Donepezil, an acetylcholine esterase inhibitor, and ABT-239, a histamine H3 receptor antagonist/inverse agonist, require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse
| Autor: | M. Beatrice Passani, Patrizio Blandina, Alessia Costa, Gustavo Provensi |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Pyrrolidines Drug Inverse Agonism Histidine Decarboxylase Pharmacology Mice 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound Cognition 0302 clinical medicine Piperidines Internal medicine Animals Receptors Histamine H3 Medicine Inverse agonist Donepezil Nootropic Agents Benzofurans Mice Knockout business.industry Histaminergic Brain Acetylcholinesterase 030104 developmental biology Endocrinology chemistry Indans Cholinergic Cholinesterase Inhibitors Histamine H3 receptor business 030217 neurology & neurosurgery Histamine Acetylcholine Histamine H3 Antagonists medicine.drug |
| Zdroj: | Neuropharmacology. 109:139-147 |
| ISSN: | 0028-3908 |
| Popis: | Histaminergic H3 receptors (H3R) antagonists enhance cognition in preclinical models and modulate neurotransmission, in particular acetylcholine (ACh) release in the cortex and hippocampus, two brain areas involved in memory processing. The cognitive deficits seen in aging and Alzheimer's disease have been associated with brain cholinergic deficits. Donepezil is one of the acetylcholinesterase (AChE) inhibitor approved for use across the full spectrum of these cognitive disorders. We addressed the question if H3R antagonists and donepezil require an intact histamine neuronal system to exert their procognitive effects. The effect of the H3R antagonist ABT-239 and donepezil were evaluated in the object recognition test (ORT), and on the level of glycogen synthase kinase 3 beta (GSK-3β) phosphorylation in normal and histamine-depleted mice. Systemic administration of ABT-239 or donepezil ameliorated the cognitive performance in the ORT. However, these compounds were ineffective in either genetically (histidine decarboxylase knock-out, HDC-KO) or pharmacologically, by means of intracerebroventricular (i.c.v.) injections of the HDC irreversible inhibitor a-fluoromethylhistidine (a-FMHis), histamine-deficient mice. Western blot analysis revealed that ABT-239 or donepezil systemic treatments increased GSK-3β phosphorylation in cortical and hippocampal homogenates of normal, but not of histamine-depleted mice. Furthermore, administration of the PI3K inhibitor LY294002 that blocks GSK-3β phosphorylation, prevented the procognitive effects of both drugs in normal mice. Our results indicate that both donepezil and ABT-239 require the integrity of the brain histaminergic system to exert their procognitive effects and strongly suggest that impairments of PI3K/AKT/GSK-3β intracellular pathway activation is responsible for the inefficacy of both drugs in histamine-deficient animals. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect