Protective effects of naringin against oxaliplatin-induced testicular damage in rats: Involvement of oxidative stress, inflammation, endoplasmic reticulum stress, apoptosis, and histopathology

Abstract

Objectives: Oxaliplatin (OXL) is a platinum-based chemotherapeutic agent widely used in the treatment of colorectal cancer. Unfortunately, this important drug also causes unwanted side effects such as neuropathy, ototoxicity, and testicular toxicity. This study aimed to investigate the possible protective effects of naringin (NRG) against OXL-induced testicular toxicity in rats.

Materials and methods: In the present study, rats were injected with OXL (4 mg/kg, b.w./day, IP) in 5% dextrose solution 30 min after oral administration of NRG (50 and 100 mg/kg, b.w./day) on the 1st, 2nd, 5th, and 6th days. Then, the rats were sacrificed on the 7th day and the testicular tissues were removed.

Results: The results showed that NRG decreased (P<0.001) lipid peroxidation, increased (P<0.001) the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and the levels of glutathione (GSH), and also maintained the testis histological architecture and integrity. NRG decreased the levels of apoptosis-related markers such as caspase-3, Bax, and Apaf-1 and increased Bcl2 in the OXL-induced testicular toxicity (P<0.001). In addition, NRG reversed the changes in mRNA transcript levels of oxidative stress, inflammation, and endoplasmic reticulum stress parameters such as Nrf2, HO-1, NQO1, RAGE, NLRP3, MAPK-14, STAT3, NF-κB, IL-1β, TNF-α, PERK, IRE1, ATF6, and GRP78 in OXL-induced testicular toxicity (P<0.001).

Conclusion: Our results demonstrated that NRG can protect against OXL-induced testicular toxicity by enhancing the anti-oxidant defense system and suppressing apoptosis, inflammation, and endoplasmic reticulum stress.

Keywords: Apoptosis; Endoplasmic reticulum – stress; Inflammation; Naringin; Oxaliplatin; Testicular toxicity.

Figure 1

Protective effects of naringin (NRG) and oxaliplatin (OXL) treatments on nuclear factor erythroid 2-related factor 2 (Nrf-2), Heme oxygenase 1 (HO-1) and NAD(P)H Quinone Dehydrogenase 1 (NQO1) mRNA expression levels in testis tissue

Figure 2

Protective effects of naringin (NRG) and oxaliplatin (OXL) treatments on nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β) and NLR Family Pyrin Domain Containing 3 (NLRP3) mRNA expression levels in testis tissue

Figure 3

Protective effects of naringin (NRG) and oxaliplatin (OXL) treatments on cysteine–aspartic acid protease (caspase-3), Bcl-2 associated X protein (Bax) and B-cell lymphoma-2 (Bcl-2) levels, and Apoptotic peptidase activating factor 1 (Apaf-1) mRNA expression levels in testis tissue

Figure 4

Protective effects of naringin (NRG) and oxaliplatin (OXL) treatments on Signal transducer and activator of transcription 3 (STAT3), Receptor for Advanced Glycation Endproducts (RAGE) and mitogen-activated protein kinase 14 (MAPK14) mRNA expression levels in testis tissue

Figure 5

Protective effects of naringin (NRG) and oxaliplatin (OXL) treatments on activating transcription factor-6 (ATF-6), protein kinase (PKR)-like ER kinase (PERK), Inositol-requiring enzyme-1 (IRE1) and Glucose-regulated protein 78 (GRP78) mRNA expression levels in testis tissue

Figure 6

Photomicrographs of testis tissue histological changes

Figure 7

Effects of naringin (NRG) and oxaliplatin (OXL) treatments on Johnsen Testicular Biopsy Score