Intranasal CEPO-FC prevents attention deficits in streptozotocin-induced rat model of Alzheimer's disease: Focus on synaptic plasticity-related factors.

Alzheimer's disease remains an issue of great controversy due to its pathology. It is characterized by cognitive impairments and neuropsychiatric symptoms. The FDA approved medications for this disease, can only mitigate the symptoms. One reason for the lack of effective medications is the inaccessibility of the brain which is encompassed by the blood-brain barrier, making intranasal (IN) route of administration potentially advantageous. Male Wistar rats underwent stereotaxic surgery to induce an Alzheimer's disease model via intracerebroventricular (ICV) streptozotocin injection, and Carbamylated Erythropoietin-Fc (CEPO-FC), a derivative of Erythropoietin without its harmful characteristics, was administered intranasally for ten consecutive days. Cognition performance for memory and attention was assessed using the Novel Object Recognition Test and the Object-Based Attention Test respectively. Depression like behavior was evaluated using the Forced Swim Test. Western blotting was done on the extracted hippocampus to quantify STIM proteins. Calbindin, PSD-95, Neuroplastin, Synaptophysin and GAP-43 genes were assessed by Realtime PCR. Behavioral tests demonstrated that IN CEPO-FC could halt cognition deficits and molecular investigations showed that, STIM proteins were decreased in Alzheimer's model, and increased after IN CEPO-FC treatment. Calbindin and PSD-95 were downregulated in our disease model and upregulated when treated with IN CEPO-FC. While Neuroplastin, and GAP-43 expressions remained unchanged. This study suggests that IN CEPO-FC in low doses could be promising for improving cognition and synaptic plasticity deficits in Alzheimer's disease and since IN route of administration is a convenient way, choosing IN CEPO-FC for clinical trial might worth consideration. See also the graphical abstract(Fig. 1).

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

Alzheimer's disease (AD) is a debilitating neurodegenerative disease, characterized by extracellular deposition of senile plaques, mostly amyloid ß-protein (Aß) 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. Aß25-35 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-3ß 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 Aß-induced learning and memory deterioration. From the molecular analysis, an increment of MAPKs and MMP-2 activity and an imbalance in Akt/GSK-3ß signaling after Aß25-35 administration was observed. CEPO-Fc treatment prevented the elevation of hippocampal of P38, ERK, MMP-2 activity and also Akt/GSK-3ß signaling impairment induced by Aß25-35 but it had no effect on JNK. It seems that CEPO-Fc prevents Aß-induced learning and memory deterioration, and also modulates hippocampal MAPKs, Akt/GSK-3ß and MMP-2 activity. This study suggests that CEPO-Fc can be considered as a potential therapeutic strategy for memory deficits like AD.