CEPO-Fc (An EPO Derivative) Protects Hippocampus Against Aβ-induced Memory Deterioration: A Behavioral and Molecular Study in a Rat Model of Aβ Toxicity.

Abstract

Alzheimer's disease (AD) is a debilitating neurodegenerative disease, characterized by extracellular deposition of senile plaques, mostly amyloid β-protein (Aβ) and neuronal loss. The neuroprotective effects of erythropoietin (EPO) have been reported in some models of neurodegenerative disease, but because of its hematopoietic side effects, its derivatives lacking hematopoietic bioactivity is recommended. In this study, the neuroprotective effects of carbamylated erythropoietin-Fc (CEPO-Fc) against beta amyloid-induced memory deficit were evaluated. Adult male Wistar rats weighing 250-300 g were bilaterally cannulated into CA1. Aβ25-35 was administered intrahippocampally for 4 consecutive days (5 μg/2.5 μL/each side/day). CEPO-Fc (500 or 5000 IU) was injected intraperitoneally during days 4-9. Learning and memory performance of rats was assessed on days 10-13 using Morris Water Maze, then hippocampi were isolated and the amount of activated forms of hippocampal MAPKs' subfamily, Akt/GSK-3β and MMP-2 were analyzed using Western blot. From the behavioral results, it was revealed that CEPO-Fc treatment in both 500 and 5000 IU significantly reversed Aβ-induced learning and memory deterioration. From the molecular analysis, an increment of MAPKs and MMP-2 activity and an imbalance in Akt/GSK-3β signaling after Aβ25-35 administration was observed. CEPO-Fc treatment prevented the elevation of hippocampal of P38, ERK, MMP-2 activity and also Akt/GSK-3β signaling impairment induced by Aβ25-35 but it had no effect on JNK. It seems that CEPO-Fc prevents Aβ-induced learning and memory deterioration, and also modulates hippocampal MAPKs, Akt/GSK-3β and MMP-2 activity. This study suggests that CEPO-Fc can be considered as a potential therapeutic strategy for memory deficits like AD.

• Authors: Etrat Hooshmandi, Fereshteh Motamedi, Maryam Moosavi, Hermann Katinger, Zahra Zakeri, Jalal Zaringhalam, Amirhossein Maghsoudi, Rasoul Ghasemi, Nader Maghsoudi
• Journal: Neuroscience (Neuroscience) Vol. 388 Pg. 405-417 (09 15 2018) ISSN: 1873-7544 [Electronic] United States
• PMID: 30102955 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Immunoglobulin Fc Fragments
• Neuroprotective Agents
• Nootropic Agents
• Peptide Fragments
• Recombinant Fusion Proteins
• amyloid beta-protein (25-35)
• Erythropoietin
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• Matrix Metalloproteinase 2
• Mmp2 protein, rat

Topics

• Alzheimer Disease (drug therapy)
• Amyloid beta-Peptides (metabolism, toxicity)
• Animals
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Erythropoietin (genetics, pharmacology)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Hippocampus (drug effects, metabolism, pathology)
• Immunoglobulin Fc Fragments (genetics)
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Maze Learning (drug effects, physiology)
• Memory (drug effects, physiology)
• Memory Disorders (drug therapy, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Nootropic Agents (pharmacology)
• Peptide Fragments (metabolism, toxicity)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats, Wistar
• Recombinant Fusion Proteins (genetics, pharmacology)
• Signal Transduction (drug effects)