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Alpha-pinene neutralizes cisplatin-induced reproductive toxicity in male rats through activation of Nrf2 pathway

  • Urology - Original Paper
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Abstract

Purpose

Testicular toxicity is one of the most important side effects of cisplatin (CP) therapy. Alpha-pinene (AP) is a naturally occurring monoterpene with antioxidant character in plants. Here, we aimed to evaluate the therapeutic activity of AP against CP-induced testicular toxicity by including the nuclear factor erythroid 2-associated factor 2 (Nrf2) pathway in rats.

Methods

Thirty male rats were divided into 5 groups: control, CP, CP + AP (5 and 10 mg/kg) and only AP (10 mg/kg). CP was administered intraperitoneally at a dose of 5 mg/kg on the first day, followed by three consecutive injections of AP. Serum reproductive hormone levels were evaluated using ELISA kits. Oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS) and apoptosis markers in testicular tissue were also determined colorimetrically. In addition, how CP affects Nrf2 pathway and the effect of AP on this situation were also addressed.

Results

Treatment with CP significantly increased OS, inflammation, ERS and apoptosis in testicular tissue. Administrations of AP resulted in an amelioration of these altered parameters. The mechanism of therapeutic effect of AP appeared to involve induction of Nrf2. Furthermore, these results were also confirmed by histological data.

Conclusion

Results suggest that AP can exhibit therapeutic effects against CP-induced testicular toxicity. It can be concluded that AP may be a potential molecule to abolish reproductive toxicity after chemotherapy.

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Data availability

The data used and analyzed in this article are available from the corresponding author upon reasonable request.

Abbreviations

4-HNE:

4-hydroxynonenal

ANOVA:

analysis of variance

AP:

alpha-pinene

ATF6:

activating transcription factor 6

CHOP:

CCAAT-enhancer-binding protein homologous protein

CP:

cisplatin

ELISA:

enzyme-linked immunosorbent assay

ERAD:

ER-associated protein degradation

ERS:

endoplasmic reticulum stress

FSH:

follicle-stimulating hormone

G6PD:

glucose-6-phosphate dehydrogenase

GPx:

glutathione peroxidase

GRP78:

glucose-regulated protein 78

GSH:

glutathione

HMGB1:

high mobility group box 1

HO-1:

heme oxygenase-1

IP:

intraperitoneal

IL-6:

interleukin-6

Keap1:

Kelch-ECH-associated protein 1

LH:

luteinizing hormone

MPO:

myeloperoxidase

NF-κB:

nuclear factor kappa B

Nrf2:

nuclear factor erythroid 2-associated factor 2

NQO-1:

NAD(P)H quinone dehydrogenase-1

OS:

oxidative stress

ROS:

reactive oxygen species

SOD:

superoxide dismutase

TNF-α:

tumor necrosis factor-alpha

UPR:

unfolded protein response

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Acknowledgements

The authors wish to thank Sait Al and Ibrahim Aydin from Surgical Practice and Research Center of Karadeniz Technical University (Trabzon, Turkiye) for professional assistance with the experimental studies.

Funding

This study was supported by Office of Scientific Research Projects of Karadeniz Technical University (Project Number: TSA-2023-10656).

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Authors and Affiliations

  1. Department of Nutrition and Dietetics, Faculty of Health Sciences, Karadeniz Technical University, 61080, Trabzon, Turkey

    Selim Demir

  2. Department of Medical Biochemistry, Faculty of Medicine, Karadeniz Technical University, 61080, Trabzon, Turkey

    Ahmet Mentese & Yuksel Aliyazicioglu

  3. Department of Medical Pathology, Faculty of Medicine, Karadeniz Technical University, 61080, Trabzon, Turkey

    Zeynep Turkmen Usta

  4. Department of Medical Biochemistry, Graduate School of Health Sciences, Karadeniz Technical University, 61080, Trabzon, Turkey

    Nihal Turkmen Alemdar

  5. Department of Medical Services and Techniques, Vocational School of Health Services, Recep Tayyip Erdogan University, 53100, Rize, Turkey

    Nihal Turkmen Alemdar

  6. Department of Chemistry and Chemical Processing Technologies, Macka Vocational School, Karadeniz Technical University, 61750, Trabzon, Turkey

    Elif Ayazoglu Demir

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Contributions

SD, AM and ZTU designed the experiment. SD, AM, ZTU, NTA and EAD performed the experiment. SD, AM and ZTU performed tha data analysis. SD wrote the manuscript. YA revised the manuscript. All authors read and approved the fnal manuscript.

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Correspondence to Selim Demir.

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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.

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This study was approved by the Local Animal Research Ethics Committee of Karadeniz Technical University (Protocol no: 2022/44) and conducted in accordance with the animal research reporting of in vivo experiments (ARRIVE) guidelines and the UK Animals (Scientific Procedures) Act 1986 and related guidelines, EU Directive 2010/63/EU for animal experimentation and National Institutes of Health guidelines.

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Demir, S., Mentese, A., Usta, Z.T. et al. Alpha-pinene neutralizes cisplatin-induced reproductive toxicity in male rats through activation of Nrf2 pathway. Int Urol Nephrol 56, 527–537 (2024). https://doi.org/10.1007/s11255-023-03817-5

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