Roflumilast, a Phosphodiesterase-4 Inhibitor, Ameliorates Sleep Deprivation-Induced Cognitive Dysfunction in C57BL/6J Mice

Abstract

Sleep deprivation (SD) interferes with long-term memory and cognitive functions by over-activation of phosphodiesterase (PDEs) enzymes. PDE4, 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 PDE4B inhibitor, on sleep deprivation induced cognitive dysfunction in a mouse model. Memory assessment was performed using a novel object recognition task and the hippocampal cAMP level was estimated by the ELISA method. The alterations in the expressions of PDE4B, amyloid-beta (A{beta}), CREB, BDNF, and synaptic proteins (Synapsin I, SAP 97, PSD 95) were assessed to gain insights into the possible mechanisms of action of ROF using the Western blot technique. Results show that ROF reversed SD induced cognitive decline in mice. ROF down-regulated PDE4B and A{beta} expressions in the brain. Additionally, ROF improved the cAMP level and the protein 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 the PDE4B-mediated cAMP/CREB/BDNF signaling cascade.