title: Paradoxical role of PKA inhibitor on amyloidβ-induced memory deficit.
abstract: In spite of characterizing the role of protein kinase A (PKA) in activating biochemical mechanisms, few studies have investigated the effects of PKA inhibitors on memory functions. In the present study, we used Pavlovian fear conditioning paradigm to evaluate memory alterations caused by two doses of H89 (as a conditional inhibitor of PKA) alone and in combination with amyloid-β (Aβ) in rats. Moreover, we used the Western blotting method to investigate the alterations in markers of transcription, oxidative stress, inflammation, and apoptosis pathways involved in memory impairment. Stereotaxic surgery was done to inject Aβ (30 ng/side) directly into the hippocampal CA1 area bilaterally and H89 (5 or 10 μM) intracerebroventricular unilaterally. One series of rats were trained 7 days after injections, then contextual and tone tests were conducted on days 8 and 9, respectively. Second series of rats were trained 14 days after the injections and tests were carried out on days 15 and 16. Our behavioral results showed that H89 (5 μM) not only has no destructive effect on memory, but also attenuates memory deficit caused by Aβ in combination groups. In contrast, H89 (10μM) has a reversible destructive effect on memory. Our molecular findings indicated that low dose of H89 increases CREB phosphorylation, Nrf2 and HO-1 which results in survival resistance to the stress. On the contrary, H89 with higher concentration leads to substantial increase of NF-κB and caspase-3 levels, which impair memory functions. In conclusion, our data suggest that H89 as a PKA inhibitor influences memory process through a dose and time dependent manner.
authors.affiliation: Department of Pharmacology and Toxicology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Elham
authors.initials: E
authors.lastname: Amini
authors.affiliation: Department of Pharmacology and Toxicology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Nassireslami
authors.affiliation: Department of Pharmacology and Toxicology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Borna
authors.initials: B
authors.lastname: Payandemehr
authors.affiliation: Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Fariba
authors.initials: F
authors.lastname: Khodagholi
authors.affiliation: Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Forough
authors.initials: F
authors.lastname: Foolad
authors.affiliation: Department of Pharmacology and Toxicology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Sara
authors.initials: S
authors.lastname: Khalaj
authors.affiliation: Department of Pharmacology and Toxicology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mostafa Pirali
authors.initials: MP
authors.lastname: Hamedani
authors.affiliation: Department of Neuroscience, Faculty of Advance Science and Technology in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Leyla
authors.initials: L
authors.lastname: Azimi
authors.affiliation: Department of Pharmacology and Toxicology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Department of Neuroscience, Faculty of Advance Science and Technology in Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: msharifzadeh@sina.tums.ac.ir.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Sharifzadeh
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003214:Conditioning, Classical / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005239:Fear; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007546:Isoquinolines / Q000627:therapeutic use*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D007546:Isoquinolines; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D013449:Sulfonamides; D051547:Heme Oxygenase-1; D050882:CREB-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D053148:Caspase 3; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: Alzheimer's disease; Caspase-3; Fear conditioning; NF-κB; Protein kinase A inhibitor; p-CREB