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Background: Intracerebroventricular (ICV) administration of streptozotocin (STZ) has been used as a metabolic model of sporadic Alzheimer's disease (AD). Erythropoietin (EPO) possesses neuroprotective and memory‐improving effects, which might be advantageous in treating different characteristics of AD. Nevertheless, the hematopoietic effect of EPO has hindered its application as a neuroprotective agent. Previous studies have shown that a new Epo derivative called carbamylated Erythropoietin‐Fc (CEPO‐Fc), yield noticeable neuroprotective effects without affecting hematopoiesis. In this study, the neuroprotective effects of CEPO‐Fc on icv‐STZ induced memory impairment and hippocampal apoptosis were examined. Method: Adult male Wistar rats weighing 250‐300 g were used. STZ was administered on days 1 and 3 (3 mg/kg in divided doses/icv), and CEPO‐Fc was administered at the dose of 5000 IU/ip/daily during days 4‐14. The animals were trained in Morris water maze during days 15‐17, and the memory retention test was performed on the 18th day. Following behavioral studies, the animals were sacrificed and their hippocampi isolated to determine the amounts of cleaved caspase‐3 (the landmark of apoptosis). Result: The results showed that CEPO‐Fc treatment at the dose of 5000 IU/kg/ip was able to prevent the learning and memory deficit induced by icv‐STZ. Western blot analysis revealed that STZ prompted the cleavage of caspase‐3 in the hippocampus while pretreatment with CEPO‐Fc significantly reduced the cleavage of this protein. Conclusion: Collectively, our findings suggest that CEPO‐Fc could restore STZ‐induced learning and memory impairment as well as apoptosis in the hippocampal region in a rat model of sporadic AD induced by icv‐STZ. [ABSTRACT FROM AUTHOR]