intraperitoneal carbamylated erythropoietin improves memory and hippocampal apoptosis in beta-amyloid rat model of alzheimer’s disease through stimulating autophagy and inhibiting necroptosis

Introduction: alzheimer’s disease (ad) is marked by the deposition of amyloid-β (aβ) plaques and tau tangles. although erythropoietin (epo) provides neuroprotective and memory-improving properties, its application has been limited due to the hematopoietic effects. carbamylated erythropoietin-fc (cepo-fc) was developed as a non-erythropoietic epo derivative that possesses neuroprotective potential. however, the molecular mechanisms behind the protective effects of cepo-fc’s in ad are still under consideration. therefore, herein investigated the therapeutic properties of intraperitoneal (i.p.) dose of cepo-fc on aβ-induced neurotoxicity in adult male wistar rats. methods: the rats received microinjections of aβ25-35 (5 μg/2.5 μl, per side) in the dorsal hippocampus for four consecutive days. cepo-fc was injected intraperitoneally in two doses of 500 and 5000 iu during the next six days. learning and memory performance were studied (days 10-13) using the morris water maze task. immunoblotting was also undertaken to assess the molecular levels of leading indicators of apoptosis (bax, bcl-2, and caspase-3), necroptosis (phosphorylated-receptor-interacting serine/threonine-protein kinase 3 (p-rip3)), as well as autophagy (phosphorylated-beclin-1 (p-beclin-1) and phosphorylated-1a/1b-light chain 3 (p-lc3-ii)) in the hippocampus. results: behavioral analysis indicated that cepo-fc 500 and 5000 iu reversed memory impairment. moreover, the hippocampus’s molecular study showed upregulation of p-lc3-ii/lc3-ii and suppression of bax/bcl-2, caspase-3, and p-rip3/rip3 processes. conclusion: our findings imply that the neuroprotective characteristics of cepo-fc in the ad rats are mediated through autophagy activation and regulation of apoptosis and necroptosis processes. these results suggest that an i.p. dose of cepo-fc could be used to protect against ad-induced neurotoxicity.