Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui Province Key Laboratory of R&D of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, China.
Br J Pharmacol. 2019 May;176(9):1282-1297. doi: 10.1111/bph.14626. Epub 2019 Apr 2.
Sleep deprivation compromises learning and memory in both humans and animals, and can be reversed by administration of modafinil, a drug promoting wakefulness. Dysfunctional autophagy increases activation of apoptotic cascades, ultimately leading to increased neuronal death, which can be alleviated by autophagy inhibitors. This study aimed to investigate the alleviative effect and mechanism of modafinil on the excessive autophagy occurring in the hippocampus of mice with deficiency of learning and memory induced by sleep deprivation.
The Morris water maze was used to assess the effects of modafinil on male C57BL/6Slac mice after 48-hr sleep deprivation. The HT-22 hippocampal neuronal cell line was also used. Nissl staining, transmission electron microscope, immunofluorescence, Western blot, transient transfection, and autophagy inducer were used to study the effect and mechanism of modafinil on hippocampal neurons with excessive autophagy and apoptosis.
Modafinil improved learning and memory in sleep-deprived mice, associated with the inhibition of excessive autophage and apoptosis and an enhanced activation of the PI3K/Akt/mTOR/P70S6K signalling pathway in hippocampal neurons. These effects of modafinil were abolished by rapamycin. In addition, modafinil suppressed the aberrant autophagy and apoptosis induced by rapamycin and reactivated PI3K/Akt/mTOR/P70S6K signals in HT-22 cells.
These results suggested that modafinil alleviated impaired learning and memory of sleep-deprived mice potentially by suppressing excessive autophagy and apoptosis of hippocampal neurons. This novel mechanism may add to our knowledge of modafinil in the clinical treatment of impaired memory caused by sleep loss.
睡眠剥夺会损害人类和动物的学习和记忆能力，而通过促进觉醒的药物莫达非尼进行治疗可以逆转这种损害。功能失调的自噬会增加凋亡级联的激活，最终导致神经元死亡增加，而自噬抑制剂可以减轻这种情况。本研究旨在探讨莫达非尼对睡眠剥夺引起的学习和记忆缺陷小鼠海马过度自噬的缓解作用及其机制。
使用 Morris 水迷宫评估莫达非尼对睡眠剥夺 48 小时后的雄性 C57BL/6Slac 小鼠的影响。还使用了 HT-22 海马神经元细胞系。使用尼氏染色、透射电镜、免疫荧光、Western blot、瞬时转染和自噬诱导剂来研究莫达非尼对过度自噬和凋亡的海马神经元的作用及其机制。
莫达非尼改善了睡眠剥夺小鼠的学习和记忆能力，这与抑制过度自噬和凋亡以及增强海马神经元中 PI3K/Akt/mTOR/P70S6K 信号通路的激活有关。这些莫达非尼的作用被雷帕霉素所消除。此外，莫达非尼抑制了雷帕霉素诱导的异常自噬和凋亡，并重新激活了 HT-22 细胞中的 PI3K/Akt/mTOR/P70S6K 信号。
这些结果表明，莫达非尼通过抑制海马神经元的过度自噬和凋亡，缓解了睡眠剥夺小鼠受损的学习和记忆能力。这一新的机制可能为我们了解莫达非尼在治疗因睡眠不足导致的记忆受损方面的临床应用提供新的认识。
