Rolipram rescues memory consolidation deficits caused by sleep deprivation: Implication of the cAMP/PKA and cAMP/Epac pathways

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.