Sleep deprivation interferes with long-term memory and cognitive functions by over-activation of phosphodiesterase (PDE) enzymes. PDE4 is a non-redundant regulator of the cyclic nucleotides (cAMP), is densely expressed in the hippocampus, and is involved in learning and memory processes. In the present study, we investigated the effects of Roflumilast (ROF), a PDE4 inhibitor, on sleep deprivation induced cognitive dysfunction in a mouse model. Memory assessment was performed using a novel object recognition task and the cAMP level was estimated by ELISA. The alterations in the expressions of PDE4B, amyloid beta, CREB, BDNF, and synaptic proteins (Synapsin I, SAP 97, PSD 95) were assessed to gain insights on the possible mechanisms of action of ROF using the western blot technique. Results show that ROF reverse SD induced cognitive decline in mice. ROF down-regulated PDE4B and amyloid beta expressions. Additionally, ROF improved cAMP levels and the expressions of synapsin I, SAP 97, and PSD 95 in the hippocampal region of SD mice. Taken together, these results suggest that ROF can suppress the deleterious effects of SD-induced cognitive dysfunction via PDE4-mediated cAMP/CREB/BDNF cascade. Highlights{blacksquare} Sleep deprivation (SD) impaired recognition memory in mice. {blacksquare}SD increased PDE4B, amyloid-beta (A{beta}), and reduced cAMP, pCREB, BDNF, and synaptic proteins (Synapsin I, SAP 97, PSD 95) expression. {blacksquare}Treatment with Roflumilast improved memory and decreased A{beta} pathology in sleep-deprived mice. {blacksquare}Increased in cAMP level correlates with improved expression of synaptic proteins and memory
