A Novel Neuroprotective Derived Peptide of Erythropoietin Improved Cognitive Function in Vascular Dementia Mice

The effective therapeutics for vascular dementia are still lacking. Here, we designed a novel derived peptide of erythropoietin-DEPO and evaluated its safety, erythropoiesis effect, and neuroprotective effects in mice of vascular dementia. For evaluating the safety and erythropoiesis, DEPO was injected into naive C57BL6 mice (n = 5) for 4-8 weeks, and venous blood was collected at 1, 2, and 4 weeks after DEPO treatment. Neuroprotective effects of DEPO were studied in both cultured neurons and bilateral common carotid artery stenosis (BCAS) mice (n = 10/group). After 4-week DEPO administration, neurobehavioral tests and histology were applied to evaluate cognitive function and brain tissue damage of mice, respectively. Molecule docking, western blotting, pharmacological or genetic interference with EPOR, and JAK/STAT/AKT pathway were used to determine the mechanism of neuroprotective effects of DEPO. DEPO did not increase the hemoglobin concentration or red blood cell number in mice after 4-week treatment compared to the Vehicle group (p > 0.05). DEPO treatment alleviated spatial reference memory impairment and the anxiety level in mice (p < 0.05). Both gray and white matter injuries were significantly alleviated by DEPO treatment. DEPO activated JAK/STAT pathway in cultured neurons and protected neurons against chronic ischemia (p < 0.05). Pharmacological or genetic interference with JAK2 signaling or EPOR inhibited the pro-survival effect of DEPO on chronic ischemia neurons (p < 0.05). DEPO is a novel safe erythropoietin-derived peptide and exerted its neuroprotective effects in vascular dementia mice through activating EPOR and its downstream JAK/STAT signaling pathway. DEPO is a potential alternative agent for treatment of vascular dementia or chronic cerebral ischemia.