Phosphodiesterase inhibitors roflumilast and vardenafil prevent sleep deprivation-induced deficits in spatial pattern separation. 2020

Pim R A Heckman, and Femke Roig Kuhn, and Frank Raven, and Youri G Bolsius, and Jos Prickaerts, and Peter Meerlo, and Robbert Havekes
Neurobiology Expert Group, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, The Netherlands.

Sleep deprivation (SD) is known to impair hippocampus-dependent memory processes, in part by stimulating the phosphodiesterase (PDE) activity. In the present study, we assessed in mice whether SD also affects spatial pattern separation, a cognitive process that specifically requires the dentate gyrus (DG) subregion of the hippocampus. Adult male mice were trained in an object pattern separation (OPS) task in the middle of the light phase and then tested 24 hr thereafter. In total, we conducted three studies using the OPS task. In the first study, we validated the occurrence of pattern separation and tested the effects of SD. We found that 6 hr of SD during the first half of the light phase directly preceding the test trial impaired the spatial pattern separation performance. As a next step, we assessed in two consecutive studies whether the observed SD-induced performance deficits could be prevented by the systemic application of two different PDE inhibitors that are approved for human use. Both the PDE4 inhibitor roflumilast and PDE5 inhibitor vardenafil successfully prevented SD-induced deficits in spatial pattern separation. As a result, these PDE inhibitors have clinical potential for the prevention of memory deficits associated with loss of sleep.

UI MeSH Term Description Entries
D008297 Male Males
D008569 Memory Disorders Disturbances in registering an impression, in the retention of an acquired impression, or in the recall of an impression. Memory impairments are associated with DEMENTIA; CRANIOCEREBRAL TRAUMA; ENCEPHALITIS; ALCOHOLISM (see also ALCOHOL AMNESTIC DISORDER); SCHIZOPHRENIA; and other conditions. Memory Loss,Age-Related Memory Disorders,Memory Deficits,Memory Disorder, Semantic,Memory Disorder, Spatial,Memory Disorders, Age-Related,Retention Disorders, Cognitive,Semantic Memory Disorder,Spatial Memory Disorder,Age Related Memory Disorders,Age-Related Memory Disorder,Cognitive Retention Disorder,Cognitive Retention Disorders,Deficit, Memory,Deficits, Memory,Memory Deficit,Memory Disorder,Memory Disorder, Age-Related,Memory Disorders, Age Related,Memory Disorders, Semantic,Memory Disorders, Spatial,Memory Losses,Retention Disorder, Cognitive,Semantic Memory Disorders,Spatial Memory Disorders
D003521 Cyclopropanes Three-carbon cycloparaffin cyclopropane (the structural formula (CH2)3) and its derivatives.
D006624 Hippocampus A curved elevation of GRAY MATTER extending the entire length of the floor of the TEMPORAL HORN of the LATERAL VENTRICLE (see also TEMPORAL LOBE). The hippocampus proper, subiculum, and DENTATE GYRUS constitute the hippocampal formation. Sometimes authors include the ENTORHINAL CORTEX in the hippocampal formation. Ammon Horn,Cornu Ammonis,Hippocampal Formation,Subiculum,Ammon's Horn,Hippocampus Proper,Ammons Horn,Formation, Hippocampal,Formations, Hippocampal,Hippocampal Formations,Hippocampus Propers,Horn, Ammon,Horn, Ammon's,Proper, Hippocampus,Propers, Hippocampus,Subiculums
D000069058 Vardenafil Dihydrochloride A piperazine derivative, PHOSPHODIESTERASE 5 INHIBITOR and VASODILATOR AGENT that is used as a UROLOGICAL AGENT in the treatment of ERECTILE DYSFUNCTION. 1-(((3-(3,4-dihydro-5-methyl)-4-oxo-7-propylimidazo(5,1-f)-as-triazin-2-yl)-4-ethoxyphenyl)sulfonyl)-4-ethylpiperazine,Levitra,Vardenafil,Vardenafil Hydrochloride,Vardenafil Hydrochloride Anhydrous,Vardenafil Hydrochloride Trihydrate,Anhydrous, Vardenafil Hydrochloride,Dihydrochloride, Vardenafil,Hydrochloride Anhydrous, Vardenafil,Hydrochloride Trihydrate, Vardenafil,Hydrochloride, Vardenafil,Trihydrate, Vardenafil Hydrochloride
D000631 Aminopyridines Pyridines substituted in any position with an amino group. May be hydrogenated but must retain at least one double bond. Aminopyridine
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001549 Benzamides BENZOIC ACID amides.
D012892 Sleep Deprivation The state of being deprived of sleep under experimental conditions, due to life events, or from a wide variety of pathophysiologic causes such as medication effect, chronic illness, psychiatric illness, or sleep disorder. Inadequate Sleep,Insufficient Sleep,Insufficient Sleep Syndrome,REM Sleep Deprivation,Sleep Debt,Sleep Fragmentation,Sleep Insufficiency,Deprivation, REM Sleep,Deprivation, Sleep,Fragmentation, Sleep,Insufficiencies, Sleep,Insufficiency, Sleep,Insufficient Sleep Syndromes,Sleep Deprivation, REM,Sleep Insufficiencies,Sleep, Inadequate,Sleep, Insufficient,Syndrome, Insufficient Sleep
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus

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