Neuroprotective Effects of neuroEPO Using an In Vitro Model of Stroke

Abstract

Erythropoietin (EPO) is a glycoprotein initially identified as a hormone synthesized and secreted by the kidney that regulates erythropoiesis. EPO, and a group of its derivatives, are being evaluated as possible neuroprotective agents in cerebral ischemia. The objective of this study, using an in vitro model, was to determine how neuroEPO—which is a variant of EPO with a low sialic acid content—protects neurons from the toxic action of glutamate. Primary neuronal cultures were obtained from the forebrains of Wistar rat embryos after 17 days of gestation. Excitotoxicity was induced after nine days of in vitro culture by treatment with a medium containing 100 µM glutamate for 15 min. After this time, a new medium containing 100 ng of neuroEPO/mL was added. Morphological cell change was assessed by phase-contrast microscopy. Oxidative stress was analysed by measuring antioxidant and oxidant activity. After 24 h, the treatment with 100 ng of neuroEPO/mL showed a significant (p < 0.01) decrease in mortality, compared to cells treated with glutamate alone. neuroEPO treatment decreased mortality and tended to reproduce the morphological characteristics of the control. The oxidative stress induced by glutamate is reduced after neuroEPO treatment. These results confirm that neuroEPO has a protective effect against neuronal damage induced by excitotoxicity, improving antioxidant activity in the neuron, and protecting it from oxidative stress.

Erythropoietin Alleviates Burn-induced Muscle Wasting

“…Overexpressed EPO improved rat heart fibrosis through the PI3K/Akt/TLR4 pathway to suppress the release of mediators such as TGF-β1, proinflammatory cytokines, and matrix metalloproteinase [58]. EPO exerts neuroprotective effect in neurodegenerative diseases [104], ischemic brain injury [105,106], spinal cord injury [107] and motor neuron death post-burn [69]. EPO has also been found to improve muscular dysfunction in various experimental models, possible through increasing autophagy as well as decreasing apoptosis in type 2 diabetic skeletal muscles [65], reducing apoptosis in a crushing injury model [108] and preventing cancer-induced muscle alteration [67].…”

Oxygen Sensing in Neurodegenerative Diseases: Current Mechanisms, Implication of Transcriptional Response, and Pharmacological Modulation

“…Besides antioxidants, the research of molecules that act on mitochondria represents an innovative approach aimed at mitigating local ROS production or at reducing their induced damage (Brieger et al, 2012). These compounds include EPO, a cytokine induced by hypoxia expressed in the brain that has been demonstrated to exert many fundamental effects such as neuroprotection and neuroregeneration (Brines and Cerami, 2005;Carelli et al, 2018;Digicaylioglu et al, 1995;Rey et al, 2021bRey et al, , 2019, neurodevelopment (Victor et al, 2021), neuroplasticity (Brines and Cerami, 2005), when stimulated by mild local hypoxia (Wakhloo et al, 2020) or when administered as recombinant human (rh)EPO in different in vitro and in vivo pre-clinical experimental models (Fernando et al, 2018;Maurice et al, 2013;Rey et al, 2021bRey et al, , 2019. The neuroprotective effects of rhEPO have been demonstrated also in two clinical trials in PD affected patients (Jang et al, 2014;Pedroso et al, 2012).…”

The Effect of Erythropoietin and Its Derivatives on Ischemic Stroke Therapy: A Comprehensive Review

“…The study concluded that neuro-EPO application starting within 12 h after ischemia improved neurological scores and behavior of the spontaneous exploratory activity after 7 days of ischemia ( Teste et al, 2012 ). Using an in vitro model of cerebral ischemia, in which oxidative stress was induced by glutamate in cultured neurons, neuro-EPO (100 ng/ml) treatment preserved neurons from oxidative stress through upregulation of Bcl-2 and inhibition of glutamate-induced caspase-3 activation ( Fernando et al, 2018 ; Garzón et al, 2018 ). In addition, neuro-EPO was used in AD models and showed improvement in cognitive function ( Maurice et al, 2013 ; Rodríguez Cruz et al, 2017 ).…”