Erythropoietin and Non-Erythropoietic Derivatives in Cognition.

Samuel S. Newton,Monica Sathyanesan

doi:10.3389/fphar.2021.728725

Abstract

Cognitive deficits are widespread in psychiatric disorders, including major depression and schizophrenia. These deficits are known to contribute significantly to the accompanying functional impairment. Progress in the development of targeted treatments of cognitive deficits has been limited and there exists a major unmet need to develop more efficacious treatments. Erythropoietin (Epo) has shown promising procognitive effects in psychiatric disorders, providing support for a neurotrophic drug development approach. Several preclinical studies with non-erythropoietic derivatives have demonstrated that the modulation of behavior is independent of erythropoiesis. In this review, we examine the molecular, cellular and cognitive actions of Epo and non-erythropoietic molecular derivatives by focusing on their neurotrophic, synaptic, myelin plasticity, anti-inflammatory and neurogenic mechanisms in the brain. We also discuss the role of receptor signaling in Epo and non-erythropoietic EPO-mimetic molecules in their procognitive effects.

Highlights

The prevalence of cognitive dysfunction, which includes deficits in any of the broad domains of attention, learning and memory, language, perception and executive function, is widespread in neuropsychiatric disorders (Millan et al, 2012)
A low (10 pM) concentration of EPO required a long exposure for 24 h toincrease the anti-apoptotic gene Bcl-xl and strikingly decreased the pro-apoptotic gene Bak, indicating that EPO produces differential time and concentration-dependent effects (Renzi et al, 2002). Neurotrophic factor genes such as brain derived neurotrophic factor (BDNF), VGF and neuritin are elevated by EPO and the non-erythropoietic derivative, carbamoylated EPO (CEPO), in the rat hippocampus (Girgenti et al, 2009; Sathyanesan et al, 2018), and in the dentate gyrus (Tiwari et al, 2019)
The data showed c-AMP regulated binding protein (CREB)-signaling to be a significantly activated pathway, and phospho-CREB was shown to be upregulated in the dentate gyrus (Sampath et al, 2020)

Summary

Introduction

The prevalence of cognitive dysfunction, which includes deficits in any of the broad domains of attention, learning and memory, language, perception and executive function, is widespread in neuropsychiatric disorders (Millan et al, 2012). We consider the clinical and preclinical evidence in favor of a neuroprotective and neurotrophic mechanism of action molecule, erythropoietin and its non-erythropoietic derivatives, to better understand and treat cognitive dysfunction. Promising results from clinical testing of erythropoietin (EPO) in multiple psychiatric diseases (Table 1) strengthen the hypothesis that it produces behavioral effects via central mechanisms associated with the neurobiology of cognition.

Results

Conclusion