Huntington's disease (HD) is characterised by progressive symptoms including cognitive deficits and sleep/wake disturbances reflected in an abnormal electroencephalography (EEG). Modafinil, a wake-promoting and cognitive-enhancing drug, has been considered as a treatment for HD. We used HD (R6/2) mice to investigate the potential for using modafinil to treat sleep-wake disturbance in HD. R6/2 mice show sleep-wake and EEG changes similar to those seen in HD patients, with increased rapid eye movement sleep (REMS), decreased wakefulness/increased non-REMS (NREMS), and pathological changes in EEG spectra, particularly an increase in gamma power. We recorded EEG from R6/2 and wild-type mice treated with modafinil acutely (with single doses between 25 and 100 mg/kg; at 12 and 16 weeks of age), or chronically (64 mg/kg modafinil/day from 6 to 15 weeks). Acutely, modafinil increased wakefulness in R6/2 mice and restored NREMS to wild-type levels at 12 weeks. It also suppressed the pathologically increased REMS. This was accompanied by decreased delta power, increased peak frequency of theta, and increased gamma power. At 16 weeks, acute modafinil also restored wakefulness and NREMS to wild-type levels. However, whilst REMS decreased, it did not return to normal levels. By contrast, in the chronic treatment group, modafinil-induced wakefulness was maintained at 15 weeks (after 9 weeks of treatment). Interestingly, chronic modafinil also caused widespread suppression of power across the EEG spectra, including a reduction in gamma that increases pathologically in R6/2 mice. The complex EEG effects of modafinil in R6/2 mice should provide a baseline for further studies to investigate the translatability of these result to clinical practice.

中文翻译：

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亨廷顿病 R6/2 小鼠模型急性或慢性给药后莫达非尼的唤醒和脑电图频谱效应。


亨廷顿病 (HD) 的特点是进行性症状，包括脑电图 (EEG) 异常所反映的认知缺陷和睡眠/觉醒障碍。莫达非尼是一种促进清醒和增强认知的药物，被认为是治疗 HD 的药物。我们使用 HD (R6/2) 小鼠来研究使用莫达非尼治疗 HD 睡眠觉醒障碍的潜力。 R6/2小鼠表现出与HD患者相似的睡眠-觉醒和脑电图变化，快速眼动睡眠（REMS）增加，觉醒减少/非快速眼动睡眠（NREMS）增加，以及脑电图谱的病理变化，特别是增加在伽马功率。我们记录了 R6/2 和野生型小鼠的脑电图，这些小鼠急性接受莫达非尼治疗（单剂量在 25 至 100 mg/kg 之间；在 12 至 16 周龄），或慢性治疗（64 mg/kg 莫达非尼/天，从 6 至 16 周龄）。 15 周）。莫达非尼迅速增加了 R6/2 小鼠的清醒度，并在 12 周时将 NREMS 恢复至野生型水平。它还抑制了病理性增加的 REMS。这伴随着 delta 功率的降低、theta 峰值频率的增加以及 gamma 功率的增加。第 16 周时，急性莫达非尼也使清醒度和 NREMS 恢复至野生型水平。然而，尽管 REMS 下降，但并未恢复到正常水平。相比之下，在长期治疗组中，莫达非尼诱导的清醒状态维持在 15 周（治疗 9 周后）。有趣的是，长期服用莫达非尼也会导致脑电图频谱功率的广泛抑制，包括 R6/2 小鼠中病理性增加的伽马值减少。莫达非尼对 R6/2 小鼠的复杂脑电图影响应该为进一步研究提供基线，以调查这些结果到临床实践的可转化性。