Inhibition of PKA attenuates memory deficits induced by β-amyloid (1–42), and decreases oxidative stress and NF-κB transcription factors

• Published in: Behavioural brain research Vol. 226; no. 1; pp. 301 - 308
• Main Authors: Eftekharzadeh, Bahareh, Ramin, Mahmoudreza, Khodagholi, Fariba, Moradi, Shahla, Tabrizian, Kaveh, Sharif, Rojin, Azami, Kian, Beyer, Cordian, Sharifzadeh, Mohammad
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 2012; Elsevier
• Subjects: Adult and adolescent clinical studies; Alzheimer's disease; Amyloid beta-Peptides - administration & dosage; Amyloid β; Animals; Behavioral psychophysiology; Biological and medical sciences; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Fundamental and applied biological sciences. Psychology; Glutathione - metabolism; H-89; Hippocampus - drug effects; Hippocampus - metabolism; Isoquinolines - administration & dosage; Male; Maze Learning - drug effects; Medical sciences; Memory Disorders - chemically induced; Memory Disorders - genetics; Memory Disorders - metabolism; Memory, Short-Term - drug effects; Morris water maze; Neurology; NF-kappa B - genetics; NF-kappa B - metabolism; NFκB transcription factor; Organic mental disorders. Neuropsychology; Oxidative Stress - drug effects; Peptide Fragments - administration & dosage; Protein Kinase Inhibitors - administration & dosage; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Psychopathology. Psychiatry; Rats; Rats, Wistar; Sulfonamides - administration & dosage; APP; MWM; AD; Morris water maze; NFκB; DTNB; PKA; H-89; SOD; HO-1; γ-GCS; MAPK; CO; Aβ; NFκB transcription factor; tHBQ; Amyloid β; ROS; GSH; Alzheimer's disease; Oxidative stress; Memory disorder; Nervous system diseases; Cognitive disorder; Alzheimer disease; Space perception; Cerebral disorder; Acquisition process; β Amyloid protein; Central nervous system disease; Degenerative disease; Transcription factor NFκB; Inhibition; Perceptive learning; Transcription factor
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2011.08.015

► The effects of PKA inhibitor H-89 on Aβ-induced memory deficit was studied in rats. ► Spatial memory retention was assessed 9 and 19 days after infusions of H-89 and Aβ. ► Intra-hippocampal infusion of H-89 prevented the Aβ-induced memory impairment. ► NFκB signal transduction pathway is involved in Aβ-induced memory deficit. ► Evaluation of NFκB, γ-GCS, HO-1, GSH and SOD confirmed the protective effect of H-89. 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 (5 μM/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.