Diacerein ameliorates testosterone-induced benign prostatic hyperplasia in rats: Effect on oxidative stress, inflammation and apoptosis

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Highlights

  • Diacerein treatment protected against benign prostatic hyperplasia (BPH).

  • Diacerein improved prostatic biochemical and structural features in BPH.

  • Diacerein demonstrated anti-inflammatory and anti-oxidant effects in BPH.

  • Diacerein showed anti-proliferative and apoptotic effect in BPH.

Abstract

Benign prostatic hypertrophy (BPH) is a serious medical condition among elderly male population. BPH pathogenesis has been linked to inflammation, cellular proliferation, oxidative stress and apoptosis. Diacerein (DIA) is a FDA approved anthraquinone drug that is used to treat joint diseases such as osteoarthritis. DIA has been studied for its potent anti-inflammatory and antioxidant effects, yet its role in managing BPH has not been investigated. In this study, DIA administration for two weeks at 50 mg/kg in testosterone-induced BPH rats significantly reduced prostate weight and index. Moreover, prostatic biochemical and structural features in BPH rats were significantly improved upon DIA treatment. Mechanistically, DIA treatment associated prostatic anti-hyperplastic effects were linked to downregulation of Nrf-2/HO-1 axis, downregulation of inflammatory TNF-a, IL-1β, IL-6, downregulation of the cell proliferative marker PCNA and upregulation of caspase-3 levels. In addition, DIA treatment upregulated prostatic antioxidant GSH, the enzymatic SOD and CAT activities and reduced prostatic lipid peroxidation levels. Altogether, the present study provides evidence that DIA treatment might limit BPH progression via its potent anti-oxidant, anti-inflammatory, anti-proliferative and apoptosis inducing effects.

Introduction

Benign prostatic hyperplasia (BPH) is a common urological disorder among men. It is associated with increased proliferation of prostatic epithelial and stromal cells resulting in increasing their size and number and enlargement of prostate. BPH incidence increases with age. Indeed, it affects 8% of men aged 40 years, 50% of men aged 60 years and almost 90% as the age reaches 85 years [1]. BPH is accompanied by distressing and disabling lower urinary tract symptoms due to loss of elastic tissue between the proliferating prostatic tissues leading to urethral opening constriction. Additionally, many complications are linked to BPH including acute urine retention, hematuria, urinary tract infections and urinary stones. Of note, about 33% of BPH patients mostly go through medical or surgical procedures [2].

The underlying molecular mechanisms implicated in BPH development are not fully revealed. However, various pathogenic mechanisms have been suggested including oxidative stress, inflammation, direct infection, urinary reflux and hormonal imbalance [3]. Indeed, the androgenic pathway is thought to be predominant. Elevated dihydrotestosterone (DHT), a potent prostatic androgen is produced by reduction of testosterone in presence of 5 alpha reductase enzyme [4]. DHT binds to androgen receptor with high affinity, triggering transcription of genes encoding differentiation and growth-promoting factors. This in turn leads to stimulation of prostatic proliferation [5]. Additionally, development of BPH has been associated with chronic prostate inflammation as observed in most of prostatic biopsy samples of BPH patients. Chronic inflammation in BPH is correlated with a bigger prostate volume, higher potential of acute urinary retention and higher serum concentration of prostate-specific antigen (PSA). Of note, chronic inflammation plays crucial role in apoptosis and proliferation imbalance in prostatic tissue [6]. Therefore, despite being different from prostate cancer, BPH and prostate cancer have some important common features, including involvement of chronic inflammation as underlying pathogenic mechanism, hormone-dependent growth and response to antiandrogen therapy [7], [8].

Alpha‐1 adrenergic blockers, Non‐steroidal anti‐inflammatory drugs (NSAIDs) and 5 α‐reductase inhibitors are the commonly used medications for treatment of BPH. However, drug‐related adverse effects of these therapies limit their clinical application [9]. For example, the use of finasteride and dutasteride, 5α-reductase enzyme inhibitors, may be accompanied by increased risk of prostate cancer and osteoporosis, decreased libido, erectile dysfunction, nasal congestion and acne. Meanwhile, the use of α1-adrenergic blockers is associated with erectile dysfunction, ejaculatory disorders, insomnia, dizziness and weakness [10]. Therefore, finding alternative effective and safe therapy is becoming urgent need to improve BPH patients’ lifestyle [11].

Diacerein (DIA, 4,5-diacetoxy-9,10-dihydro-9,10-dioco-2-anthracenecarboxylic acid) is an anti-inflammatory and analgesic anthraquinone that is approved for treatment of osteoarthritis [12]. Its active metabolite, rhein possess anti-inflammatory effects via inhibiting production of various cytokines such as TNF-α, IL-1β and IL-6. Additionally, it has been reported to suppress NF-κB pathway signalling [13]. DIA is also called diacerhein or diacetylrhein) and can be found in herbal remedies such as yellow dock (Rumex crispus). Indeed, natural product and/or natural product structures are currently playing a crucial role in the processes of drug discovery and development for management of various human diseases [14].

