Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, Kingdom of Saudi Arabia.
Eur Rev Med Pharmacol Sci. 2021 Jun;25(12):4385-4393. doi: 10.26355/eurrev_202106_26148.
Cyclophosphamide (CYP), methotrexate (MTX) and 5-fluorouracil (5-FU) (CMF) are chemotherapeutic agents known to cause acute and long-term cognitive impairment in cancer patients. Cognitive function is regulated mainly by neuronal circuitry in the brain, especially the cortex and hippocampus as well as other components of the limbic area. Neuroinflammation mediated by proinflammatory cytokines is a well-known cause of cognitive impairment. Our previous study showed that metformin induced cognitive impairment and neuroinflammation in CMF-treated rats. Understanding the effects and mechanisms of CMF and MET treatment on chemotherapy-related cognitive impairment and the relationship with neuroinflammation may help prevent some of the adverse effects of this type of chemotherapy in cancer patients.
Rats were divided into four groups: control (normal saline), CMF (50 mg/kg CYP, 2 mg/kg MTX, 50 mg/kg 5-FU; two doses administered by intraperitoneal injection over two weeks), MET (2.5 mg/ml - oral administration daily), and CMF+MET group. IL-1α, IRS-1, Akt-a and TNF-α levels in brain tissues were measured by ELISA and data were analyzed by one-way ANOVA test followed by Tukey's test.
Compared with the control group, IL-1α levels were significantly increased in the CMF+MET group, whereas there were no significant differences in the MET and CMF groups. On the other hand, IRS-1, TNF-α and Akt-a expression and mitochondrial complex 1 activity indicated that systemic CMF and MET treatment did not change the expression of these proteins in the brain compared to the control group.
Our results indicate that cognitive function is impaired by the administration of two doses of CMF and MET over a period of two weeks as a result of IL-1α overexpression in the brain.
环磷酰胺（CYP）、甲氨蝶呤（MTX）和 5-氟尿嘧啶（5-FU）（CMF）是已知会导致癌症患者出现急性和长期认知障碍的化疗药物。认知功能主要由大脑中的神经元回路调节，尤其是大脑皮层和海马体以及边缘区域的其他成分。由促炎细胞因子介导的神经炎症是认知障碍的已知原因。我们之前的研究表明，二甲双胍会在 CMF 治疗的大鼠中引起认知障碍和神经炎症。了解 CMF 和 MET 治疗对化疗相关认知障碍的影响和机制，以及与神经炎症的关系，可能有助于预防癌症患者接受此类化疗的一些不良反应。
大鼠分为四组：对照组（生理盐水）、CMF 组（50mg/kg CYP、2mg/kg MTX、50mg/kg 5-FU；两周内通过腹腔注射给予两剂）、MET 组（2.5mg/ml-每日口服）和 CMF+MET 组。通过 ELISA 测量脑组织中 IL-1α、IRS-1、Akt-a 和 TNF-α 的水平，并通过单因素方差分析检验 followed by Tukey's 检验进行数据分析。
与对照组相比，CMF+MET 组的 IL-1α 水平显著升高，而 MET 组和 CMF 组则没有显著差异。另一方面，IRS-1、TNF-α 和 Akt-a 的表达和线粒体复合物 1 活性表明，与对照组相比，全身 CMF 和 MET 治疗并未改变这些蛋白质在大脑中的表达。
我们的结果表明，由于大脑中 IL-1α 的过度表达，两周内给予两剂 CMF 和 MET 会导致认知功能受损。
