Side Effects of Sleep Deprivation Improved by Roflumilast a Phosphodiesterase-4-Inhibitor

Sleep has a regulatory role in cellular and metabolic balance. Deprivation of sleep harms social and biological well-being. For example, sleep deprivation (SD) significantly impairs hippocampus function and alters memory. It predisposes neuronal amyloid-beta buildup in the brain linked to increased amyloid deposition in the brain.



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It impairs neurogenesis and protein expression of neurotrophic factors like CREB and BDNF. The neurotrophic factors are vital regulators of learning and memory. Regulation of these factors links to hippocampus atrophy.

Phosphodiesterases (PDEs) are a varied group of enzymes that play a role in intracellular signaling regulation. PDE4 isomers are found in the brain.

The effects of Roflumilast (ROF), a PDE4B inhibitor, on sleep deprivation-induced cognitive impairment in a mouse model was the subject of a study.

PDE4 inhibition leads to better cognitive outcome

Increased production of PDE4 enzymes hydrolyzes cAMP into its inactive form 5-AMP, which is present in the hippocampal region of SD mice, in the brains of Alzheimer’s disease (AD) patients, and those with cognitive impairment.

In a mouse model, inhibiting levels of PDE4 improved learning and memory by boosting hippocampus cAMP levels. Furthermore, inhibiting PDE4 has corrected synaptic protein deficiencies such as synaptophysin. In rat models, PDE4 inhibition reversed the cognitive impairment caused by muscarinic receptor antagonists and modified NMDA receptor-mediated transmission processes. Although NMDA does not directly alter PDE4 expression, the balance between PDE4 and NMDA-mediated adenylyl cyclase is crucial in memory. As a result, numerous reports suggest that PDE4s could be a therapeutic target for neurological diseases.

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The USFDA has approved Roflumilast (ROF), a cAMP-specific PDE4B inhibitor, for use in chronic obstructive pulmonary disease (COPD). At non-emetic doses, ROF boosts hippocampus neuron viability and improves memory in rodents and monkeys. A clinical investigation discovered that giving healthy people ROF for three days increases their learning and memory. Long-term SD results in an AD-like pathogenic state, with more neuronal accumulations, lower cAMP levels, and lower synaptic protein expressions.

The current study shows that ROF via PDE4B inhibition alleviates amyloid pathology, cAMP signaling, and synaptic protein expression, which is the fundamental mechanism in cognitive restoration in SD mice.

In an AD transgenic mouse model, SD increases amyloid plaque levels. Chronic sleep restriction (3 hours per day for five days per week, for four weeks) increases the hippocampus buildup of amyloid-beta plaques in mice brains, according to a recent study, which leads to cognitive decline. Inflammatory reactions, synaptic dysfunctions, and neuronal death are all triggered by deposition in cortical and hippocampal areas. Amyloid-beta also disrupts cAMP-response element-binding protein (CREBP) transmission in neurons. Scientists in the study imply that neuronal damage in SD occurs by multifactorial combination.

Clinical significance

In SD mice brains, increased PDE4B and amyloid-beta expression were found, along with a substantial drop in cAMP levels. In SD mice, ROF treatment corrected molecular alterations such as amyloid-beta pathology and enhanced cognitive performance, which links to PDE4B inhibition. This might be a breakthrough in the management of Alzheimer’s disease.

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In a mouse model of SD-induced cognitive impairment, the study scientist revealed biochemical, behavioral, and histopathological evidence that substantiates Roflumilast’s protective properties. The roflumilast treatment enhances recognition memory in SD mice. This occurs by inhibiting PDE4B, which is mediated through cAMP/CREB/BDNF signaling and the downregulation of Amyloid-beta pathology.


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



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