Cancer Research and Molecular Biology Laboratory, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan, 200005, Oyo, Nigeria.
Neurochem Res. 2023 Sep;48(9):2767-2783. doi: 10.1007/s11064-023-03941-9. Epub 2023 Apr 25.
Epirubicin's (EPI) efficacy as a chemotherapeutic agent against breast cancer is limited by EPI's neurotoxicity associated with increased oxidative and inflammatory stressors. 3-Indolepropionic acid (3-IPA) derived from in vivo metabolism of tryptophan is reported to possess antioxidative properties devoid of pro-oxidant activity. In this regard, we investigated the effect of 3-IPA on EPI-mediated neurotoxicity in forty female rats (180-200 g; five cohorts (n = 6) treated as follows: Untreated control; EPI alone (2.5 mg/Kg); 3-IPA alone (40 mg/Kg body weight); EPI (2.5 mg/Kg) + 3-IPA (20 mg/Kg) and EPI (2.5 mg/Kg) + 3-IPA (40 mg/Kg) for 28 days. Experimental rats were treated with EPI via intraperitoneal injection thrice weekly or co-treated with 3-IPA daily by gavage. Subsequently, the rat's locomotor activities were measured as endpoints of neurobehavioural status. After sacrifice, inflammation, oxidative stress and DNA damage biomarkers were assessed in rats' cerebrum and cerebellum alongside histopathology. Our results demonstrated that locomotor and exploratory deficits were pronounced in EPI-alone treated rats and improved in the presence of 3-IPA co-treatment. EPI-mediated decreases in tissue antioxidant status, increases in reactive oxygen and nitrogen species (RONS), as well as in lipid peroxidation (LPO) and xanthine oxidase (XO) were lessened in the cerebrum and cerebellum of 3-IPA co-treated rats. Increases in nitric oxide (NO) and 8-hydroxydeguanosin (8-OHdG) levels and myeloperoxidase MPO activity were also abated by 3-IPA. Light microscopic examination of the cerebrum and cerebellum revealed EPI-precipitated histopathological lesions were subsequently alleviated in rats co-treated with 3-IPA. Our findings demonstrate that supplementing endogenously derived 3-IPA from tryptophan metabolism enhances tissue antioxidant status, protects against EPI-mediated neuronal toxicity, and improves neurobehavioural and cognitive levels in experimental rats. These findings may benefit breast cancer patients undergoing Epirubicin chemotherapy.
表柔比星（EPI）作为一种治疗乳腺癌的化疗药物的疗效受到与其相关的氧化和炎症应激增加的神经毒性的限制。3-吲哚丙酸（3-IPA）是色氨酸体内代谢的产物，据报道具有抗氧化特性而没有促氧化剂活性。在这方面，我们研究了 3-IPA 对四十只雌性大鼠（180-200g；五组（n=6）的 EPI 介导的神经毒性的影响：未处理的对照组；EPI 单独（2.5mg/Kg）；3-IPA 单独（40mg/Kg 体重）；EPI（2.5mg/Kg）+3-IPA（20mg/Kg）和 EPI（2.5mg/Kg）+3-IPA（40mg/Kg），治疗 28 天。实验大鼠通过腹腔注射每周三次给予 EPI，或通过灌胃每天给予 3-IPA 进行联合治疗。随后，作为神经行为状态的终点，测量大鼠的运动活动。处死大鼠后，评估其大脑和小脑中的炎症、氧化应激和 DNA 损伤生物标志物，以及组织病理学。我们的结果表明，EPI 单独治疗的大鼠运动和探索能力明显受损，而在 3-IPA 联合治疗的情况下有所改善。EPI 介导的组织抗氧化状态降低、活性氧和氮物种（RONS）增加、脂质过氧化（LPO）和黄嘌呤氧化酶（XO）增加，在 3-IPA 联合治疗的大鼠大脑和小脑中减轻。一氧化氮（NO）和 8-羟基鸟嘌呤（8-OHdG）水平增加以及髓过氧化物酶（MPO）活性也被 3-IPA 抑制。大脑和小脑的光镜检查显示，EPI 引发的组织病理学损伤随后在 3-IPA 联合治疗的大鼠中得到缓解。我们的研究结果表明，从色氨酸代谢中补充内源性的 3-IPA 可增强组织抗氧化状态，防止 EPI 介导的神经元毒性，并提高实验大鼠的神经行为和认知水平。这些发现可能有益于接受表柔比星化疗的乳腺癌患者。
