Dorcas Aremu Teminijesu, Ramírez Ortega Daniela, Blanco Ayala Tonali, González Esquivel Dinora Fabiola, Pineda Benjamín, Pérez de la Cruz Gonzalo, Salazar Alelí, Flores Itamar, Meza-Sosa Karla F, Sánchez Chapul Laura, Rangel-López Edgar, Gómez-Manzo Saúl, Márquez Navarro Adrián, Roldán Roldán Gabriel, Pérez de la Cruz Verónica
Doctorado en Ciencias Biológicas, Centro Tlaxcala Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala 90070, Mexico.
Neurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico.
Cells. 2024 Dec 2;13(23):1989. doi: 10.3390/cells13231989.
Cisplatin (CIS) is a potent chemotherapeutic agent primarily used to treat hematologic malignancies and solid tumors, including lymphomas, sarcomas, and some carcinomas. Patients receiving this treatment for tumors outside the nervous system develop cognitive impairment. Alterations in the kynurenine pathway (KP) following CIS treatment suggest that certain KP metabolites may cross the blood-brain barrier, leading to increased production of the neuromodulator kynurenic acid (KYNA), which is associated with cognitive impairment. This study aimed to evaluate the effects of modulating brain KYNA levels by the administration of N-acetylcysteine (NAC), an inhibitor of kynurenine aminotransferase II (KATII), an enzyme responsible for KYNA biosynthesis on the cognitive and neuromuscular deficits induced by CIS. Female Wistar rats were divided into four groups: control, NAC (300 mg/day/8 days), CIS (3 mg/kg i.p/5 days), and NAC + CIS (both treatments co-administered in parallel). Seven days after the last CIS administration, cognitive performance, muscle strength, brain KYNA levels, KATII activity, and brain tissue redox profile (lipid peroxidation and oxidized/reduced glutathione (GSH/GSSG) ratio) were assessed. CIS did not affect short-term memory but induced long-term memory deficits and reduced muscle strength, effects which were prevented by NAC co-administration. CIS decreased the GSH/GSSG ratio and the number of cells in the brain cortex while it increased lipid peroxidation, KYNA levels, and marginal KATII activity. All these effects were attenuated by the co-administration of NAC. These findings suggest that NAC mitigates the side effects of CIS, such as chemo-brain and muscle weakness, by improving the redox imbalance and modulating KYNA levels by limiting its non-enzymatic production by reactive oxygen species (ROS).
顺铂（CIS）是一种强效化疗药物，主要用于治疗血液系统恶性肿瘤和实体瘤，包括淋巴瘤、肉瘤和一些 carcinomas。接受这种治疗非神经系统肿瘤的患者会出现认知障碍。顺铂治疗后犬尿氨酸途径（KP）的改变表明，某些 KP 代谢产物可能穿过血脑屏障，导致神经调节剂犬尿喹啉酸（KYNA）的产生增加，这与认知障碍有关。本研究旨在评估通过给予 N-乙酰半胱氨酸（NAC）来调节脑 KYNA 水平的效果，N-乙酰半胱氨酸是犬尿氨酸转氨酶 II（KATII）的抑制剂，KATII 是一种负责 KYNA 生物合成的酶，对顺铂诱导的认知和神经肌肉缺陷的影响。雌性 Wistar 大鼠分为四组：对照组、NAC（300mg/天/8 天）、顺铂（3mg/kg 腹腔注射/5 天）和 NAC + 顺铂（两种治疗并行联合给药）。最后一次顺铂给药后 7 天，评估认知能力、肌肉力量、脑 KYNA 水平、KATII 活性和脑组织氧化还原状态（脂质过氧化和氧化型/还原型谷胱甘肽（GSH/GSSG）比值）。顺铂不影响短期记忆，但会导致长期记忆缺陷并降低肌肉力量，NAC 联合给药可预防这些影响。顺铂降低了 GSH/GSSG 比值和大脑皮层中的细胞数量，同时增加了脂质过氧化、KYNA 水平和边缘 KATII 活性。NAC 联合给药减轻了所有这些影响。这些发现表明，NAC 通过改善氧化还原失衡并通过限制活性氧（ROS）的非酶促产生来调节 KYNA 水平，从而减轻顺铂的副作用，如化疗脑和肌肉无力。
