Chemotherapy-induced cognitive impairment in cancer patients is known as "chemobrain". Doxorubicin and Cyclophosphamide are two chemotherapeutic agents used in combination to treat solid tumors. L-carnitine was reported for its anti-oxidant and anti-inflammatory activities. The goal of the present study was to elucidate the neuroprotective effect of L-carnitine against chemobrain induced by Doxorubicin and Cyclophosphamide in rats. Rats were divided into five groups: Control group; Doxorubicin (4mg/kg, IV) and Cyclophosphamide (40mg/kg, IV)-treated group; two L-carnitine-treated groups (150 and 300mg/kg, ip) with Doxorubicin and Cyclophosphamide; and L-carnitine alone-treated group (300mg/kg). Doxorubicin and Cyclophosphamide induced histopathological changes in rats’ hippocampi and prefrontal cortices, as well as reduced memory as evidenced by behavioural testing. L-carnitine treatment showed opposite effects. In addition, chemotherapy treatment enhanced oxidative stress via reducing catalase and glutathione levels, and inducing lipid peroxidation. By contrast, L-carnitine treatment showed powerful antioxidant effects reversing chemotherapy-induced oxidative damage. Moreover, chemotherapy combination induced inflammation via their effect on nuclear factor kappa B (p65), interleukin-1β, and tumor necrosis factor-α. However, L-carnitine treatment corrected such inflammatory responses. Furthermore, Doxorubicin and Cyclophosphamide reduced synaptic plasticity via hindering expression of brain-derived neurotrophic factor, phosphorylated cyclase response element binding protein, synaptophysin, and postsynaptic density protein 95 whereas protein expression of such synaptic plasticity biomarkers was enhanced by L-carnitine treatment. Finally, acetylcholinesterase activity was found to be enhanced by chemotherapy treatment affecting rats’ memory while L-carnitine treatment reduced acetylcholinesterase activity. L-carnitine also showed hepatoprotective and renal protective effects suggesting liver/brain and kidney/brain axes as possible mechanisms for its neuroprotective effects.

Graphical Abstract

中文翻译：

---

左旋肉碱调节阿霉素和环磷酰胺引起的大鼠认知障碍；对氧化应激、炎症、突触可塑性、肝/脑和肾/脑轴的见解

癌症患者化疗引起的认知障碍被称为“化疗脑”。阿霉素和环磷酰胺是两种联合使用治疗实体瘤的化疗药物。据报道，左旋肉碱具有抗氧化和抗炎活性。本研究的目的是阐明左旋肉碱对阿霉素和环磷酰胺诱导的大鼠趋化脑的神经保护作用。将大鼠分为五组：对照组；阿霉素(4mg/kg，IV)和环磷酰胺(40mg/kg，IV)治疗组；两个左旋肉碱治疗组（150 和 300mg/kg，腹腔注射），使用阿霉素和环磷酰胺；和单独左旋肉碱治疗组（300mg/kg）。阿霉素和环磷酰胺引起大鼠海马和前额皮质的组织病理学变化，以及行为测试所证明的记忆力下降。左旋肉碱治疗显示出相反的效果。此外，化疗通过降低过氧化氢酶和谷胱甘肽水平并诱导脂质过氧化来增强氧化应激。相比之下，左旋肉碱治疗显示出强大的抗氧化作用，可以逆转化疗引起的氧化损伤。此外，化疗组合通过对核因子 kappa B (p65)、白介素-1β 和肿瘤坏死因子-α 的影响而诱导炎症。然而，左旋肉碱治疗纠正了这种炎症反应。此外，阿霉素和环磷酰胺通过阻碍脑源性神经营养因子、磷酸化环化酶反应元件结合蛋白、突触素和突触后密度蛋白 95 的表达来降低突触可塑性，而左旋肉碱治疗可增强此类突触可塑性生物标志物的蛋白质表达。最后，发现化疗治疗影响大鼠的记忆，从而增强乙酰胆碱酯酶活性，而左旋肉碱治疗则降低乙酰胆碱酯酶活性。左旋肉碱还表现出肝保护和肾保护作用，表明肝/脑和肾/脑轴是其神经保护作用的可能机制。

图形概要