Department of Pharmacology and Toxicology, College of Pharmacy, Department of Pharmacy Practice, College of Pharmacy, Department of Pharmaceutics, College of Pharmacy, Qassim University, Kingdom of Saudi Arabia.
Eur Rev Med Pharmacol Sci. 2022 Apr;26(7):2353-2362. doi: 10.26355/eurrev_202204_28465.
Chemotherapy can cause cognitive impairment in cancer survivors. CMF, the combination of cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU), is employed for the treatment of several types of cancers, such as metastatic breast cancer. Metformin (MET) is an antidiabetic medication used to treat type 2 diabetes that can reportedly alleviate some toxic effects. In the current study, we investigated the ability of MET to alleviate the effects of CMF in neuronal toxicity.
Rats were treated with two doses of CMF (intraperitoneal injection) and MET (in the daily drinking water). Rats were subjected to fear conditioning memory tests to evaluate memory function following treatment, and brain samples were collected and homogenized using neuronal lysis buffer for assessment of glutamate and dopamine levels by high-performance liquid chromatography (HPLC).
Fear conditioning memory tests revealed a significant reduction in memory function in CMF and CMF+MET groups vs. controls, but no significant change in MET groups vs. controls was detected. Similarly, CMF and CMF+MET groups revealed a significant increase in glutamate and dopamine levels in the brain of MET, CMF, and MET+CMF groups vs. controls based on HPLC results. In addition, although glutamate and dopamine levels were increased, levels varied between groups, with highest levels in the CMF+MET group.
Our results demonstrate that cognitive impairment in CMF and CMF+MET groups could result from increased glutamate and dopamine levels in the brain, leading to brain toxicity and failure of MET to alleviate the toxic effects of CMF.
化疗可能导致癌症幸存者认知功能障碍。CMF（环磷酰胺（CYP）、甲氨蝶呤（MTX）和 5-氟尿嘧啶（5-FU）的联合用药）用于治疗多种类型的癌症，如转移性乳腺癌。二甲双胍（MET）是一种用于治疗 2 型糖尿病的抗糖尿病药物，据报道可减轻一些毒性作用。在本研究中，我们研究了 MET 减轻 CMF 对神经元毒性影响的能力。
大鼠接受两种剂量的 CMF（腹腔注射）和 MET（每日饮用水）治疗。大鼠接受恐惧条件反射记忆测试，以评估治疗后的记忆功能，然后收集大脑样本并使用神经元裂解缓冲液匀浆，通过高效液相色谱（HPLC）评估谷氨酸和多巴胺水平。
恐惧条件反射记忆测试显示，CMF 和 CMF+MET 组的记忆功能明显降低，而 MET 组与对照组相比没有明显变化。同样，根据 HPLC 结果，CMF 和 CMF+MET 组的大脑中的谷氨酸和多巴胺水平显著升高，而 MET、CMF 和 MET+CMF 组的大脑中的谷氨酸和多巴胺水平显著升高。此外，尽管谷氨酸和多巴胺水平升高，但各组之间的水平存在差异，CMF+MET 组的水平最高。
我们的结果表明，CMF 和 CMF+MET 组的认知障碍可能是由于大脑中谷氨酸和多巴胺水平升高所致，导致脑毒性和 MET 未能减轻 CMF 的毒性作用。
