Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Kingdom of Saudi Arabia.
Eur Rev Med Pharmacol Sci. 2022 Feb;26(3):743-749. doi: 10.26355/eurrev_202202_27981.
Chemotherapy causes long-term cognitive impairment in cancer survivors. A combination of cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU) (i.e., CMF) is widely used for cancer treatment. Metformin (MET), an oral antidiabetic drug, confers protection against the adverse effects of chemotherapeutic agents, such as CYP. To elucidate the potential mechanism underlying cognitive dysfunction, we investigated the impact of CMF and MET treatment on the activities of mitochondrial respiratory chain complexes I and IV, as well as lipid peroxidation, in hippocampal neurons.
Hippocampal neurons (H19-7) cells were treated for 24 h with MET (0.5 mM) alone; CYP (1 µM), MTX (0.5 µM), and 5-FU (1 µM); and MET (0.5 mM) + CYP (1 µM), MTX (0.5 mM), and 5-FU (1 µM). A 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay was performed to evaluate cell survival. Neurons were collected and homogenized in a neuronal lysis buffer to assess mitochondrial complexes (I and IV) activity and lipid peroxidation.
Compared to the control, MET-treated cells showed no significant difference in survival rate; however, CMF- and CMF + MET-treated cells showed a significant reduction in survival rate. In addition, relative to the control, CMF- and CMF + MET-treated cells showed a reduction in mitochondrial complex I activity, whereas no significant changes were observed in mitochondrial complex IV activity. MET-treated cells showed no significant differences in lipid peroxidation, but CMF- and CMF + MET-treated cells showed a slight increase in lipid peroxidation.
The reduction in the activity of mitochondrial complex I and a slight increase in lipid peroxidation levels may explain the cognitive impairment following CMF and MET treatments.
化疗会导致癌症幸存者出现长期认知障碍。环磷酰胺（CYP）、甲氨蝶呤（MTX）和 5-氟尿嘧啶（5-FU）（即 CMF）的联合应用广泛用于癌症治疗。二甲双胍（MET）是一种口服降糖药，可预防 CYP 等化疗药物的不良影响。为了阐明认知功能障碍的潜在机制，我们研究了 CMF 和 MET 治疗对海马神经元中线粒体呼吸链复合物 I 和 IV 活性以及脂质过氧化的影响。
用 MET（0.5mM）单独；CYP（1µM）、MTX（0.5µM）和 5-FU（1µM）；以及 MET（0.5mM）+CYP（1µM）、MTX（0.5mM）和 5-FU（1µM）处理海马神经元（H19-7）细胞 24 小时。通过 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐测定法评估细胞存活率。收集神经元并在神经元裂解缓冲液中匀浆以评估线粒体复合物（I 和 IV）活性和脂质过氧化。
与对照组相比，MET 处理的细胞存活率无显著差异；然而，CMF 和 CMF+MET 处理的细胞存活率显著降低。此外，与对照组相比，CMF 和 CMF+MET 处理的细胞线粒体复合物 I 活性降低，而线粒体复合物 IV 活性无显著变化。MET 处理的细胞脂质过氧化无显著差异，但 CMF 和 CMF+MET 处理的细胞脂质过氧化略有增加。
线粒体复合物 I 活性降低和脂质过氧化水平略有增加可能解释了 CMF 和 MET 治疗后认知障碍的发生。
