Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia.
Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo PN 11754, Egypt.
J Trace Elem Med Biol. 2023 Dec;80:127287. doi: 10.1016/j.jtemb.2023.127287. Epub 2023 Aug 22.
Cisplatin (CIS) is a chemotherapeutic agent widely used to cure several cancers. It exerts detrimental cellular effects that restrain its clinical application as an antineoplastic agent, as testicular damage. Pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, is used to treat type-2 diabetes mellitus. PIO has been reported to exert anti-inflammatory and antioxidant effects in different tissues. The present study aimed to investigate the effect of PIO in a rat model of cisplatin-induced testicular toxicity and address the possible role of the Toll-like receptors (TLR4) / myeloid differentiation factor 88 (MyD88) / nuclear factor-kappa B (NF-kB) signal pathway.
Rats received a single dose of cisplatin (7 mg/kg, IP) on the first day and PIO (10 mg/kg, P.O.) for 7 days. At the end of the treatment period, rats were killed. Testicular weights, histopathological alterations, and serum testosterone levels were determined. Moreover, tissue samples were collected for the estimation of oxidative stress parameters, inflammatory markers, and the determination of TLR4 /MyD88/NF-kB signaling.
Concurrent PIO administration with CIS markedly improved testicular weights, histopathological alteration, and serum testosterone level changes. Moreover, Concurrent PIO administration abrogated oxidative stress status and inflammatory markers caused by CIS administration. Furthermore, PIO inhibited the expression levels of TLR4, MyD88, and NF-κBp65, proteins that are activated by CIS administration.
These findings suggested that PIO can protect against cisplatin-induced testicular toxicity in rats through inhibition of the TLR4 /MyD88/NF-kB signal pathway.
顺铂（cisplatin，cis）是一种广泛用于治疗多种癌症的化疗药物。它会产生有害的细胞效应，限制其作为抗肿瘤药物的临床应用，如睾丸损伤。吡格列酮（pioglitazone，PIO）是一种过氧化物酶体增殖物激活受体-γ（peroxisome proliferator-activated receptor-gamma，PPAR-γ）激动剂，用于治疗 2 型糖尿病。有报道称，PIO 在不同组织中具有抗炎和抗氧化作用。本研究旨在探讨 PIO 对顺铂诱导的睾丸毒性大鼠模型的影响，并探讨 Toll 样受体（Toll-like receptors，TLR4）/髓样分化因子 88（myeloid differentiation factor 88，MyD88）/核因子-κB（nuclear factor-kappa B，NF-κB）信号通路的可能作用。
大鼠于第 1 天接受单次顺铂（7mg/kg，腹腔注射），第 1 天给予 PIO（10mg/kg，口服）治疗 7 天。治疗期末处死大鼠。测定睾丸重量、组织学改变和血清睾酮水平。此外，收集组织样本以评估氧化应激参数、炎症标志物，并测定 TLR4/MyD88/NF-κB 信号通路。
顺铂联合 PIO 给药显著改善了睾丸重量、组织学改变和血清睾酮水平的变化。此外，顺铂联合 PIO 给药可改善顺铂给药引起的氧化应激状态和炎症标志物。此外，PIO 抑制了 TLR4、MyD88 和 NF-κBp65 的表达水平，这些蛋白是顺铂给药激活的。
这些发现表明，PIO 通过抑制 TLR4/MyD88/NF-κB 信号通路，可防止顺铂诱导的大鼠睾丸毒性。
