Boyd Leah, Berisha Adrian, Gomez Adrian M, Gibson Erin M, Borniger Jeremy C
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA.
Sleep. 2025 Jul 11;48(7). doi: 10.1093/sleep/zsaf073.
Sleep disruption is common in people with cancer and survivors, but understanding the mechanisms driving these problems is difficult due to heterogeneity among cancers, patients, and treatment modalities. We investigated whether the common antifolate chemotherapeutic agent methotrexate (MTX) promotes changes in sleep independent of cancer in adult mice.
Adult mice (>7 weeks old, both sexes, n = 13) were exposed to either a clinically relevant chemotherapy regimen with methotrexate (n = 7) or saline (control, n = 6) accompanied by continuous EEG/EMG telemetry recording. Sleep states were scored as either wake, non-rapid eye movement (NREM) sleep, or REM sleep in 5-second epochs weekly during MTX or saline treatment and then 2 weeks following the last injection to examine enduring changes in sleep-wake cycles.
MTX exposure caused NREM sleep fragmentation, indicated by (1) shorter and more frequent NREM sleep bouts, (2) more transitions between wake and NREM sleep, and (3) more accumulated NREM sleep bouts over time. These effects were first detected after the second MTX injection and lasted into the 2-week follow-up recording. MTX did not alter delta power in NREM sleep, indicating no changes to sleep quality. The total time spent in each vigilance state remained unaffected by MTX use. Finally, when given MTX, male mice displayed more fragmented sleep compared to female mice.
Methotrexate promotes NREM sleep fragmentation, without affecting sleep quality or time spent asleep. This effect is stronger in males. These data suggest that chemotherapy can cause long-term sleep disruption independent of cancer presence.
睡眠中断在癌症患者及其幸存者中很常见，但由于癌症、患者和治疗方式的异质性，了解导致这些问题的机制很困难。我们研究了常见的抗叶酸化疗药物甲氨蝶呤（MTX）是否会在成年小鼠中促进独立于癌症的睡眠变化。
成年小鼠（>7周龄，雌雄均有，n = 13）接受与临床相关的甲氨蝶呤化疗方案（n = 7）或生理盐水（对照组，n = 6），同时进行连续的脑电图/肌电图遥测记录。在MTX或生理盐水治疗期间，每周以5秒为一个时间段对睡眠状态进行评分，分为清醒、非快速眼动（NREM）睡眠或快速眼动（REM）睡眠，然后在最后一次注射后2周，以检查睡眠-觉醒周期的持久变化。
MTX暴露导致NREM睡眠碎片化，表现为：（1）NREM睡眠时段更短且更频繁；（2）清醒和NREM睡眠之间的转换更多；（3）随着时间的推移，累积的NREM睡眠时段更多。这些影响在第二次MTX注射后首次被检测到，并持续到2周的随访记录中。MTX并未改变NREM睡眠中的δ波功率，表明睡眠质量没有变化。每种警觉状态下花费的总时间不受MTX使用的影响。最后，给予MTX时，雄性小鼠的睡眠碎片化程度比雌性小鼠更高。
甲氨蝶呤促进NREM睡眠碎片化，而不影响睡眠质量或睡眠时间。这种影响在雄性中更强。这些数据表明，化疗可导致独立于癌症存在的长期睡眠中断。