Given the reported anti-inflammatory potential of DIA and the serious side effects of the currently available medications for BPH, the present current study aims to evaluate the prospective protective effect of DIA treatment against BPH and to outline the possible underlying molecular mechanism of DIA’s effect.

Section snippets

Experimental design

All procedures were performed in accordance with the guidelines of the National Institutes of Health for the care and use of laboratory animals and were approved by the Research Ethical Committee, Faculty of Medicine, Mansoura University.

Thirty-eight weeks old male Sprague Dawley rats weighing (180–220 g) were kept under standard conditions of temperature (22 ± 2 °C), humidity (40–50%) and lightening (alternatively 12-hour light and dark cycles) in sterile cages for one week habituation with

Effect of DIA treatment on prostate index and sperms’ parameters

As shown in Fig. 2A and Table 2, injection of testosterone markedly increased prostate index by 1.77 fold in BPH group compared to normal control group. However, DIA treatment reduced prostate index by 39.62% compared to BPH group. Sperms in BPH group were adversely affected by testosterone injection where sperms’ count and motility were decreased by 47.7% and 32.14%, respectively when compared with normal control group. Sperms’ abnormalities were increased by 5.5 fold in BPH group compared to

Discussion

BPH is a common disease among males [19]. Many studies have reported that hormonal imbalance, chronic inflammation, age and metabolic syndrome might contribute to BPH development [20], [21], however the exact underlying molecular mechanism is still elusive. The two major classes of currently used therapies to manage BPH in elderly men are: α-blockers and 5α-Reductase Inhibitors [22], [23]. Several side effects have been reported upon continuous use of these drugs. For instance, sympathetic

Funding

The authors appreciate support provided by the research center at AlMaarefa University.

CRediT authorship contribution statement

Mohamed El-Sherbiny: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing. Mohamed El-Shafey: Conceptualization, Data curation, Formal analysis, Methodology, Validation. Mosaab Salah El-din El-Agawy: Conceptualization, Data curation, Formal analysis, Methodology, Validation. Abdelaty Shawky Mohamed: Conceptualization, Data curation, Formal analysis, Methodology,

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References (45)

  • M. Almezgagi et al.

    Diacerein: Recent insight into pharmacological activities and molecular pathways

    Biomed. Pharmacother.

    (2020)
  • N.E. El-Ashmawy et al.

    Modulatory Effect of Silymarin on Apoptosis in Testosterone -Induced Benign Prostatic Hyperplasia in Rats

    Pathol. Oncol. Res.

    (2020)
  • A.B. Abdel-Naim et al.

    2-Methoxyestradiol Attenuates Testosterone-Induced Benign Prostate Hyperplasia in Rats through Inhibition of HIF-1α/TGF-β/Smad2 Axis

    Oxid. Med. Cell. Longev

    (2018)
  • E.M. Elbaz et al.

    Immunomodulatory effect of diallyl sulfide on experimentally-induced benign prostate hyperplasia via the suppression of CD4+T/IL-17 and TGF-β1/ERK pathways

    Inflammopharmacology

    (2020)
  • D.H. Youn et al.

    Berberine Improves Benign Prostatic Hyperplasia via Suppression of 5 Alpha Reductase and Extracellular Signal-Regulated Kinase in Vivo and in Vitro

    Front. Pharmacol.

    (2018)
  • J. Zhang et al.

    Nimbolide-Induced Oxidative Stress Abrogates STAT3 Signaling Cascade and Inhibits Tumor Growth in Transgenic Adenocarcinoma of Mouse Prostate Model

    Antioxid. Redox Signal.

    (2016)
  • D.D. Ørsted et al.

    The link between benign prostatic hyperplasia and prostate cancer

    Nat. Rev. Urol.

    (2013)
  • L. Zang et al.

    Qianliexin capsule exerts anti-inflammatory activity in chronic non-bacterial prostatitis and benign prostatic hyperplasia via NF-κB and inflammasome

    J. Cell Mol. Med.

    (2021)
  • B.-R. Jin et al.

    Anti-Proliferative Effects of HBX-5 on Progression of Benign Prostatic Hyperplasia

    Molecules (Basel, Switzerland)

    (2018)
  • J.M. Hirshburg et al.

    Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review

    J. Clin. Aesthet. Dermatol.

    (2016)
  • A.A. Fouad et al.

    Diacerein Downregulates NLRP3/Caspase-1/IL-1β and IL-6/STAT3 Pathways of Inflammation and Apoptosis in a Rat Model of Cadmium Testicular Toxicity

    Biol. Trace Elem. Res.

    (2020)
  • K.L.C. da Silva et al.

    Atorvastatin and diacerein reduce insulin resistance and increase disease tolerance in rats with sepsis

    J. Inflamm. (Lond.)

    (2018)
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