title: Inhibition of PKA attenuates memory deficits induced by β-amyloid (1-42), and decreases oxidative stress and NF-κB transcription factors.
abstract: Alzheimer's disease (AD), the most relevant cause of dementia in elderly, is characterized by amyloid β (Aβ) containing plaques and neurofibrillatory tangles, synaptic and neuronal loss, along with progressive cognitive impairment in short-term memory. However, mechanistic links between protein kinase A (PKA), oxidative stress and memory loss in response to Aβ remain elusive. In the present study, we examined the effects of post-training bilateral intra-hippocampal infusions of the specific protein kinase AII inhibitor, H-89, on memory deficits induced by Aβ (1-42) in Aβ-pretreated rats. H-89 and Aβ were administered immediately after completion of training. All animals were trained for 4 consecutive days and tested 9 and 19 days after the infusions. Significant differences were observed in the time and distance of finding the hidden platform in Aβ treated animals after 19 days. Interestingly, intra-hippocampal infusion of H-89 (5μM/side) significantly prevented the Aβ-induced memory impairment. Furthermore, evaluation of NFκB (nuclear factor-κB), and antioxidant enzymes, such as γ-GCS (glutamylcysteine synthetase), HO-1 (hemeoxygenase-1), GSH (glutathione), and SOD (superoxide dismutase) confirmed the protective effect of H-89. Given the possible neuroprotective effects of H-89 on Aβ-induced memory impairment, our results may open a new avenue for the prevention of AD by PKAII signaling pathway inhibitor.
authors.affiliation: Department of Pharmacology and Toxicology, Pharmaceutical Sciences research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Eftekharzadeh
authors.forename: Mahmoudreza
authors.initials: M
authors.lastname: Ramin
authors.forename: Fariba
authors.initials: F
authors.lastname: Khodagholi
authors.forename: Shahla
authors.initials: S
authors.lastname: Moradi
authors.forename: Kaveh
authors.initials: K
authors.lastname: Tabrizian
authors.forename: Rojin
authors.initials: R
authors.lastname: Sharif
authors.forename: Kian
authors.initials: K
authors.lastname: Azami
authors.forename: Cordian
authors.initials: C
authors.lastname: Beyer
authors.forename: Mohammad
authors.initials: M
authors.lastname: Sharifzadeh
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage*; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007546:Isoquinolines / Q000008:administration & dosage; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008569:Memory Disorders / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008570:Memory, Short-Term / Q000187:drug effects; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000008:administration & dosage
chemical_list: D016229:Amyloid beta-Peptides; D007546:Isoquinolines; D016328:NF-kappa B; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C075222:amyloid beta-protein (1-42); D017868:Cyclic AMP-Dependent Protein Kinases; D005978:Glutathione; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide