Maher Ahmed, El Sayed Nesrine, Nafea Heba, Gad Mohamed
Biochemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
CNS Neurol Disord Drug Targets. 2022;21(7):631-639. doi: 10.2174/1871527320666210816105144.
Over the last few years, the number of people suffering from sleeping disorders has increased significantly despite negative effects on cognition and an association with brain inflammation.
We assessed memory deficits caused by Sleep Deprivation (SD) to determine the therapeutic effect of phosphodiesterase 4 (PDE4) inhibitors on SD-induced memory deficits and to investigate whether the modulation of memory deficits by PDE4 inhibitors is mediated by a protein kinase A (PKA)-independent pathway in conjunction with a PKA-dependent pathway.
Adult male mice were divided into four groups. Three SD groups were deprived of Rapid Eye Movement (REM) sleep for 12 h a day for six consecutive days. They were tested daily in the Morris water maze to evaluate learning and memory. One of the SD groups was injected with a PDE4 inhibitor, rolipram (1 mg/kg ip), whereas another had rolipram co-administered with chlorogenic acid (CHA, 20 mg/kg ip), an inhibitor of PKA. After 6 days, the mice were sacrificed, and the hippocampi were evaluated for cyclic AMP (cAMP) and nuclear factor Nrf-2 levels. The hippocampal expression of PKA, phosphorylated cAMP Response Element-Binding Protein (CREB), and phosphorylated glycogen synthase 3β (Ser389) were also evaluated.
SD caused a significant decrease in cAMP levels in the brain and had a detrimental effect on learning and memory. The administration of rolipram or rolipram+CHA resulted in an improvement in cognitive function.
The present study provides evidence that restoration of memory with PDE4 inhibitors occurs through a dual mechanism involving the PKA and Epac pathways.
在过去几年中，尽管睡眠障碍对认知有负面影响且与脑部炎症有关联，但患有睡眠障碍的人数仍显著增加。
我们评估了睡眠剥夺（SD）引起的记忆缺陷，以确定磷酸二酯酶4（PDE4）抑制剂对SD诱导的记忆缺陷的治疗效果，并研究PDE4抑制剂对记忆缺陷的调节是否通过与蛋白激酶A（PKA）依赖性途径相结合的PKA非依赖性途径介导。
成年雄性小鼠分为四组。三个SD组连续六天每天剥夺快速眼动（REM）睡眠12小时。每天在莫里斯水迷宫中对它们进行测试，以评估学习和记忆能力。其中一个SD组注射PDE4抑制剂咯利普兰（1毫克/千克腹腔注射），而另一个组将咯利普兰与PKA抑制剂绿原酸（CHA，20毫克/千克腹腔注射）联合给药。6天后，处死小鼠，评估海马体中的环磷酸腺苷（cAMP）和核因子Nrf-2水平。还评估了海马体中PKA、磷酸化的环磷酸腺苷反应元件结合蛋白（CREB）和磷酸化的糖原合酶3β（Ser389）的表达。
SD导致大脑中cAMP水平显著降低，并对学习和记忆产生有害影响。给予咯利普兰或咯利普兰+CHA可改善认知功能。
本研究提供了证据，表明PDE4抑制剂通过涉及PKA和Epac途径的双重机制恢复记忆。
