fibers and infiltration of the stroma with inflammatory cells and congested blood vessels. Similar results were also recorded in previously done studies [20],[36]. Rohrman and his team observed a higher incidence of benign, enlarged prostate in diabetic men than in those without diabetes [37]. The high blood glucose can disturb the correct normal function of immunological cells, and in prostatic acini developing hyperplasia; inflammation causes cellular proliferation events and nuclear structure deterioration through oxidative stress, cytokine production, and stimulation of growth factors [36],[38],[39].

The inflammatory cellular infiltration revealed in this study was limited. The same was also reported by Abd El-Haleem and Zidan [21] and were against the results reported by Ribeiro et al. [40]. Some researchers [40] documented considerable prostatitis in diabetic rats compared with control rats, and occupied most of the prostate gland. The difference between the results may be due to the difference of the method of induction of diabetes.

In diabetic rats treated with G. biloba, the prostate gland nearly restored its normal structure. The acini were lined by one layer of tall columnar cells with basal nuclei and the cells were resting on regular basement membrane. The acini had dark luminal acidophilic secretions and many papillary projections. No epithelial stratifications were noticed. The acinar cells had apical microvilli and euchromatic basal nuclei. The cytoplasm had rough endoplasmic reticulum, many mitochondria, and secretory granules having different densities and sizes.

G. biloba is a complex mixture of ingredients with a perfect wide spectrum of pharmacological activities and it may act through several different mechanisms including reactive oxygen species scavenger and/or stimulating antioxidant ability [41]. Antioxidants have been shown to improve diabetes by improving the function of β-cells in experimental animal models and suggested that stimulating antioxidant defense mechanisms in pancreatic islets may be a useful pharmacologic approach in managing diabetes and its complications [42]. Rhee et al. [43] found that administration of Ginkgo decreased the levels of the pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β and in the pancreas of STZ-induced mice alleviating the pancreatic inflammation and improving the β-cell function. Peng et al. [44] claimed that Ginkgo can improve the age-related prostatic hyperplasia and deformed acinar shape by improving the imbalance between androgen and estrogen levels, overexpression of epithelial and stromal growth factors associated with chronic inflammation, and that because Ginkgo has blood flowing, anti-inflammatory and free radical eliminating effects. Also, Ginkgo was shown to be highly effective regarding the suppression of intracellular production of procollagen and subsequently deposition of collagen in the interstitial tissues.


  Conclusion Top


The current study reported destructive effects of the experimentally induced DM on the structure of the prostate gland of albino rats. It also showed that Ginkgo administration ameliorated the prostate gland structural damage. Therefore, we conclude that treatment by Ginkgo may have a promising therapeutic effect against the structural damaging effects of diabetes against the prostate gland. We recommend more clinical studies to establish a stronger evidence for the effect of Ginkgo on diabetes-induced complications.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14]



 

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