Roflumilast ameliorates cognitive deficits in a mouse model of amyloidogenesis and tauopathy: Involvement of nitric oxide status, Aβ extrusion transporter ABCB1, and reversal by PKA inhibitor H89

• Published in: Progress in neuro-psychopharmacology & biological psychiatry 2021-12, Vol.111, p.110366, Article 110366
• Main Authors: Ashour, Nada H., El-Tanbouly, Dalia M., El Sayed, Nesrine S., Khattab, Mahmoud M.
• Format: Article
• Language: English
• Subjects: ABCB1; Alzheimer Disease - metabolism; Aminopyridines - pharmacology; Amyloid beta-Peptides - metabolism; Animals; Antibiotics, Antineoplastic - administration & dosage; Arginase; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzamides - pharmacology; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - prevention & control; Cyclopropanes - pharmacology; Disease Models, Animal; Hippocampus - metabolism; Isoquinolines - metabolism; Male; Mice; Nitric Oxide - metabolism; Phosphodiesterase 4 Inhibitors - pharmacology; Protein kinase A; Protein Kinase Inhibitors - metabolism; Roflumilast; Streptozocin - administration & dosage; Sulfonamides - metabolism; Tau; Tauopathies - metabolism
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2021.110366

The biological cascade of second messenger–cyclic adenosine monophosphate (cAMP) –as a molecular mechanism implicated in memory and learning regulation has captured the attention of neuroscientists worldwide. cAMP triggers its foremost effector, protein kinase A (PKA), resulting in the activation of innumerable downstream targets. Roflumilast (ROF), a phosphodiesterase 4 inhibitor, has demonstrated a greater efficiency in enhancing cAMP signaling in various neurological disorders. This study was conducted to identify various downstream targets of PKA as mechanistic tools through which ROF could hinder the progressive cognitive impairment following central streptozotocin (STZ) administration in mice. Animals were injected with STZ (3 mg/kg/i.c.v) once. Five hours later, mice received ROF (0.4 mg/kg) with or without the PKA inhibitor, H89, for 21 days. ROF highly preserved the structure of hippocampal neurons. It improved the ability of mice to develop short-term memories and retrieve spatial memories in Y-maze and Morris water maze tests, respectively. ROF enhanced the gene expression of ABCB1 transporters and pregnane X receptors (PXR), and hampered Aβ accumulation in hippocampus. Simultaneously, it interfered with the processes of tau phosphorylation and nitration. This effect was associated with an upsurge in hippocampal arginase activity as well as a decline in glycogen synthase kinase-3β activity, nitric oxide synthase (NOS) activity, and inducible NOS expression. Contrariwise, ROF's beneficial effects were utterly abolished by co-administration of H89. In conclusion, boosting PKA, by ROF, modulated PXR/ABCB1 expression and arginase/NOS activities to restrict the main post-translational modifications of tau, Aβ deposition and, accordingly, cognitive deterioration of sporadic Alzheimer's disease. [Display omitted] •Roflumilast ameliorates cognitive deficits and hippocampal neurotoxicity.•Roflumilast mitigates Aβ, phosphorylated and nitrated tau accumulation.•Roflumilast boosts pregnane X receptors/ABCB1 transporters expression.•Roflumilast modulates arginase/nitric oxide synthase activities.•Roflumilast's effects are abolished by co-administration of a PKA inhibitor.