Erythropoietin (EPO) is a cytokine known to have effective cytoprotective action in the brain, particularly in ischemic, traumatic, inflammatory, and neurodegenerative conditions. We previously reported the neuroprotective effect of a low sialic form of EPO, Neuro-EPO, applied intranasally in rodent models of stroke or cerebellar ataxia and in a non-transgenic mouse model of Alzheimer's disease (AD). Here we analyzed the protective effect of Neuro-EPO in APPSwe mice, a reference transgenic mouse model of AD. Mice were administered 3 times a day, 3 days in the week with Neuro-EPO (125, 250 μg/kg) intranasally, between 12 and 14 months of age. Motor responses, general activity, and memory responses were analyzed during and after treatment. The deficits in spontaneous alternation, place learning in the water-maze, and novel object recognition observed in APPSwe mice were alleviated by the low dose of Neuro-EPO. Oxidative stress, neuroinflammation, trophic factor levels, and a synaptic marker were analyzed in the hippocampus or cortex of the animals. The increases in lipid peroxidation or in GFAP and Iba-1 contents in APPSwe mice were significantly reduced after Neuro-EPO. Activation of intrinsic and extrinsic apoptotic pathways was analyzed. The increases in Bax/Bcl-2 ratio, TNFα, or Fas ligand levels observed in APPSwe mice were reduced by Neuro-EPO. Finally, immunohistochemical and ELISA analyses of Aβ1-42 levels in the APPSwe mouse cortex and hippocampus showed a marked reduction in Aβ deposits and in soluble and insoluble Aβ1-42 forms. This study therefore confirmed the neuroprotective activity of EPO, particularly for an intranasally deliverable formulation, devoid of erythropoietic side effects, in a transgenic mouse model of AD. Neuro-EPO alleviated memory alterations, oxidative stress, neuroinflammation, apoptosis induction, and amyloid load in 14-month-old APPSwe mice.

Background: NeuroEPO, a nasal pharmaceutical solution of recombinant human erythropoietin with low sialic acid, was in clinical development for the treatment of mildmoderate Alzheimer's disease. Method:A double-blind, randomized, placebo-controlled, multicenter, prospective, with adaptive design, phase II/III clinical trial involving 174 patients with mild-tomoderate Alzheimer's, was conducted. NeuroEPO or placebo, with different doses, was administered by nasal route 3 times a weeks for 48 weeks. The primary outcome measure was score on the 11-item cognitive subscale of the Alzheimer's disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment). Secondary outcome measures included Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus), Global Dementia Scale (GDS), activities of daily living (ADL), hippocampal volume change over time (measured with MRI), neuropsychological scales, electroencephalography (EEG) and adverse events.Result: There were statistically significant differences between neuroEPO and placebo in median change from baseline in the primary outcome at week 48. The change in ADAS-cog11 scores final-initial (PP population) for patients in the neuroEPO 0.5 mg (n= 50, median change: -4.0), neuroEPO 1.0 mg (n=49, median change: -5.0) and placebo (n=49, median change: 4.0) groups. A difference of 8.0 points CI 95% (6.0; 10.0) neuroEPO 0.5 mg vs. placebo and 9.0 points CI 95% (6.8; 11.2) neuroEPO 1.0 mg vs. placebo at week 48, (p=0.000), was observed. Patients receiving both doses of neuroEPO also showed a significant difference in global improvement (CIBIC-Plus, p=0.000) and electroencephalography (EEG, p=0.003) compared with placebo group. About hippocampal volume change, 105 patients were analyzed. From them, 58% remained stable and 42% decline hippocampus volume. No serious adverse events related with neuroEPO were reported. Conclusion:NeuroEPO improved clinical outcomes in patients with Alzheimer's disease with good security profile. Therefore, it could be useful in the treatment of these kind of patients.

Background. Cognitive impairment is a feature of Parkinsons Disease (PD) from the early stages but currently, no treatment for cognitive deficits in PD is available. Erythropoietin (EPO) has been studied for its potential neuroprotective properties in neurologic disorders with a beneficial action on cognition. Objective: We want to know if NeuroEPO, a new formulation of EPO with low content of sialic acid has effects on cognitive function in PD in a double-blind randomized placebo and after a post-trial intervention. Methods: The sample was composed of 26 PD patients (HY stages I-II), where 15 received intranasal NeuroEPO for 5 weeks and another age and gender-matched 11 patients were randomly assigned to the placebo. During a post-trial all the sample received 9 months of intensive NeuroEPO treatment. Cognitive functions were assessed using a comprehensive neuropsychological battery before, one week and 6 months after the first intervention and 9months after the post-trial. The effects of NeuroEPO were evaluated using a multivariate linear mixed-effects model using a latent variable for cognition instead of the raw neuropsychological scores. Results: We found a significant and direct effect of the dose of NeuroEPO (p=0.00001) on cognitive performance with a strong positive influence of educational level (p=0.0004) and negative impact of age (p=0.007). Conclusions: This preliminary results showed a positive effect of NeuroEPO on cognition in PD patients.

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