h-89 and Cognitive-Dysfunction

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.

Topics: Alzheimer Disease; Aminopyridines; Amyloid beta-Peptides; Animals; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzamides; Cognitive Dysfunction; Cyclopropanes; Disease Models, Animal; Hippocampus; Isoquinolines; Male; Mice; Nitric Oxide; Phosphodiesterase 4 Inhibitors; Protein Kinase Inhibitors; Streptozocin; Sulfonamides; Tauopathies

Alzheimer's disease (AD) is an important chronic neurodegenerative disorder and is mainly associated with cognitive dysfunction. At present, bioactive compounds from traditional medicinal plants have received much attention for the enhancement of cognitive function. Danshensu, a phenolic acid isolated from herbal medicines, has various pharmacological activities in the central nervous system, including anxiolytic-like and neuroprotective properties. The present study aimed to investigate the ameliorating effects of danshensu on scopolamine- and amyloid-β (Aβ) protein-induced cognitive impairments in mice. Danshensu (3 and 10 mg/kg, p.o.) effectively ameliorated scopolamine-induced cognitive dysfunction in mice, as measured in passive avoidance and Y-maze tasks. In a mechanistic study, danshensu inhibited monoamine oxidase A (MAO-A) activity but not MAO-B. Additionally, danshensu treatment increased the dopamine level and the phosphorylation levels of protein kinase A (PKA) and cAMP response element binding protein (CREB), in the cortex of the brain. Furthermore, the ameliorating effect of danshensu against scopolamine-induced cognitive impairment was fully blocked by H89, a PKA inhibitor. Finally, danshensu also ameliorated Aβ-induced cognitive impairments in an animal model of AD. The results revealed that danshensu treatment significantly improved scopolamine and Aβ-induced cognitive impairments in mice by facilitation of dopamine signaling cascade such as PKA and CREB due to MAO-A inhibition. Thus, danshensu could be used as a promising therapeutic agent for preventing and treating AD.

Topics: Amyloid beta-Peptides; Animals; Avoidance Learning; Cognitive Dysfunction; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Dopamine; Drugs, Chinese Herbal; Isoquinolines; Lactates; Male; Maze Learning; Mice; Mice, Inbred ICR; Monoamine Oxidase Inhibitors; Muscarinic Antagonists; Phosphorylation; Scopolamine; Signal Transduction; Sulfonamides; Synaptic Transmission

Tau is a microtubule-associated protein, and the oligomeric and hyperphosphorylated forms of tau are increased significantly after neurotrauma and considered important factors in mediating cognitive dysfunction. Blockade of adenosine A

Topics: Adenosine; Adenosine A2 Receptor Agonists; Adult; Aged; Animals; Brain Injuries, Traumatic; Cognitive Dysfunction; Disease Models, Animal; Female; Glycogen Synthase Kinase 3 beta; Glycogen Synthase Kinases; Hippocampus; Humans; Indoles; Isoquinolines; Male; Maleimides; Mice; Mice, Knockout; Middle Aged; Neurons; Phenethylamines; Phosphorylation; Protein Kinase Inhibitors; Receptor, Adenosine A2A; Signal Transduction; Sulfonamides; tau Proteins; Triazines; Triazoles