Enduring non-rapid eye movement sleep fragmentation following methotrexate chemotherapy in cancer-naïve mice
Leah Boyd1, Adrian Berisha1, Adrian M Gomez1
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Study Objectives:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Chemotherapy drug methotrexate (MTX) fragments non-rapid eye movement sleep in mice, independent of cancer. This sleep disruption, particularly in males, persists after treatment, suggesting a chemotherapy side effect.
Area of Science:
- Neuroscience
- Pharmacology
- Sleep Medicine
Background:
- Sleep disruption is a prevalent issue for cancer patients and survivors.
- The underlying mechanisms are complex due to variations in cancer type, patient factors, and treatments.
- Investigating specific chemotherapeutic agents can elucidate independent effects on sleep.
Purpose of the Study:
- To determine if methotrexate (MTX), a common antifolate chemotherapy, alters sleep patterns in adult mice.
- To assess whether MTX-induced sleep changes occur independently of cancer presence.
- To evaluate the duration of any observed sleep alterations.
Main Methods:
- Adult male and female mice received either MTX or saline (control) via chemotherapy regimen.
- Continuous electroencephalography (EEG) and electromyography (EMG) telemetry monitored sleep states (wake, NREM, REM).
- Sleep was analyzed weekly during treatment and for two weeks post-treatment to track changes.
Main Results:
- Methotrexate induced NREM sleep fragmentation, characterized by shorter, more frequent NREM bouts and increased wake-NREM transitions.
- These fragmentation effects emerged after the second MTX dose and persisted into the follow-up period.
- No changes in NREM sleep delta power (sleep quality) or total time in vigilance states were observed; male mice showed greater fragmentation than females.
Conclusions:
- Methotrexate administration leads to NREM sleep fragmentation in mice, independent of cancer.
- This fragmentation does not impact overall sleep quality or duration but is more pronounced in males.
- The findings suggest that chemotherapy agents like MTX can be a source of long-term sleep disruption in patients.
