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 overactivation of phosphodiesterase (PDEs) enzymes. PDE4, a nonredundant 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-β (Aβ), 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 downregulated PDE4B and Aβ 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 PDE4Bmediated cAMP/CREB/BDNF signaling cascade.

Development of White Cabbage, Coffee, and Red Onion Extracts as Natural Phosphodiesterase-4B (PDE4B) Inhibitors for Cognitive Dysfunction: In Vitro and In Silico Studies

“…Phosphodiesterase-4 (PDE4), the largest family of PDE, is the most complicated and maybe the most broadly expressed PDE in the body [ 11 ], and it particularly hydrolyzes cAMP into its inactive form, 5-AMP [ 12 ]. Phosphodiesterase-4B (PDE4B) is strongly expressed in the cornu ammonis 2 and cornu ammonis 3 areas of the hippocampus, the cerebellar granular layer, piriform, and parietal cortex [ 13 ]. The continuous rise in the production of PDE4 has been observed in the brains of AD patients, specifically those with hippocampal dysfunction and cognitive impairment [ 14 – 16 ].…”

Resveratrol prevents cognitive deficits induced by sleep deprivation via modulating sirtuin 1 associated pathways in the hippocampus

“…It showed that rodents exposed to sleep deprivation through the gentle stimulation, activity wheel, or modified multiple platform methods exhibited memory impairment in several behavioral tasks, such as the Y maze test, the novel object recognition test, and the Morris water maze test. [10][11][12] The hippocampus is a crucial region of the brain related to learning and memory and is vulnerable to sleep deprivation. Hippocampal neuroinflammation can be linked to cognitive impairment in certain pathological conditions, including sepsis, neuropsychiatric disorders, and neurodegenerative diseases.…”

PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson’s disease in rats

“…Roflumilast is established to be brain penetrant targeting PDE4 sites in the cortico-striatal-thalamic circuitry including the nigral area (Vanmierlo et al 2016 ; Heckman et al 2018 ). Furthermore, roflumilast has been proposed as a favorable candidate for the treatment of neurological disorders such as Alzheimer’s disease, cerebral ischemia, sleep deprivation-induced cognitive deficits, and depression via improving neuroinflammation, memory, and cognition (Wang et al 2020a ; Vilhena et al 2021 ; Bhat et al 2022 ; Zaki et al 2023 ). Recently, Desouky et al ( 2023 ) illustrated that roflumilast is capable of prompting proteasomal degradation of detrimental α-Syn deposits in PD animal model.…”