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CNS & Neurological Disorders - Drug Targets

Author(s): Ahmed Maher, Nesrine El Sayed *, Heba Nafea and Mohamed Gad

DOI: 10.2174/1871527320666210816105144

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Rolipram Rescues Memory Consolidation Deficits Caused by Sleep Deprivation: Implication of the cAMP/PKA and cAMP/Epac Pathways

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Abstract

Background: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusion: The present study provides evidence that restoration of memory with PDE4 inhibitors occurs through a dual mechanism involving the PKA and Epac pathways.

Keywords: Sleep deprivation, cAMP, Nrf-2, rolipram, chlorogenic acid, Epac.

Graphical Abstract

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