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: Bahareh Eftekharzadeh, Mahmoudreza Ramin, Fariba Khodagholi, Shahla Moradi, Kaveh Tabrizian, Rojin Sharif, Kian Azami, Cordian Beyer, Mohammad Sharifzadeh
• Journal: Behavioural brain research (Behav Brain Res) Vol. 226 Issue 1 Pg. 301-8 (Jan 01 2012) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 21856333 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Isoquinolines
• NF-kappa B
• Peptide Fragments
• Protein Kinase Inhibitors
• Sulfonamides
• amyloid beta-protein (1-42)
• Cyclic AMP-Dependent Protein Kinases
• Glutathione
• N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide

Topics

• Amyloid beta-Peptides (administration & dosage)
• Animals
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Glutathione (metabolism)
• Hippocampus (drug effects, metabolism)
• Isoquinolines (administration & dosage)
• Male
• Maze Learning (drug effects)
• Memory Disorders (chemically induced, genetics, metabolism)
• Memory, Short-Term (drug effects)
• NF-kappa B (genetics, metabolism)
• Oxidative Stress (drug effects)
• Peptide Fragments (administration & dosage)
• Protein Kinase Inhibitors (administration & dosage)
• Rats
• Rats, Wistar
• Sulfonamides (administration & dosage)