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Neuroprotective drugs to protect the brain against cerebral ischemia and reperfusion (I/R) injury are urgently needed. Mammalian cell-produced recombinant human erythropoietin (rhuEPO M ) has been demonstrated to have excellent neuroprotective functions in preclinical studies, but its neuroprotective properties could not be consistently translated in clinical trials. The clinical failure of rhuEPO M was thought to be mainly due to its erythropoietic activity-associated side effects. To exploit its tissue-protective property, various EPO derivatives with tissue-protective function only have been developed. Among them, asialo-rhuEPO, lacking terminal sialic acid residues, was shown to be neuroprotective but non-erythropoietic. Asialo-rhuEPO can be prepared by enzymatic removal of sialic acid residues from rhuEPO M (asialo-rhuEPO E ) or by expressing human EPO gene in glycoengineered transgenic plants (asialo-rhuEPO P ). Both types of asialo-rhuEPO, like rhuEPO M , displayed excellent neuroprotective effects by regulating multiple cellular pathways in cerebral I/R animal models. In this review, we describe the structure and properties of EPO and asialo-rhuEPO, summarize the progress on neuroprotective studies of asialo-rhuEPO and rhuEPO M , discuss potential reasons for the clinical failure of rhuEPO M with acute ischemic stroke patients, and advocate future studies needed to develop asialo-rhuEPO as a multimodal neuroprotectant for ischemic stroke treatment.

Objectives: To determine if radial artery (RA) access compared with femoral artery (FA) access for percutaneous coronary intervention (PCI) is associated with a lower incidence of acute kidney injury (AKI)., Background: AKI results in substantial morbidity and cost following PCI. Prior studies comparing the occurrence of AKI associated with radial artery (RA) versus femoral artery (FA) access have mixed results., Methods: Using a large state-wide database, 14,077 patients (8,539 with RA and 5,538 patents with FA access) were retrospectively compared to assess the occurrence of AKI following PCI. To reduce selection bias and balance clinical data across the two groups, a novel machine learning method called a Generalized Boosted Model was conducted on the arterial access site generating a weighted propensity score for each variable. A logistic regression analysis was then performed on the occurrence of AKI following PCI using the weighted propensity scores from the Generalized Boosted Model., Results: As shown in other studies, multiple variables were associated with an increase in AKI after PCI. Only RA access (OR 0.82; 95% CI 0.74-0.91) and male gender (OR 0.80; 95% CI 0.72-0.89) were associated with a lower occurrence of AKI. Based on the calculated Mehran scores, patients were stratified into groups with an increasing risk of AKI. RA access was consistently found to have a lower risk of AKI compared with FA access across these groups of increasing risk., Conclusions: Compared with FA access, RA access is associated with an 18% lower rate of AKI following PCI. This effect was observed among different levels of risk for developing AKI. Although developed from a retrospective analysis, this study supports the use of RA access when technically possible in a diverse group of patients., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Patrick S. Kietrsunthorn et al.)

Mammalian cell-produced recombinant human erythropoietin (rhuEPO M ) has been shown to be a multimodal neuroprotectant targeting an array of key pathological mechanisms in experimental stroke models. However, the rhuEPO M clinical trials were terminated due to increased risk of thrombosis, largely ascribed to its erythropoietic function. We recently took advantage of a plant-based expression system lacking sialylation capacity to produce asialo-rhuEPO P , a rhuEPO derivative without sialic acid residues. In the present study, we proved that asialo-rhuEPO P is non-erythropoietic by repeated intravenous injection (44 μg/kg bw) in mice showing no increase in hemoglobin levels and red blood cell counts, and confirmed that it is non-immunogenic by measuring humoral response after immunizing the mice. We demonstrate that it is neuroprotective in a cerebral ischemia and reperfusion (I/R) mouse model, exhibiting ~ 50% reduction in cerebral infarct volume and edema, and significant improvement in neurological deficits and histopathological outcome. Our studies further revealed that asialo-rhuEPO P , like rhuEPO M , displays pleiotropic neuroprotective effects, including restoring I/R-interrupted mitochondrial fission and fusion proteins, preventing I/R injury-induced increase in mitophagy and autophagy markers, and inhibiting apoptosis to benefit nerve cell survival. Most importantly, asialo-rhuEPO P lacking erythropoietic activity and immunogenicity holds great translational potential as a multimodal neuroprotectant for stroke treatment., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)