Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the Aβ_25-35 non-transgenic mouse model of Alzheimer’s disease

Abstract

Erythropoietin (EPO) promotes neurogenesis and neuroprotection. We here compared the protection induced by two EPO formulations in a rodent model of Alzheimer's disease (AD): rHu-EPO and a low sialic form, Neuro-EPO. We used the intracerebroventricular administration of aggregated Aβ₂₅₋₃₅ peptide, a non-transgenic AD model. rHu-EPO was tested at 125-500 µg/kg intraperitoneally and Neuro-EPO at 62-250 µg/kg intranasally (IN). Behavioural procedures included spontaneous alternation, passive avoidance, water-maze and object recognition, to address spatial and non-spatial, short- and long-term memories. Biochemical markers of Aβ₂₅₋₃₅ toxicity in the mouse hippocampus were examined and cell loss in the CA1 layer was determined. rHu-EPO and Neuro-EPO led to a significant prevention of Aβ₂₅₋₃₅-induced learning deficits. Both EPO formulations prevented the induction of lipid peroxidation in the hippocampus, showing an antioxidant activity. rHu-EPO (250 µg/kg) or Neuro-EPO (125 µg/kg) prevented the Aβ₂₅₋₃₅-induced increase in Bax level, TNFα and IL-1β production and decrease in Akt activation. A significant prevention of the Aβ₂₅₋₃₅-induced cell loss in CA1 was also observed. EPO is neuroprotective in the Aβ₂₅₋₃₅ AD model, confirming its potential as an endogenous neuroprotection system that could be boosted for therapeutic efficacy. We here identified a new IN formulation of EPO showing high neuroprotective activity. Considering its efficacy, ease and safety, IN Neuro-EPO is a new promising therapeutic agent in AD.

Epobis is a Nonerythropoietic and Neuroprotective Agonist of the Erythropoietin Receptor with Anti-Inflammatory and Memory Enhancing Effects

“…Since EPO and EPO derivatives are known to have beneficial effects on memory formation [4, 11, 13, 14, 16, 40, 50–52], it was evaluated whether Epobis also can improve memory formation in healthy animals. Epobis was found to improve the social recognition of healthy adult rats 3 days, but not 1 h, after treatment (Figure 6), suggesting that Epobis-induced changes in gene transcription and other downstream effects lasting more than 1 h are required for the beneficial effects on memory to appear or that the effects on memory peak several days after Epobis exposure.…”

“…Moreover, EPO has beneficial effects on memory and mood of animals and humans with depression-like symptoms [11]. Animal studies using EPO or EPO derivatives have demonstrated an improved memory and a reduced endothelial and neuronal degeneration in models of Alzheimer's disease [12–14], a protection against experimental cerebral malaria and pneumococcal meningitis [15, 16], downregulation of proinflammatory cytokines and upregulation of anti-inflammatory cytokines in a model of amyotrophic lateral sclerosis [17], a reduction of progressive retinal degeneration [18], and neuroprotective effects in relation to status epilepticus [19] and cervical subacute spinal cord compression [20]. Importantly, most of these beneficial effects of EPO are believed to be unrelated to the erythropoietic effects of EPO but not necessarily unrelated to signaling through the EPO receptor [1–3].…”

Erythropoietin: From a Biosimilar to Innovative Products Protected by Industrial Property Assets

“…The international PCT filing was done in June 2017 (PCT/CU2017/050005). The effect of Neuro-EPO on nervous cells was also published in Parra and Rodríguez 2012 [17], Maurice et al, 2013 [18] and Rodríguez et al, 2017 [19]. New clinical trials to test the efficacy of the basic rhEPO in other indications are designed and will be conducted, so new patent applications could arise.…”

Charting a course for erythropoietin in traumatic brain injury

“…Second, another avenue of investigation for EPO and TBI could involve targeting more specific pathways controlled by EPO such as protein kinase B (Akt) that can foster a number of protective pathways in the nervous system with EPO [112–115]. Other pathways that can modulate the protective effects of EPO include mTOR [68,80,82,83], AMPK [41,96], sirtuins [72,116,117], wingless pathways [68,72,91,118,119], and forkhead transcription factors [57,113,120].…”